@article{lawrie_mitchell_dhammi_wallace_hodgson_roe_2020, title={Role of long non-coding RNA in DEET- and fipronil-mediated alteration of transcripts associated with Phase I and Phase II xenobiotic metabolism in human primary hepatocytes}, volume={167}, ISSN={["1095-9939"]}, DOI={10.1016/j.pestbp.2020.104607}, abstractNote={Human exposure to environmental chemicals both individually and in combination occurs frequently world-wide most often with unknown consequences. Use of molecular approaches to aide in the assessment of risk involved in chemical exposure is a growing field in toxicology. In this study, we examined the impact of two environmental chemicals used in and around homes, the insect repellent DEET (N,N-diethyl-m-toluamide) and the phenylpyrazole insecticide fipronil (fluocyanobenpyrazole) on transcript levels of enzymes potentially involved in xenobiotic metabolism and on long non-coding RNAs (lncRNAs). Primary human hepatocytes were treated with these two chemicals both individually and in combination. Using RNA-Seq, we found that 10 major enzyme categories involved in phase 1 and phase 2 xenobiotic metabolism were significantly (α = 0.05) up- and down-regulated (i.e., 100 μM DEET–19 transcripts, 89% up and 11% down; 10 μM fipronil–52 transcripts, 53% up and 47% down; and 100 μM DEET +10 μM fipronil–69 transcripts, 43% up and 57% down). The altered genes were then mapped to the human genome and their proximity (within 1,000,000 bp) to lncRNAs examined. Unique proximities were discovered between altered lncRNA and altered P450s (CYP) and other enzymes (DEET, 2 CYP; Fipronil, 6 CYP and 15 other; and DEET + fipronil, 7 CYP and 21 other). Many of the altered P450 transcripts were in multiple clusters in the genome with proximal altered lncRNAs, suggesting a regulator function for the lncRNA. At the gene level there was high percent identity for lncRNAs near P450 clusters, but this relationship was not found at the transcript level. The role of these altered lncRNAs associated with xenobiotic induction, human diseases and chemical mixtures is discussed.}, journal={PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY}, author={Lawrie, Roger D. and Mitchell, Robert D., III and Dhammi, Anirudh and Wallace, Andrew and Hodgson, Ernest and Roe, R. Michael}, year={2020}, month={Jul} }
 @article{mitchell_wallace_hodgson_roe_2017, title={Differential Expression Profile of lncRNAs from Primary Human Hepatocytes Following DEET and Fipronil Exposure}, volume={18}, ISSN={["1422-0067"]}, DOI={10.3390/ijms18102104}, abstractNote={While the synthesis and use of new chemical compounds is at an all-time high, the study of their potential impact on human health is quickly falling behind, and new methods are needed to assess their impact. We chose to examine the effects of two common environmental chemicals, the insect repellent N,N-diethyl-m-toluamide (DEET) and the insecticide fluocyanobenpyrazole (fipronil), on transcript levels of long non-protein coding RNAs (lncRNAs) in primary human hepatocytes using a global RNA-Seq approach. While lncRNAs are believed to play a critical role in numerous important biological processes, many still remain uncharacterized, and their functions and modes of action remain largely unclear, especially in relation to environmental chemicals. RNA-Seq showed that 100 µM DEET significantly increased transcript levels for 2 lncRNAs and lowered transcript levels for 18 lncRNAs, while fipronil at 10 µM increased transcript levels for 76 lncRNAs and decreased levels for 193 lncRNAs. A mixture of 100 µM DEET and 10 µM fipronil increased transcript levels for 75 lncRNAs and lowered transcript levels for 258 lncRNAs. This indicates a more-than-additive effect on lncRNA transcript expression when the two chemicals were presented in combination versus each chemical alone. Differentially expressed lncRNA genes were mapped to chromosomes, analyzed by proximity to neighboring protein-coding genes, and functionally characterized via gene ontology and molecular mapping algorithms. While further testing is required to assess the organismal impact of changes in transcript levels, this initial analysis links several of the dysregulated lncRNAs to processes and pathways critical to proper cellular function, such as the innate and adaptive immune response and the p53 signaling pathway.}, number={10}, journal={INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, author={Mitchell, Robert D., III and Wallace, Andrew D. and Hodgson, Ernest and Roe, R. Michael}, year={2017}, month={Oct} }
 @article{mitchell_dhammi_wallace_hodgson_roe_2016, title={Impact of Environmental Chemicals on the Transcriptome of Primary Human Hepatocytes: Potential for Health Effects}, volume={30}, ISSN={1095-6670}, url={http://dx.doi.org/10.1002/JBT.21801}, DOI={10.1002/jbt.21801}, abstractNote={New paradigms for human health risk assessment of environmental chemicals emphasize the use of molecular methods and human‐derived cell lines. In this study, we examined the effects of the insect repellent DEET (N,N‐diethyl‐m‐toluamide) and the phenylpyrazole insecticide fipronil (fluocyanobenpyrazole) on transcript levels in primary human hepatocytes. These chemicals were tested individually and as a mixture. RNA‐Seq showed that 100 μM DEET significantly increased transcript levels (α = 0.05) for 108 genes and lowered transcript levels for 64 genes and fipronil at 10 μM increased the levels of 2246 transcripts and decreased the levels for 1428 transcripts. Fipronil was 21‐times more effective than DEET in eliciting changes, even though the treatment concentration was 10‐fold lower for fipronil versus DEET. The mixture of DEET and fipronil produced a more than additive effect (levels increased for 3017 transcripts and decreased for 2087 transcripts). The transcripts affected for all chemical treatments were classified by GO analysis and mapped to chromosomes. The overall treatment responses, specific pathways, and individual transcripts affected were discussed at different levels of fold‐change. Changes found in transcript levels in response to treatments will require further research to understand their importance in overall cellular, organ, and organismic function.}, number={8}, journal={Journal of Biochemical and Molecular Toxicology}, publisher={Wiley}, author={Mitchell, Robert D., III and Dhammi, Anirudh and Wallace, Andrew and Hodgson, Ernest and Roe, R. Michael}, year={2016}, month={Apr}, pages={375–395} }
 @article{hodgson_wallace_shah_choi_joo_2014, title={Human Variation and Risk Assessment: Microarray and Other Studies Utilizing Human Hepatocytes and Human Liver Subcellular Preparations}, volume={28}, ISSN={["1099-0461"]}, DOI={10.1002/jbt.21534}, abstractNote={ABSTRACT}, number={1}, journal={JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY}, author={Hodgson, Ernest and Wallace, Andrew D. and Shah, Ruchir R. and Choi, Kyoungju and Joo, Hyun}, year={2014}, month={Jan}, pages={1–10} }
 @misc{hodgson_2012, title={Human environments: Definition, scope, and the role of toxicology}, volume={112}, journal={Toxicology and human environments}, author={Hodgson, E.}, year={2012}, pages={1–10} }
 @misc{hodgson_2012, title={Metabolic interactions of environmental toxicants in humans}, volume={112}, journal={Toxicology and human environments}, author={Hodgson, E.}, year={2012}, pages={349–372} }
 @book{pesticide biotransformation and disposition_2012, publisher={Waltham, MA: Academic Press}, year={2012} }
 @article{hodgson_2012, title={Progress in molecular biology and translational science toxicology and human environments summary and conclusions}, volume={112}, journal={Toxicology and human environments}, author={Hodgson, E.}, year={2012}, pages={417–421} }
 @misc{hodgson_2012, title={The future of human health risk assessment of environmental chemicals}, volume={112}, journal={Toxicology and human environments}, author={Hodgson, E.}, year={2012}, pages={307–322} }
 @misc{hodgson_2012, title={Toxins and venoms}, volume={112}, journal={Toxicology and human environments}, author={Hodgson, E.}, year={2012}, pages={373–415} }
 @article{joo_choi_hodgson_2010, title={Human metabolism of atrazine}, volume={98}, ISSN={["1095-9939"]}, DOI={10.1016/j.pestbp.2010.05.002}, abstractNote={Atrazine (ATZ) metabolism by human liver microsomes (HLM), cytochrome P450 (CYP) isoforms, and human liver (HL) S9 fractions, was investigated using HPLC/PDA and LC/MS/MS. CYP-dependent metabolites from pooled HLM are desethylatrazine (DEA), desisopropylatrazine (DIA), 1-hydroxyisopropylatrazine (HIATZ), and 2-hydroxyethyl atrazine (HEATZ). DEA and DIA were major metabolites in pooled HLM. CYP1A2 and 2C19, respectively, were major isoforms for DEA and DIA production. CYP3A4, while less active, is generally at high concentrations, produces both DEA and DIA and is significant. The percent total normalized rates (%TNR) for CYP1A2 and 3A4 in pooled HLM were 63% and 24% for DEA, and 35% and 56% for DIA production. Single donor HLM samples, showed correlations for CYP1A2 (r = 0.92) and 3A4 (r = 0.81) for DEA and DIA production, while variations in production of DEA and DIA were 8.5- and 6.0-fold, respectively. Pooled S9 fractions also mediate glutathione conjugation of atrazine, DEA and DIA.}, number={1}, journal={PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY}, author={Joo, Hyun and Choi, Kyoungju and Hodgson, Ernest}, year={2010}, month={Sep}, pages={73–79} }
 @article{croom_wallace_hodgson_2010, title={Human variation in CYP-specific chlorpyrifos metabolism}, volume={276}, ISSN={["0300-483X"]}, DOI={10.1016/j.tox.2010.08.005}, abstractNote={Chlorpyrifos, an organophophorothioate insecticide, is bioactivated to the neurotoxic metabolite, chlorpyrifos-oxon (CPO) by cytochromes P450 (CYPs). To determine the variability in chlorpyrifos bioactivation, CPO production by human liver microsomes from 17 individual donors was compared relative to phenotype and genotype. CPO production varied over 14-fold between individuals in incubations utilizing 20 μM chlorpyrifos as substrate, while CPO production varied 57-fold in incubations with 100 μM chlorpyrifos. For all but two samples, the formation of the less toxic metabolite, 3,5,6-trichloro-2-pyridinol (TCP), was greater than CPO production. TCP production varied 9-fold in incubations utilizing 20 μM chlorpyrifos as substrate and 19-fold using 100 μM chlorpyrifos. Chlorpyrifos metabolism by individual human liver microsomes was significantly correlated with CYP2B6, CYP2C19 and CYP3A4 related activity. CPO formation was best correlated with CYP2B6 related activity at low (20 μM) chlorpyrifos concentrations while CYP3A4 related activity was best correlated with CPO formation at high concentrations (100 μM) of chlorpyrifos. TCP production was best correlated with CYP3A4 activity at all substrate concentrations of chlorpyrifos. The production of both CPO and TCP was significantly lower at a concentration of 20 μM chlorpyrifos as compared to 100 μM chlorpyrifos. Calculations of percent total normalized rates (% TNR) and the chemical inhibitors ketoconazole and ticlopidine were used to confirm the importance of CYP2B6, CYP2C19, and CYP3A4 for the metabolism of chlorpyrifos. The combination of ketoconazole and ticlopidine inhibited the majority of TCP and CPO formation. CPO formation did not differ by CYP2B6 genotype. Individual variations in CPO production may need to be considered in determining the risk of chlorpyrifos poisoning.}, number={3}, journal={TOXICOLOGY}, author={Croom, Edward L. and Wallace, Andrew D. and Hodgson, Ernest}, year={2010}, month={Oct}, pages={184–191} }
 @article{croom_stevens_hines_wallace_hodgson_2009, title={Human hepatic CYP2B6 developmental expression: The impact of age and genotype}, volume={78}, ISSN={["1873-2968"]}, DOI={10.1016/j.bcp.2009.03.029}, abstractNote={Although CYP2B6 is known to metabolize numerous pharmaceuticals and toxicants in adults, little is known regarding CYP2B6 ontogeny or its possible role in pediatric drug/toxicant metabolism. To address this knowledge gap, hepatic CYP2B6 protein levels were characterized in microsomal protein preparations isolated from a pediatric liver bank (N = 217). Donor ages ranged from 10 weeks gestation to 17 years of age with a median age of 1.9 months. CYP2B6 levels were measured by semi-quantitative western blotting. Overall, CYP2B6 expression was detected in 75% of samples. However, the percentage of samples with detectable CYP2B6 protein increased with age from 64% in fetal samples to 95% in samples from donors >10 years of age. There was a significant, but only 2-fold increase in median CYP2B6 expression after the neonatal period (birth to 30 days postnatal) although protein levels varied over 25-fold in both age groups. The median CYP2B6 level in samples over 30 postnatal days to 17 years of age (1.3 pmol/mg microsomal protein) was lower than previously reported adult levels (2.2–22 pmol/mg microsomal protein), however, this likely relates to the median age of these samples, i.e., 10.3 months. CYP2B6 expression did not vary significantly by gender. Furthermore, CYP2B6 levels did not correlate with CYP3A4, CYP3A5.1 or CYP3A7 activity, consistent with different mechanisms controlling the ontogeny and constitutive expression of these enzymes and the lack of significant induction in the pediatric samples.}, number={2}, journal={BIOCHEMICAL PHARMACOLOGY}, author={Croom, Edward L. and Stevens, Jeffrey C. and Hines, Ronald N. and Wallace, Andrew D. and Hodgson, Ernest}, year={2009}, month={Jul}, pages={184–190} }
 @article{hodgson_rose_2008, title={Metabolic interactions of agrochemicals in humans}, volume={64}, ISSN={["1526-4998"]}, DOI={10.1002/ps.1563}, abstractNote={Abstract}, number={6}, journal={PEST MANAGEMENT SCIENCE}, author={Hodgson, Ernest and Rose, Randy L.}, year={2008}, month={Jun}, pages={617–621} }
 @article{hodgson_rose_2007, title={Human metabolic interactions of environmental chemicals}, volume={21}, ISSN={["1099-0461"]}, DOI={10.1002/jbt.20175}, abstractNote={Abstract}, number={4}, journal={JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY}, author={Hodgson, Ernest and Rose, Randy L.}, year={2007}, pages={182–186} }
 @article{joo_choi_rose_hodgson_2007, title={Inhibition of fipronil and nonane metabolism in human liver microsomes and human cytochrome P450 isoforms by chlorpyrifos}, volume={21}, ISSN={["1095-6670"]}, DOI={10.1002/jbt.20161}, abstractNote={Abstract}, number={2}, journal={JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY}, author={Joo, Hyun and Choi, Kyoungju and Rose, Randy L. and Hodgson, Ernest}, year={2007}, pages={76–80} }
 @misc{hodgson_rose_2007, title={The importance of cytochrome P4502B6 in the human metabolism of environmental chemicals}, volume={113}, ISSN={["0163-7258"]}, DOI={10.1016/j.pharmthera.2006.10.002}, abstractNote={Cytochrome P450 (CYP) 2B6 (CYP2B6) is a human CYP isoform found in variable amounts in the liver and other organs. It is known to be inducible and polymorphic and has a wide range of xenobiotic substrates. Studies of CYP2B6 to date have concentrated heavily on clinical drugs. In the present communication, however, we concentrate on its role in the metabolism of environmental xenobiotics. The term environment is used, in its broadest sense, to include natural ecosystems and agroecosystems as well as the industrial and indoor domestic environments. In essence, this excludes only clinical drugs and drugs of abuse. Many of these chemicals, including agrochemicals and industrial chemicals, can serve as substrates, inhibitors and/or inducers of CYP2B6, these activities being often modified by the existence of polymorphic variants. Metabolism-based interactions between environmental chemicals are discussed, as well as the emerging possibility of metabolic interactions between environmental chemicals and clinical drugs.}, number={2}, journal={PHARMACOLOGY & THERAPEUTICS}, author={Hodgson, Ernest and Rose, Randy L.}, year={2007}, month={Feb}, pages={420–428} }
 @article{das_cao_cherrington_hodgson_rose_2006, title={Fipronil induces CYP isoforms and cytotoxicity in human hepatocytes}, volume={164}, ISSN={["1872-7786"]}, DOI={10.1016/j.cbi.2006.09.013}, abstractNote={Recent studies have demonstrated the potential of pesticides to either inhibit or induce xenobiotic metabolizing enzymes in humans. Exposure of human hepatocytes to doses of fipronil (5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-[(trifluoromethyl) sulfinyl]-1H-pyrazole-3-carbonitrile) ranging from 0.1 to 25 μM resulted in a dose dependent increase in CYP1A1 mRNA expression (3.5 to ∼55-fold) as measured by the branched DNA assay. In a similar manner, CYP3A4 mRNA expression was also induced (10–30-fold), although at the higher doses induction returned to near control levels. CYP2B6 and 3A5 were also induced by fipronil, although at lower levels (2–3-fold). Confirmation of bDNA results were sought through western blotting and/or enzyme activity assays. Western blots using CYP3A4 antibody demonstrated a dose responsive increase from 0.5 to 1 μM followed by decreasing responses at higher concentrations. Similar increases and decreases were observed in CYP3A4-specific activity levels as measured using 6β-hydroxytestosterone formation following incubation with testosterone. Likewise, activity levels for a CYP1A1-specific substrate, luciferin CEE, demonstrated that CYP1A1 enzyme activities were maximally induced by 1 μM fipronil followed by dramatically declining activity measurements at 10 and 25 μM. Cytotoxic effects of fipronil and fipronil sulfone were examined using the adenylate kinase and the trypan blue exclusion assays in HepG2 cells and human hepatocytes. The results indicate both that HepG2 cells and primary human hepatocytes are sensitive to the cytotoxic effects of fipronil. The maximum induction of adenylate kinase was ca. 3-fold greater than the respective controls in HepG2 and 6–10-fold in the case of primary hepatocytes. A significant time- and dose-dependent induction of adenylate kinase activity in HepG2 cells was noted from 0.1 to 12.5 μM fipronil followed by decreasing activities at 25 and 50 μM. For fipronil sulfone, cytotoxic effects increased throughout the dose range. The trypan blue assay indicated that cytotoxic effects contributing to an increase of greater than 10% of control values was indicated at doses above 12.5 μM. However, fipronil sulfone induced cytotoxic effects at lower doses. The possibility that cytotoxic effects were due to apoptosis was indicated by significant time- and dose-dependent induction of caspase-3/7 activity in both HepG2 cells and human hepatocytes. Fipronil mediated activation of caspase-3/7 in concurrence with compromised ATP production and viability are attributed to apoptotic cell death.}, number={3}, journal={CHEMICO-BIOLOGICAL INTERACTIONS}, author={Das, Parikshit C. and Cao, Yan and Cherrington, Nathan and Hodgson, Ernest and Rose, Randy L.}, year={2006}, month={Dec}, pages={200–214} }
 @article{cho_rose_hodgson_2006, title={In vitro metabolism of naphthalene by human liver microsomal cytochrome P450 enzymes}, volume={34}, ISSN={["1521-009X"]}, DOI={10.1124/dmd.105.005785}, abstractNote={The Polycyclic Aromatic Hydrocarbon Naphthalene Is An Environmental Pollutant, A Component Of Jet Fuel, And, Since 2000, Has Been Reclassified As A Potential Human Carcinogen. Few Studies Of The In Vitro Human Metabolism Of Naphthalene Are Available, And These Focus Primarily On Lung Metabolism. The Current Studies Were Performed To Characterize Naphthalene Metabolism By Human Cytochromes P450. Naphthalene Metabolites From Pooled Human Liver Microsomes (Phlms) Were Trans-1,2-Dihydro-1,2-Naphthalenediol (Dihydrodiol), 1-Naphthol, And 2-Naphthol. Metabolite Production Generated KM Values Of 23, 40, And 116 μM And VMax Values Of 2860, 268, And 22 Pmol/Mg Protein/Min, Respectively. P450 Isoform Screening Of Naphthalene Metabolism Identified Cyp1A2 As The Most Efficient Isoform For Producing Dihydrodiol And 1-Naphthol, And Cyp3A4 As The Most Effective For 2-Naphthol Production. Metabolism Of The Primary Metabolites Of Naphthalene Was Also Studied To Identify Secondary Metabolites. Whereas 2-Naphthol Was Readily Metabolized By Phlms To Produce 2,6- And 1,7-Dihydroxynaphthalene, Dihydrodiol And 1-Naphthol Were Inefficient Substrates For Phlms. A Series Of Human P450 Isoforms Was Used To Further Explore The Metabolism Of Dihydrodiol And 1-Naphthol. 1,4-Naphthoquinone And Four Minor Unknown Metabolites From 1-Naphthol Were Observed, And Cyp1A2 And 2D6*1 Were Identified As The Most Active Isoforms For The Production Of 1,4-Naphthoquinone. Dihydrodiol Was Metabolized By P450 Isoforms To Three Minor Unidentified Metabolites With Cyp3A4 And Cyp2A6 Having The Greatest Activity Toward This Substrate. The Metabolism Of Dihydrodiol By P450 Isoforms Was Lower Than That Of 1-Naphthol. These Studies Identify Primary And Secondary Metabolites Of Naphthalene Produced By Phlms And P450 Isoforms.}, number={1}, journal={DRUG METABOLISM AND DISPOSITION}, author={Cho, TM and Rose, RL and Hodgson, E}, year={2006}, month={Jan}, pages={176–183} }
 @article{usmani_cho_rose_hodgson_2006, title={Inhibition of the human liver microsomal and human cytochrome P450 1A2 and 3A4 metabolism of estradiol by deployment-related and other chemicals}, volume={34}, ISSN={["0090-9556"]}, DOI={10.1124/dmd.106.010439}, abstractNote={Cytochromes P450 (P450s) are major catalysts in the metabolism of xenobiotics and endogenous substrates such as estradiol (E2). It has previously been shown that E2 is predominantly metabolized in humans by CYP1A2 and CYP3A4 with 2-hydroxyestradiol (2-OHE2) the major metabolite. This study examines effects of deployment-related and other chemicals on E2 metabolism by human liver microsomes (HLM) and individual P450 isoforms. Kinetic studies using HLM, CYP3A4, and CYP1A2 showed similar affinities (Km) for E2 with respect to 2-OHE2 production. Vmax and CLint values for HLM are 0.32 nmol/min/mg protein and 7.5 μl/min/mg protein; those for CYP3A4 are 6.9 nmol/min/nmol P450 and 291 μl/min/nmol P450; and those for CYP1A2 are 17.4 nmol/min/nmol P450 and 633 μl/min/nmol P450. Phenotyped HLM use showed that individuals with high levels of CYP1A2 and CYP3A4 have the greatest potential to metabolize E2. Preincubation of HLM with a variety of chemicals, including those used in military deployments, resulted in varying levels of inhibition of E2 metabolism. The greatest inhibition was observed with organophosphorus compounds, including chlorpyrifos and fonofos, with up to 80% inhibition for 2-OHE2 production. Carbaryl, a carbamate pesticide, and naphthalene, a jet fuel component, inhibited ca. 40% of E2 metabolism. Preincubation of CYP1A2 with chlorpyrifos, fonofos, carbaryl, or naphthalene resulted in 96, 59, 84, and 87% inhibition of E2 metabolism, respectively. Preincubation of CYP3A4 with chlorpyrifos, fonofos, deltamethrin, or permethrin resulted in 94, 87, 58, and 37% inhibition of E2 metabolism. Chlorpyrifos inhibition of E2 metabolism is shown to be irreversible.}, number={9}, journal={DRUG METABOLISM AND DISPOSITION}, author={Usmani, Khawja A. and Cho, Taehyeon M. and Rose, Randy L. and Hodgson, Ernest}, year={2006}, month={Sep}, pages={1606–1614} }
 @article{choi_joo_rose_hodgson_2006, title={Metabolism of chlorpyrifos and chlorpyrifos oxon by human hepatocytes}, volume={20}, DOI={10.1002/jbt.20145}, abstractNote={Abstract}, number={6}, journal={Journal of Biochemical and Molecular Toxicology}, author={Choi, K. and Joo, H. and Rose, R. L. and Hodgson, E.}, year={2006}, pages={279–291} }
 @article{casabar_wallace_hodgson_rose_2006, title={Metabolism of endosulfan-alpha by human liver microsomes and its utility as a simultaneous in vitro probe for CYP2B6 and CYP3A4}, volume={34}, ISSN={["0090-9556"]}, DOI={10.1124/dmd.106.010199}, abstractNote={Endosulfan-α is metabolized to a single metabolite, endosulfan sulfate, in pooled human liver microsomes (Km = 9.8 μM, Vmax = 178.5 pmol/mg/min). With the use of recombinant cytochrome P450 (P450) isoforms, we identified CYP2B6 (Km = 16.2 μM, Vmax = 11.4 nmol/nmol P450/min) and CYP3A4 (Km = 14.4 μM, Vmax = 1.3 nmol/nmol P450/min) as the primary enzymes catalyzing the metabolism of endosulfan-α, although CYP2B6 had an 8-fold higher intrinsic clearance rate (CLint = 0.70 μl/min/pmol P450) than CYP3A4 (CLint = 0.09 μl/min/pmol P450). Using 16 individual human liver microsomes (HLMs), a strong correlation was observed with endosulfan sulfate formation and S-mephenytoin N-demethylase activity of CYP2B6 (r2 = 0.79), whereas a moderate correlation with testosterone 6 β-hydroxylase activity of CYP3A4 (r2 = 0.54) was observed. Ticlopidine (5 μM), a potent CYP2B6 inhibitor, and ketoconazole (10 μM), a selective CYP3A4 inhibitor, together inhibited approximately 90% of endosulfan-α metabolism in HLMs. Using six HLM samples, the percentage total normalized rate (% TNR) was calculated to estimate the contribution of each P450 in the total metabolism of endosulfan-α. In five of the six HLMs used, the percentage inhibition with ticlopidine and ketoconazole in the same incubation correlated with the combined % TNRs for CYP2B6 and CYP3A4. This study shows that endosulfan-α is metabolized by HLMs to a single metabolite, endosulfan sulfate, and that it has potential use, in combination with inhibitors, as an in vitro probe for CYP2B6 and 3A4 catalytic activities.}, number={10}, journal={DRUG METABOLISM AND DISPOSITION}, author={Casabar, Richard C. T. and Wallace, Andrew D. and Hodgson, Ernest and Rose, Randy L.}, year={2006}, month={Oct}, pages={1779–1785} }
 @misc{kavlock_barr_boekelheide_breslin_breysse_chapin_gaido_hodgson_marcus_shea_et al._2006, title={NTP-CERHR Expert Panel update on the reproductive and developmental toxicity of di(2-ethylhexyl) phthalate}, volume={22}, number={3}, journal={Reproductive Toxicology (Elmsford, N.Y.)}, author={Kavlock, R. and Barr, D. and Boekelheide, K. and Breslin, W. and Breysse, P. and Chapin, R. and Gaido, K. and Hodgson, E. and Marcus, M. and Shea, K. and et al.}, year={2006}, pages={291–399} }
 @misc{hodgson_rose_2006, title={Organophosphorus chemicals: Potent inhibitors of the human metabolism of steroid hormones and xenobiotics}, volume={38}, ISSN={["1097-9883"]}, DOI={10.1080/03602530600569984}, abstractNote={Although it has been known for some time that organophosphate chemicals containing the P = S moiety are irreversible inhibitors of cytochrome P450, this knowledge has not been generally applied to the human metabolism of xenobiotics. Recent studies have demonstrated that organophosphate insecticides containing this moiety are potent inhibitors of the metabolism of both xenobiotics and endogenous substrates by human liver microsomes and by specific human cytochrome P450 isoforms.}, number={1-2}, journal={DRUG METABOLISM REVIEWS}, author={Hodgson, E and Rose, RL}, year={2006}, pages={149–162} }
 @article{brimfield_novak_hodgson_2006, title={Thiodiglycol, the hydrolysis product of sulfur mustard: Analysis of in vitro biotransformation by mammalian alcohol dehydrogenases using nuclear magnetic resonance}, volume={213}, ISSN={["1096-0333"]}, DOI={10.1016/j.taap.2005.11.009}, abstractNote={Thiodiglycol (2,2'-bis-hydroxyethylsulfide, TDG), the hydrolysis product of the chemical warfare agent sulfur mustard, has been implicated in the toxicity of sulfur mustard through the inhibition of protein phosphatases in mouse liver cytosol. The absence of any inhibitory activity when TDG was present in assays of pure enzymes, however, led us to investigate the possibility for metabolic activation of TDG to inhibitory compound(s) by cytosolic enzymes. We have successfully shown that mammalian alcohol dehydrogenases (ADH) rapidly oxidize TDG in vitro, but the classic spectrophotometric techniques for following this reaction provided no information on the identity of TDG intermediates and products. The use of proton NMR to monitor the oxidative reaction with structural confirmation by independent synthesis allowed us to establish the ultimate product, 2-hydroxyethylthioacetic acid, and to identify an intermediate equilibrium mixture consisting of 2-hydroxyethylthioacetaldehyde, 2-hydroxyethylthioacetaldehyde hydrate and the cyclic 1,4-oxathian-2-ol. The intermediate nature of this mixture was determined spectrophotometrically when it was shown to drive the production of NADH when added to ADH and NAD.}, number={3}, journal={TOXICOLOGY AND APPLIED PHARMACOLOGY}, author={Brimfield, A. A. and Novak, Mark J. and Hodgson, Ernest}, year={2006}, month={Jun}, pages={207–215} }
 @misc{hodgson_rose_2005, title={Human metabolism and metabolic interactions of deployment-related chemicals}, volume={37}, ISSN={["1097-9883"]}, DOI={10.1081/DMR-200046955}, abstractNote={It has been suggested that chemicals and, more specifically, chemical interactions, are involved as causative agents in deployment-related illnesses. Unfortunately, this hypothesis has proven difficult to test, because toxicological investigations of deployment-related chemicals are usually carried out on surrogate animals and are difficult to extrapolate to humans. Other parts of the problem, such as the definition of variation within human populations and the development of methods for designating groups or individuals at significantly greater risk, cannot be carried out on surrogate animals, and the data must be derived from humans. The relatively recent availability of human cell fractions, such as microsomes, cytosol, etc., human cells such as primary hepatocytes, recombinant human enzymes, and their isoforms and polymorphic variants has enabled a significant start to be made in developing the human data needed. These initial studies have examined the human metabolism by cytochrome P450, other phase I enzymes, and their isoforms and, in some cases, their polymorphic variants of compounds such as chlorpyrifos, carbaryl, DEET, permethrin, and pyridostigmine bromide, and, to a lesser extent, other chemicals from the same chemical and use classes, including solvents, jet fuel components, and sulfur mustard metabolites. A number of interactions at the metabolic level have been described both with respect to other xenobiotics and to endogenous metabolites. Probably the most dramatic have been seen in the ability of chlorpyrifos to inhibit not only the metabolism of other xenobiotics such as carbaryl and DEET but also to inhibit the metabolism of steroid hormones.}, number={1}, journal={DRUG METABOLISM REVIEWS}, author={Hodgson, E and Rose, RL}, year={2005}, pages={1–39} }
 @article{alavanja_bonner_furlong_allen_hodgson_2005, title={Molecular Biomarker Workshop - Agricultural Health Study - Discussion and conclusions}, volume={19}, ISSN={["1095-6670"]}, DOI={10.1002/jbt.20083}, abstractNote={Abstract}, number={3}, journal={JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY}, author={Alavanja, MCR and Bonner, MR and Furlong, CE and Allen, R and Hodgson, E}, year={2005}, pages={192–193} }
 @article{rose_hodgson_2005, title={Pesticide metabolism and potential for metabolic interactions}, volume={19}, ISSN={["1099-0461"]}, DOI={10.1002/jbt.20077}, abstractNote={Abstract}, number={4}, journal={JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY}, author={Rose, RL and Hodgson, E}, year={2005}, pages={276–277} }
 @article{rose_tang_choi_cao_usmani_cherrington_hodgson_2005, title={Pesticide metabolism in humans, including polymorphisms}, volume={31}, journal={Scandinavian Journal of Work, Environment & Health}, author={Rose, R. L. and Tang, J. and Choi, J. and Cao, Y. and Usmani, A. and Cherrington, N. and Hodgson, E.}, year={2005}, pages={156–163} }
 @article{edwards_rose_hodgson_2005, title={The metabolism of nonane, a JP-8 jet fuel component, by human liver microsomes, P450 isoforms and alcohol dehydrogenase and inhibition of human P450 isoforms by JP-8}, volume={151}, ISSN={["1872-7786"]}, DOI={10.1016/j.cbi.2004.12.003}, abstractNote={Nonane, a component of jet-propulsion fuel 8 (JP-8), is metabolized to 2-nonanol and 2-nonanone by pooled human liver microsomes (pHLM). Cytochrome P450 (CYP) isoforms 1A2, 2B6 and 2E1 metabolize nonane to 2-nonanol, whereas alcohol dehydrogenase, CYPs 2B6 and 2E1 metabolize 2-nonanol to 2-nonanone. Nonane and 2-nonanol showed no significant effect on the metabolism of testosterone, estradiol or N,N-diethyl-m-toluamide (DEET), but did inhibit carbaryl metabolism. JP-8 showed modest inhibition of testosterone, estradiol and carbaryl metabolism, but had a more significant effect on the metabolism of DEET. JP-8 was shown to inhibit CYPs 1A2 and 2B6 mediated metabolism of DEET, suggesting that at least some of the components of JP-8 might be metabolized by CYPs 1A2 and/or 2B6.}, number={3}, journal={CHEMICO-BIOLOGICAL INTERACTIONS}, author={Edwards, JE and Rose, RL and Hodgson, E}, year={2005}, month={Feb}, pages={203–211} }
 @article{hodgson_rose_2005, title={Toxicology of AHS important chemicals}, volume={19}, ISSN={["1095-6670"]}, DOI={10.1002/jbt.20076}, abstractNote={Abstract}, number={3}, journal={JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY}, author={Hodgson, E and Rose, RL}, year={2005}, pages={180–181} }
 @article{usmani_hodgson_rose_2004, title={In vitro metabolism of carbofuran by human, mouse, and rat cytochrome P450 and interactions with chlorpyrifos, testosterone, and estradiol}, volume={150}, ISSN={["1872-7786"]}, DOI={10.1016/j.cbi.2004.09.015}, abstractNote={Carbofuran is a carbamate pesticide used in agricultural practice throughout the world. Its effect as a pesticide is due to its ability to inhibit acetylcholinesterase activity. Though carbofuran has a long history of use, there is little information available with respect to its metabolic fate and disposition in mammals. The present study was designed to investigate the comparative in vitro metabolism of carbofuran from human, rat, and mouse liver microsomes (HLM, RLM, MLM, respectively), and characterize the specific enzymes involved in such metabolism, with particular reference to human metabolism. Carbofuran is metabolized by cytochrome P450 (CYP) leading to the production of one major ring oxidation metabolite, 3-hydroxycarbofuran, and two minor metabolites. The affinity of carbofuran for CYP enzymes involved in the oxidation to 3-hydroxycarbofuran is significantly less in HLM (Km=1.950 mM) than in RLM (Km=0.210 mM), or MLM (Km=0.550 mM). Intrinsic clearance rate calculations indicate that HLM are 14-fold less efficient in the metabolism of carbofuran to 3-hydroxycarbofuran than RLM or MLM. A screen of 15 major human CYP isoforms for metabolic ability with respect to carbofuran metabolism demonstrated that CYP3A4 is the major isoform responsible for carbofuran oxidation in humans. CYP1A2 and 2C19 are much less active while other human CYP isoforms have minimal or no activity toward carbofuran. In contrast with the human isoforms, members of the CYP2C family in rats are likely to have a primary role in carbofuran metabolism. Normalization of HLM data with the average levels of each CYP in native HLM, indicates that carbofuran metabolism is primarily mediated by CYP3A4 (percent total normalized rate (% TNR)=77.5), although CYP1A2 and 2C19 play ancillary roles (% TNR=9.0 and 6.0, respectively). This is substantiated by the fact that ketoconazole, a specific inhibitor of CYP3A4, is an excellent inhibitor of 3-hydroxycarbofuran formation in HLM (IC50: 0.31 microM). Chlorpyrifos, an irreversible non-competitive inhibitor of CYP3A4, inhibits the formation of 3-hydroxycarbofuran in HLM (IC50: 39 microM). The use of phenotyped HLM demonstrated that individuals with high levels of CYP3A4 have the greatest potential to metabolize carbofuran to its major metabolite. The variation in carbofuran metabolism among 17 single-donor HLM samples is over 5-fold and the best correlation between CYP isoform activity and carbofuran metabolism was observed with CYP3A4 (r2=0.96). The interaction of carbofuran and the endogenous CYP3A4 substrates, testosterone and estradiol, were also investigated. Testosterone metabolism was activated by carbofuran in HLM and CYP3A4, however, less activation was observed for carbofuran metabolism by testosterone in HLM and CYP3A4. No interactions between carbofuran and estradiol metabolism were observed.}, number={3}, journal={CHEMICO-BIOLOGICAL INTERACTIONS}, author={Usmani, KA and Hodgson, E and Rose, RL}, year={2004}, month={Dec}, pages={221–232} }
 @article{tang_usmani_hodgson_rose_2004, title={In vitro metabolism of fipronil by human and rat cytochrome P450 and its interactions with testosterone and diazepam}, volume={147}, ISSN={["1872-7786"]}, DOI={10.1016/j.cbi.2004.03.002}, abstractNote={Fipronil (5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-[(trifluoromethyl)sulfinyl]-1H-pyrazole-3-carbonitrile) is a highly active, broad spectrum insecticide from the phenyl pyrazole family, which targets the γ-amino butyric acid (GABA) receptor. Although fipronil is presently widely used as an insecticide and acaricide, little information is available with respect to its metabolic fate and disposition in mammals. This study was designed to investigate the in vitro human metabolism of fipronil and to examine possible metabolic interactions that fipronil may have with other substrates. Fipronil was incubated with human liver microsomes (HLM) and several recombinant cytochrome P450 (CYP) isoforms obtained from BD Biosciences. HPLC was used for metabolite identification and quantification. Fipronil sulfone was the predominant metabolite via CYP oxidation. The Km and Vmax values for human liver microsomes are 27.2 μM and 0.11 nmol/mg protein min, respectively; for rat liver microsomes (RLM) the Km and Vmax are 19.9 μM and 0.39 nmol/mg protein min, respectively. CYP3A4 is the major isoform responsible for fipronil oxidation in humans while CYP2C19 is considerably less active. Other human CYP isoforms have minimal or no activity toward fipronil. Co-expression of cytochrome b5 (b5) is essential for CYP3A4 to manifest high activity toward fipronil. Ketoconazole, a specific inhibitor of CYP3A4, inhibits 78% of the HLM activity toward fipronil at a concentration of 2 μM. Oxidative activity toward fipronil in 19 single-donor HLMs correlated well with their ability to oxidize testosterone. The interactions of fipronil and other CYP3A4 substrates, such as testosterone and diazepam, were also investigated. Fipronil metabolism was activated by testosterone in HLM but not in CYP3A4 Supersomes®. Testosterone 6β-hydroxylation in HLM was inhibited by fipronil. Fipronil inhibited diazepam demethylation but had little effect on diazepam hydroxylation. The results suggest that fipronil has the potential to interact with a wide range of xenobiotics or endogenous chemicals that are CYP3A4 substrates and that fipronil may be a useful substrate for the characterization of CYP3A4 in HLM.}, number={3}, journal={CHEMICO-BIOLOGICAL INTERACTIONS}, author={Tang, J and Usmani, KA and Hodgson, E and Rose, RL}, year={2004}, month={Apr}, pages={319–329} }
 @article{usmani_karoly_hodgson_rose_2004, title={In vitro sulfoxidation of thioether compounds by human cytochrome P450 and flavin-containing monooxygenase isoforms with particular reference to the CYP2C subfamily}, volume={32}, ISSN={["1521-009X"]}, DOI={10.1124/dmd.32.3.333}, abstractNote={Cytochrome P450 (P450) and flavin-containing monooxygenase (FMO) enzymes are major catalysts involved in the metabolism of xenobiotics. The sulfoxidation of the thioether pesticides, phorate, disulfoton, sulprofos, and methiocarb, was investigated. Using pooled human liver microsomes (HLMs), thioether compounds displayed similar affinities; however, phorate and disulfoton displayed higher intrinsic clearance rates than either sulprofos or methiocarb. The sulfoxidation of thioethers by HLMs was found to be predominantly P450-driven (85-90%) compared with FMO (10-15%). Among 16 cDNA-expressed human P450 isoforms and 3 human FMO isoforms examined, the following isoforms and their polymorphisms had the highest rates for sulfoxidation, as follows: phorate, CYP1A2, 3A4, 2B6, 2C9*1, 2C18, 2C19, 2D6*1, and FMO1; disulfoton, CYP1A2, 3A4, 2B6, 2C9*1, 2C9*2, 2C18, 2C19, 2D6*1, and FMO1; sulprofos, CYP1A1, 1A2, 3A4, 2C9*1, 2C9*2, 2C9*3, 2C18, 2C19, 2D6*1, and FMO1; methiocarb, CYP1A1, 1A2, 3A4, 2B6, 2C9*1, 2C19, 2D6*1, and FMO1. Among these isoforms, members of the CYP2C subfamily often had the highest affinities and clearance rates. Moreover, sulfaphenazole, a CYP2C9 competitive inhibitor, inhibited disulfoton sulfoxidation by CYP2C9 (IC50 0.84 microM) as well as in HLMs. Ticlopidine, a CYP2C19 mechanism-based inhibitor, inhibited disulfoton sulfoxidation by CYP2C19 (IC50 after coincubation, 43.5 microM; IC50 after preincubation, 4.3 microM) and also in HLMs. Our results indicate that current models of the substrate binding site of the CYP2C subfamily would not effectively predict thioether pesticide metabolism. Thus, the substrate specificity of CYP2Cs is more extensive than is currently believed, and some reevaluation of structure-activity relationships may be required.}, number={3}, journal={DRUG METABOLISM AND DISPOSITION}, author={Usmani, KA and Karoly, ED and Hodgson, E and Rose, RL}, year={2004}, month={Mar}, pages={333–339} }
 @article{thompson_young_edens_olmstead_leblanc_hodgson_roe_2004, title={Non-target toxicology of a new mosquito larvicide, trypsin modulating oostatic factor}, volume={80}, ISSN={["1095-9939"]}, DOI={10.1016/j.pestbp.2004.06.009}, abstractNote={Trypsin modulating oostatic factor (TMOF), a peptide hormone originally isolated from the ovaries of adult Aedes aegypti, is currently under commercial development as a new pesticide chemistry with a novel mode of action for the control of larval mosquitoes. The objective of the current research is to evaluate potential risks of the use of TMOF as an insecticide on non-target organisms. TMOF (YDPAP6) was degraded in vitro (as determined by HPLC and LC/MS) to DPAP6, PAP6, and then AP6 by leucine aminopeptidase, a pancreatic enzyme found in the digestive system of vertebrates. The rate of degradation of TMOF and PAP6 was significantly greater than that of DPAP6, while no metabolism of AP6 was found. TMOF technical insecticide was produced on a commercial scale by recombinant yeast (heat-killed before application). The technical TMOF when administered in a single dose by gavage to male and female mice at 2000 mg dry weight/kg body weight produced no negative effects as compared to controls up to 12 days after treatment. When male and female mallard ducks were treated by gavage with 1250 mg dry weight of technical TMOF/kg body weight each day for 5 days, again no toxic effects were noted through 35 days after the last treatment. TMOF technical insecticide was also applied to the shaved skin of male and female rabbits at the rate of 2000 mg/kg for 1–2 days, with no effect. The end point observations in these in vivo experiments were mortality; changes in growth rate, behavior, body structure, and color; and possible lesions observed during necropsy. Finally, Daphnia incubated with technical TMOF in rearing water at the level of 1.0 × 106 yeast cells/ml (10 mg/ml) also demonstrated no negative effects on mortality, growth, molting, time to first brood, and production of viable neonates. It appears from these studies that TMOF can be degraded by vertebrate digestive proteases and technical TMOF is not toxic to the non-target organisms examined.}, number={3}, journal={PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY}, author={Thompson, DM and Young, HP and Edens, FW and Olmstead, AW and LeBlanc, GA and Hodgson, E and Roe, RM}, year={2004}, month={Nov}, pages={131–142} }
 @article{hodgson_2003, title={In vitro human phase I metabolism of xenobiotics I: Pesticides and related compounds used in agriculture and public health, May 2003}, volume={17}, ISSN={["1099-0461"]}, DOI={10.1002/jbt.10080}, abstractNote={Abstract}, number={4}, journal={JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY}, author={Hodgson, E}, year={2003}, pages={201–206} }
 @article{usmani_rose_hodgson_2003, title={Inhibition and activation of the human liver microsomal and human cytochrome P450 3A4 metabolism of testosterone by deployment-related chemicals}, volume={31}, ISSN={["0090-9556"]}, DOI={10.1124/dmd.31.4.384}, abstractNote={Cytochrome P450 (P450) enzymes are major catalysts involved in the metabolism of xenobiotics and endogenous substrates such as testosterone (TST). Major TST metabolites formed by human liver microsomes include 6beta-hydroxytestosterone (6beta-OHTST), 2beta-hydroxytestosterone (2beta-OHTST), and 15beta-hydroxytestosterone (15beta-OHTST). A screen of 16 cDNA-expressed human P450 isoforms demonstrated that 94% of all TST metabolites are produced by members of the CYP3A subfamily with 6beta-OHTST accounting for 86% of all TST metabolites. Similar K(m) values were observed for production of 6beta-, 2beta-, and 15beta-OHTST with human liver microsomes (HLM) and CYP3A4. However, V(max) and CL(int) were significantly higher for 6beta-OHTST than 2beta-OHTST (approximately 18-fold) and 15beta-OHTST (approximately 40-fold). Preincubation of HLM with a variety of ligands, including chemicals used in military deployments, resulted in varying levels of inhibition or activation of TST metabolism. The greatest inhibition of TST metabolism in HLM was following preincubation with organophosphorus compounds, including chlorpyrifos, phorate, and fonofos, with up to 80% inhibition noticed for several metabolites including 6beta-OHTST. Preincubation of CYP3A4 with chlorpyrifos, but not chlorpyrifos-oxon, resulted in 98% inhibition of TST metabolism. Phorate and fonofos also inhibited the production of most primary metabolites of CYP3A4. Kinetic analysis indicated that chlorpyrifos was one of the most potent inhibitors of major TST metabolites followed by fonofos and phorate. Chlorpyrifos, fonofos, and phorate inhibited major TST metabolites noncompetitively and irreversibly. Conversely, preincubation of CYP3A4 with pyridostigmine bromide increased metabolite levels of 6beta-OHTST and 2beta-OHTST. Preincubation of human aromatase (CYP19) with the test chemicals had no effect on the production of the endogenous estrogen, 17beta-estradiol.}, number={4}, journal={DRUG METABOLISM AND DISPOSITION}, author={Usmani, KA and Rose, RL and Hodgson, E}, year={2003}, month={Apr}, pages={384–391} }
 @article{usmani_rose_goldstein_taylor_brimfield_hodgson_2002, title={In vitro human metabolism and interactions of repellent N,N-diethyl-M-toluamide}, volume={30}, ISSN={["1521-009X"]}, DOI={10.1124/dmd.30.3.289}, abstractNote={Oxidative metabolism of the insect repellent N,N-diethyl-m-toluamide (DEET) by pooled human liver microsomes (HLM), rat liver microsomes (RLM), and mouse liver microsomes (MLM) was investigated. DEET is metabolized by cytochromes P450 (P450s) leading to the production of a ring methyl oxidation product, N,N-diethyl-m-hydroxymethylbenzamide (BALC), and an N-deethylated product, N-ethyl-m-toluamide (ET). Both the affinities and intrinsic clearance of HLM for ring hydroxylation are greater than those for N-deethylation. Pooled HLM show significantly lower affinities (K(m)) than RLM for metabolism of DEET to either of the primary metabolites (BALC and ET). Among 15 cDNA-expressed P450 enzymes examined, CYP1A2, 2B6, 2D6*1 (Val(374)), and 2E1 metabolized DEET to the BALC metabolite, whereas CYP3A4, 3A5, 2A6, and 2C19 produced the ET metabolite. CYP2B6 is the principal cytochrome P450 involved in the metabolism of DEET to its major BALC metabolite, whereas CYP2C19 had the greatest activity for the formation of the ET metabolite. Use of phenotyped HLMs demonstrated that individuals with high levels of CYP2B6, 3A4, 2C19, and 2A6 have the greatest potential to metabolize DEET. Mice treated with DEET demonstrated induced levels of the CYP2B family, increased hydroxylation, and a 2.4-fold increase in the metabolism of chlorpyrifos to chlorpyrifos-oxon, a potent anticholinesterase. Preincubation of human CYP2B6 with chlorpyrifos completely inhibited the metabolism of DEET. Preincubation of human or rodent microsomes with chlorpyrifos, permethrin, and pyridostigmine bromide alone or in combination can lead to either stimulation or inhibition of DEET metabolism.}, number={3}, journal={DRUG METABOLISM AND DISPOSITION}, author={Usmani, KA and Rose, RL and Goldstein, JA and Taylor, WG and Brimfield, AA and Hodgson, E}, year={2002}, month={Mar}, pages={289–294} }
 @article{choi_rose_hodgson_2002, title={In vitro human metabolism of permethrin: the role of human alcohol and aldehyde dehydrogenases}, volume={74}, ISSN={["1095-9939"]}, DOI={10.1016/S0048-3575(02)00154-2}, abstractNote={Permethrin is a pyrethroid insecticide widely used in agriculture and public health. It has been suggested that permethrin may interact with other chemicals used during military deployments and, as a result, be a potential cause of Gulf War Related Illness. To determine the causal relationship between permethrin and human health effects, the basic enzymatic pathway of permethrin metabolism in humans should be understood. In the present study we report that trans-permethrin is metabolized in human liver fractions, producing phenoxybenzyl alcohol (PBOH) and phenoxybenzoic acid (PBCOOH). We identified human alcohol (ADH) and aldehyde dehydrogenases (ALDH) as the enzymes involved in the oxidation of phenoxybenzyl alcohol, the permethrin hydrolysis product, to phenoxybenzoic acid by way of phenoxybenzaldehyde (PBCHO). Cis-permethrin was not significantly metabolized in human liver fractions. Cytochrome P450 isoforms were not involved either in the hydrolysis of trans-permethrin or in the oxidation of PBOH to PBCOOH. Purified ADH isozymes oxidized PBOH to PBCHO and PBOH was a preferred substrate to ethyl alcohol. Purified ALDH was responsible for PBCHO oxidation to PBCOOH with similar substrate affinity to a previously known substrate, benzyl alcohol. Based on these observations, it appears that PBOH is oxidized to PBCHO by ADH and subsequently to PBCOOH by ALDH, although PBCHO does not accumulate during microsomal incubation. In order to analyze permethrin and its metabolites, previous HPLC-UV methods had to be re-validated and modified. The resulting refined HPLC-UV method is described in detail.}, number={3}, journal={PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY}, author={Choi, J and Rose, RL and Hodgson, E}, year={2002}, month={Nov}, pages={117–128} }
 @article{tang_cao_rose_hodgson_2002, title={In vitro metabolism of carbaryl by human cytochrome P450 and its inhibition by chlorpyrifos}, volume={141}, ISSN={["0009-2797"]}, DOI={10.1016/S0009-2797(02)00074-1}, abstractNote={Carbaryl is a widely used anticholinesterase carbamate insecticide. Although previous studies have demonstrated that carbaryl can be metabolized by cytochrome P450 (CYP), the identification and characterization of CYP isoforms involved in metabolism have not been described either in humans or in experimental animals. The in vitro metabolic activities of human liver microsomes (HLM) and human cytochrome P450 (CYP) isoforms toward carbaryl were investigated in this study. The three major metabolites, i.e. 5-hydroxycarbaryl, 4-hydroxycarbaryl and carbaryl methylol, were identified after incubation of carbaryl with HLM or individual CYP isoforms and analysis by HPLC. Most of the 16 human CYP isoforms studied showed some metabolic activity toward carbaryl. CYP1A1 and 1A2 had the greatest ability to form 5-hydroxycarbaryl, while CYP3A4 and CYP1A1 were the most active in generation of 4-hydroxycarbaryl. The production of carbaryl methylol was primarily the result of metabolism by CYP2B6. Differential activities toward carbaryl were observed among five selected individual HLM samples with the largest difference occurring in the production of carbaryl methylol. Co-incubations of carbaryl and chlorpyrifos in HLM greatly inhibited carbaryl metabolism. The ability of HLM to metabolize carbaryl was also reduced by pre-incubation of HLM with chlorpyrifos. Chlorpyrifos inhibited the generation of carbaryl methylol, catalyzed predominately by CYP2B6, more than other pathways, correlating with an earlier observation that chlorpyrifos is metabolized to its oxon primarily by CYP2B6. Therefore, carbaryl metabolism in humans and its interaction with other chemicals is reflected by the concentration of CYP isoforms in HLM and their activities in the metabolic pathways for carbaryl. (Supported by NCDA Environmental Trust Fund)}, number={3}, journal={CHEMICO-BIOLOGICAL INTERACTIONS}, author={Tang, J and Cao, Y and Rose, RL and Hodgson, E}, year={2002}, month={Oct}, pages={229–241} }
 @article{dai_bai_hodgson_rose_2001, title={Cloning, sequencing, heterologous expression, and ch;characterization of murine cytochrome p450 3a25*(Cyp3a25), a testosterone 6 beta-hydroxylase}, volume={15}, ISSN={["1095-6670"]}, DOI={10.1002/jbt.4}, abstractNote={Abstract}, number={2}, journal={JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY}, author={Dai, D and Bai, R and Hodgson, E and Rose, RL}, year={2001}, pages={90–99} }
 @article{hodgson_2001, title={Genetically modified plants and human health risks: Can additional research reduce uncertainties and increase public confidence?}, volume={63}, ISSN={["1096-6080"]}, DOI={10.1093/toxsci/63.2.153}, abstractNote={So long as the risks to human health from transgenic plants remain potential rather than actual, and, in any event, appear lower than those from traditional plant breeding, hazard assessment need not be extensive. However, in view of current public attitudes to transgenic plants, it is necessary that those tests that are required, be based on logic, on sound science, and in accordance with the best scientific methodology. This is particularly the case with testing for food allergenicity. Current testing is largely indirect and based on comparisons with other known food allergens. Development of direct tests that involve interaction between the actual transgenic protein in question and the immune system is essential if confidence in the regulatory system is to be restored.}, number={2}, journal={TOXICOLOGICAL SCIENCES}, author={Hodgson, E}, year={2001}, month={Oct}, pages={153–156} }
 @article{dai_tang_rose_hodgson_bienstock_mohrenweiser_goldstein_2001, title={Identification of variants of CYP3A4 and characterization of their abilities to metabolize testosterone and chlorpyrifos}, volume={299}, number={3}, journal={Journal of Pharmacology and Experimental Therapeutics}, author={Dai, D. and Tang, J. and Rose, R. and Hodgson, E. and Bienstock, R. J. and Mohrenweiser, H. W. and Goldstein, J. A.}, year={2001}, pages={825–831} }
 @article{hodgson_2001, title={In vitro human phase I metabolism of xenobiotics I: Pesticides and related chemicals used in agriculture and public health, September 2001}, volume={15}, ISSN={["1099-0461"]}, DOI={10.1002/jbt.10011}, abstractNote={Abstract}, number={6}, journal={JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY}, author={Hodgson, E}, year={2001}, pages={296–299} }
 @article{tang_cao_rose_brimfield_dai_goldstein_hodgson_2001, title={Metabolism of chlorpyrifos by human cytochrome P450 isoforms and human, mouse, and rat liver microsomes}, volume={29}, number={9}, journal={Drug Metabolism and Disposition}, author={Tang, J. and Cao, Y. and Rose, R. L. and Brimfield, A. A. and Dai, D. and Goldstein, J. A. and Hodgson, E.}, year={2001}, pages={1201–1204} }
 @article{dai_cao_falls_levi_hodgson_rose_2001, title={Modulation of mouse P450 isoforms CYP1A2, CYP2B10, CYP2E1, and CYP3A by the environmental chemicals mirex, 2,2-bis(p-chlorophenyl)-1,1-dichloroethylene, vinclozolin, and flutamide}, volume={70}, ISSN={["1095-9939"]}, DOI={10.1006/pest.2001.2551}, abstractNote={Abstract Several environmental chemicals are disruptive to the reproductive and endocrine systems of many species, including humans. Mechanisms for endocrine disruption are presently under scrutiny. Xenobiotic inducible mammalian cytochrome P450 (CYP) enzymes metabolize a variety of substrates including environmental chemicals, pesticides, and drugs. The metabolism, and thus the effect, of endogenous chemicals including steroid hormones, vitamins, etc. that are transformed by CYP enzymes can be influenced by environmental exposure to CYP-inducing chemicals. This study demonstrated that structurally diverse environmental chemicals including mirex, 2,2-Bis( p -chlorophenyl)-1,1-dichloroethylene (DDE), vinclozolin, and flutamide are capable of inducing several mouse liver CYP isozymes. As demonstrated by Western blotting, mirex induced CYP1A2, 2B10, 2E1, and 3A and vinclozolin induced 1A2 and 2B10. The only isoforms significantly induced by DDE and flutamide were 3A and 1A2, respectively. Since some of these isoforms are known to be involved in metabolism of endogenous hormones, we also studied the effects of these CYP inducers on testosterone metabolism and seminal vesicle weights. Mirex and DDE treatments had profound effects on the metabolism of testosterone, resulting in 2.5- to 3-fold more hydroxylated products than controls. Lesser, but significant, increases in specific metabolites of testosterone were also observed following treatment with vinclozolin and flutamide. Seminal vesicle weights were lower for all treatment groups except DDE. Results of this study demonstrate that, due to their CYP-inducing potential, these chemicals may significantly impact testosterone metabolism and this may be a contributing factor in their antiandrogenic effects.}, number={3}, journal={PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY}, author={Dai, D and Cao, Y and Falls, G and Levi, PE and Hodgson, E and Rose, RL}, year={2001}, month={Jul}, pages={127–141} }
 @article{coleman_linderman_hodgson_rose_2000, title={Comparative metabolism of chloroacetamide herbicides and selected metabolites in human and rat liver microsomes.}, volume={108}, ISSN={["0091-6765"]}, DOI={10.2307/3434827}, abstractNote={Acetochlor [2-chloro-N-(ethoxymethyl)-N-(2-ethyl-6-methyl-phenyl)-acetamide], alachlor [N-(methoxymethyl)-2-chloro-N-(2,6-diethyl-phenyl)acetamide], butachlor [N-(butoxymethyl)-2chloro-N-(2,6-diethyl-phenyl)acetamide], and metolachlor [2-chloro-N-(2-ethyl-6-methylphenyl)-N-(2-methoxy-1-methylethyl) acetamide] are pre-emergent herbicides used in the production of agricultural crops.These herbicides are carcinogenic in rats: acetochlor and alachlor cause tumors in the nasal turbinates, butachlor causes stomach tumors, and metolachlor causes liver tumors.It has been suggested that the carcinogenicity of these compounds involves a complex metabolic activation pathway leading to a DNA-reactive dialkylbenzoquinone imine.Important intermediates in this pathway are 2-chloro-N-(2,6-diethylphenyl)acetamide (CDEPA) produced from alachlor and butachlor and 2-chloro-N-(2-methyl-6-ethylphenyl)acetamide (CMEPA) produced from acetochlor and metolachlor.Subsequent metabolism of CDEPA and CMEPA produces 2,6-diethylaniline (DEA) and 2-methyl-6-ethylaniline (MEA), which are bioactivated through para-hydroxylationand subsequent oxidation to the proposed carcinogenic product dialkylbenzoquinone imine.The current study extends our earlier studies with alachlor and demonstrates that rat liver microsomes metabolize acetochlor and metolachlor to CMEPA (0.065 nmol/min/mg and 0.0133 nmol/min/mg, respectively), whereas human liver microsomes can metabolize only acetochlor to CMEPA (0.023 nmol/min/mg).Butachlor is metabolized to CDEPA to a much greater extent by rat liver microsomes (0.045 nmol/min/mg) than by human liver microsomes (< 0.001 nmol/min/mg).We have determined that both rat and human livers metabolize both CMEPA to MEA (0.308 nmol/min/mg and 0.541 nmol/min/mg, respectively) and CDEPA to DEA (0.350 nmol/min/mg and 0.841 nmol/min/mg, respectively).We have shown that both rat and human liver microsomes metabolize MEA (0.035 nmol/min/mg and 0.069 nmol/min/mg, respectively) and DEA (0.041 nmol/min/mg and 0.040 nmol/min/mg, respectively).We have also shown that the cytochrome P450 isoforms responsible for human metabolism of acetochlor, butachlor, and metolachlor are CYP3A4 and CYP2B6.}, number={12}, journal={ENVIRONMENTAL HEALTH PERSPECTIVES}, author={Coleman, S and Linderman, R and Hodgson, E and Rose, RL}, year={2000}, month={Dec}, pages={1151–1157} }
 @article{roe_bailey_gould_sorenson_kennedy_bacheler_rose_hodgson_sutula_2000, title={Detection of resistant insects and IPM}, ISBN={0890542465}, journal={Emerging technologies for integrated pest management : concepts, research, and implementation}, publisher={St. Paul, MN : APS Press,}, author={Roe, R. M. and Bailey, W. D. and Gould, F. and Sorenson, C. E. and Kennedy, G. G. and Bacheler, J. S. and Rose, R. L. and Hodgson, E. and Sutula, C. L.}, year={2000}, pages={67} }
 @article{hodgson_rose_cao_dehal_kupfer_2000, title={Flavin-containing monooxygenase isoform specificity for the N-oxidation of tamoxifen determined by product measurement and NADPH oxidation}, volume={14}, ISSN={["1095-6670"]}, DOI={10.1002/(SICI)1099-0461(2000)14:2<118::AID-JBT8>3.0.CO;2-T}, abstractNote={The Km value for tamoxifen is 1.2 mM for mouse FMO1 (human FMO1 is not expressed in adults) and 1.4 mM for human FMO3, with no detectable activity being expressed toward tamoxifen by FMO5 from either mouse or human. These data are derived from experiments using 3H‐tamoxifen as substrate in which the product, tamoxifen N‐oxide, was measured directly. It was not possible to derive meaningful data from the measurement of NADPH consumption because Escherichia coli preparations, in the presence of tamoxifen, regardless of whether the E. coli was expressing an FMO isoform, consumed large amounts of NADPH without the appearance of tamoxifen N‐oxide or other discernable product. © 2000 John Wiley & Sons, Inc. J Biochem Toxicol 14: 118–120, 2000}, number={2}, journal={JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY}, author={Hodgson, E and Rose, RL and Cao, Y and Dehal, SS and Kupfer, D}, year={2000}, pages={118–120} }
 @article{gray_goldstein_bailar_davis_delzell_dost_greenberg_hatch_hodgson_ibrahim_et al._2000, title={The federal government's Agricultural Health Study: A critical review with suggested improvements}, volume={6}, ISSN={["1080-7039"]}, DOI={10.1080/10807030091124446}, abstractNote={The Agricultural Health Study (AHS) has approximately 90,000 pesticide applicators and their spouses enrolled in a number of studies to determine whether exposures to specific pesticides are associated with various cancers and other adverse health outcomes. Although the AHS was intended to be an integrated program of studies, some significant difficulties have emerged. In this report, we examine the design of the AHS, identify important program strengths and flaws, suggest various improvements in the program, and recommend ancillary studies that could be undertaken to strengthen the AHS. Overall, the AHS is collecting a large amount of information on potential determinants of health status among farmers and farm families. A promising feature of the AHS is the prospective cohort study of cancers among farmers in which the research design determines exposures prior to the diagnosis of disease. More effort needs to be devoted to reducing selection bias and information bias. Success of the cohort study will depend in part on follow-up surveys of the cohort to determine how exposures and disease states change as the cohort ages. The cross-sectional and case-control studies planned in the AHS are less promising because they will be subject to some of the same criticisms, such as potentially biased and imprecise exposure assessment, that have characterized the existing literature in this field. Important limitations of the AHS include low and variable rates of subject response to administered surveys, concerns about the validity of some self-reported non-cancer health outcomes, limited understanding of the reliability and validity of self-reporting of chemical use, an insufficient program of biological monitoring to validate the exposure surrogates employed in the AHS questionnaires, possible confounding by unmeasured, nonchemical risk factors for disease, and the absence of detailed plans for data analysis and interpretation that include explicit, a priori hypotheses. Although the AHS is already well underway, most of these limitations can be addressed by the investigators if adequate resources are made available. If these limitations are not addressed, the large amounts of data generated in the AHS will be difficult to interpret. If the exposure and health data can be validated, the scientific value of the AHS should be substantial and enduring. A variety of research recommendations are made to strengthen the AHS. They include reliability and validity studies of farmer reporting of chemical use, biological monitoring studies of farmers and members of farm families, and validity studies of positive and negative self-reports of disease status. Both industry and government should consider expanded research programs to strengthen the AHS.}, number={1}, journal={HUMAN AND ECOLOGICAL RISK ASSESSMENT}, author={Gray, GM and Goldstein, BD and Bailar, J and Davis, DL and Delzell, E and Dost, F and Greenberg, RS and Hatch, M and Hodgson, E and Ibrahim, MA and et al.}, year={2000}, month={Feb}, pages={47–71} }
 @article{ryu_hodgson_1999, title={Constitutive expression and induction of CYP1B1 mRNA in the mouse}, volume={13}, ISSN={["1095-6670"]}, DOI={10.1002/(SICI)1099-0461(1999)13:5<249::AID-JBT4>3.0.CO;2-L}, abstractNote={Previous studies appeared to indicate that CYP1B1 was not constitutively expressed in mouse liver. In our laboratory, we demonstrated using aromatic hydrocarbon‐responsive receptor knock‐out (AHR––/–) mice that both piperonyl butoxide (PBO) and acenaphtyhlene (ACN) are AHR‐independent inducers of murine CYP1A2 and CYP1B1 mRNA. In the current study, we demonstrate both constitutive levels and induction of CYP1B1 in mouse liver. The induction of CYP1B1 mRNA by PBO or ACN was higher in DBA/2 (Ahrd) than in C57BL/6 (Ahrb−1) mice, while 3‐methylcholanthrene induced CYP1B1 more in C57BL/6 than in DBA/2 mice. These results suggest that CYP1B1 may also be induced by more than one mechanism. In addition, constitutive expression of CYP1B1 was detected in liver, kidney, and lung of untreated C57BL/6 mice. There was no gender difference in CYP1B1 expression; however, in C57BL/6 mice, the kidney contained less CYP1B1 than either liver or lung. © 1999 John Wiley & Sons, Inc. J Biochem Toxicol 13: 249–251, 1999}, number={5}, journal={JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY}, author={Ryu, DY and Hodgson, E}, year={1999}, pages={249–251} }
 @article{coleman_liu_linderman_hodgson_rose_1999, title={In vitro metabolism of alachlor by human liver microsomes and human cytochrome P450 isoforms}, volume={122}, ISSN={["0009-2797"]}, DOI={10.1016/S0009-2797(99)00107-6}, abstractNote={Alachlor (2-chloro-N-methoxymethyl-N-(2,6-diethylphenyl)acetamide) is a widely used pre-emergent chloroacetanilide herbicide which has been classified by the USEPA as a probable human carcinogen. The putative carcinogenic metabolite, 2,6-diethylbenzoquinone imine (DEBQI), is formed through a complex series of oxidative and non-oxidative steps which have been characterized in rats, mice, and monkeys but not in humans. A key metabolite leading to the formation of DEBQI is 2-chloro-N-(2,6-diethylphenyl)acetamide (CDEPA). This study demonstrates that male human liver microsomes are able to metabolize alachlor to CDEPA. The rate of CDEPA formation for human liver microsomes (0.0031±0.0007 nmol/min per mg) is significantly less than the rates of CDEPA formation for rat liver microsomes (0.0353±0.0036 nmol/min per mg) or mouse liver microsomes (0.0106±0.0007). Further, we have screened human cytochrome P450 isoforms 1A1, 1A2, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, and 3A4 and determined that human CYP 3A4 is responsible for metabolism of alachlor to CDEPA. Further work is necessary to determine the extent to which humans are able to metabolize CDEPA through subsequent metabolic steps leading to the formation of DEBQI.}, number={1}, journal={CHEMICO-BIOLOGICAL INTERACTIONS}, author={Coleman, S and Liu, SM and Linderman, R and Hodgson, E and Rose, RL}, year={1999}, month={Aug}, pages={27–39} }
 @article{hodgson_1999, title={Induction and inhibition of pesticide-metabolizing enzymes: roles in synergism of pesticides and pesticide action}, volume={15}, ISSN={["0748-2337"]}, DOI={10.1177/074823379901500102}, abstractNote={ Synergism of the toxic action of pesticides is discussed with particular emphasis on the methylenedioxyphenyl (benzodioxole) (MDP) synergists and on how studies of these compounds may relate to the general significance of pesticide synergism. MDP compounds function as both inhibitors and inducers of cytochrome P450 isoforms, the two processes proceeding, in vivo, at different rates. Inhibition is mediated through the formation of metabolite inhibitory complexes, and induction involves both aryl hydrocarbon (Ah)-dependent and Ah-independent mechanisms. The significance of this biphasic effect on multienzyme xenobiotic metabolizing systems is illustrated by considerations of the insecticide phorate. }, number={1-2}, journal={TOXICOLOGY AND INDUSTRIAL HEALTH}, author={Hodgson, E}, year={1999}, pages={6–11} }
 @article{roe_hodgson_rose_thompson_devorshak_anspaugh_linderman_harris_tomalski_1998, title={Basic principles and rationale for the use of insect genes in bioremediation: esterases, phosphotriesterase, cytochrome P450 and epoxide hydrolase}, volume={2}, number={1998}, journal={Reviews in Toxicology}, author={Roe, R. M. and Hodgson, E. and Rose, R. L. and Thompson, D. M. and Devorshak, C. and Anspaugh, D. D. and Linderman, R. J. and Harris, S. V. and Tomalski, M. D.}, year={1998}, pages={169–178} }
 @article{luo_zeldin_blaisdell_hodgson_goldstein_1998, title={Cloning and expression of murine CYP2Cs and their ability to metabolize arachidonic acid}, volume={357}, ISSN={["1096-0384"]}, DOI={10.1006/abbi.1998.0806}, abstractNote={Five murine cytochrome P450 (CYP) 2C cDNAs were cloned and characterized, including four new members of this subfamily: CYP2C37, CYP2C38, CYP2C39, and CYP2C40. The cDNAs ranged from 1716 to 1812 bp in length and encoded polypeptides of 490 amino acid residues except for CYP2C40, which contained an additional glutamic acid residue at the carboxyl terminus. The amino acid identity of the murine CYP2Cs ranged from 69 to 92%, while the overall amino acid identity was 60%; however, within the six putative substrate recognition sites the identity was only 25 to 41%, suggesting possible differences in substrate specificity and product profiles. The CYP2C cDNAs were expressed in Escherichia coli following modification of the N-terminus. All five recombinant CYP2Cs metabolized arachidonic acid, but with different metabolic profiles and catalytic rates. Based on coelution with authentic standards on reverse-phase HPLC, themajor metabolites were tentatively identified asfollows: CYP2C29 and CYP2C39 produced 14, 15-cis-epoxyeicosatrienoic acid (EET); CYP2C37 produced 12-hydroxyeicosatetraenoic acid (HETE); CYP2C38 produced 11,12-EET; and CYP2C40 produced an unidentified metabolite that coeluted with 16-,17-, and 18-HETEs. The turnover numbers for CYP2C29, CYP2C37, CYP2C38, CYP2C39, and CYP2C40 were 0.34, 1.12, 5.15, 0.51, and 0.15 nmol/nmol/min, respectively. Reverse transcriptase-polymerase chain reaction demonstrated the presence of CYP2C29 mRNA in liver as well as in extrahepatic tissues including brain, kidney, lung, heart, and intestine. CYP2C38 and CYP2C40 were found in liver, brain, kidney, and intestine, with trace amounts in lung and heart, while CYP2C37 and CYP2C39 appeared to be liver specific.}, number={1}, journal={ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS}, author={Luo, G and Zeldin, DC and Blaisdell, JA and Hodgson, E and Goldstein, JA}, year={1998}, month={Sep}, pages={45–57} }
 @article{mileson_chen_dettbarn_ehrich_eldefrawi_gaylor_hamernik_hodgson_karczmar_padilla_et al._1998, title={Common mechanism of toxicity: A case study of organophosphorus pesticides}, volume={41}, number={1}, journal={Fundamental and Applied Toxicology}, author={Mileson, B. E and Chen, W. L. and Dettbarn, W. and Ehrich, M. and Eldefrawi, A. T. and Gaylor, D. W. and Hamernik, K. and Hodgson, E. and Karczmar, A. G. and Padilla, S. and et al.}, year={1998}, pages={8–20} }
 @book{hodgson_mailman_chambers_dow_1998, title={Dictionary of toxicology (2nd ed.)}, ISBN={0333547004}, publisher={London: MacMillan Reference; New York: Grove Dictionaries}, author={Hodgson, E. and Mailman, R. B. and Chambers, J. E. and Dow, R. E.}, year={1998} }
 @article{hodgson_cherrington_coleman_liu_falls_cao_goldstein_rose_1998, title={Flavin-containing monooxygenase and cytochrome P450 mediated metabolism of pesticides: from mouse to human}, volume={2}, number={1998}, journal={Reviews in Toxicology}, author={Hodgson, E. and Cherrington, N. and Coleman, S. C. and Liu, S. and Falls, J. G. and Cao, Y. and Goldstein, J. E. and Rose, R. L.}, year={1998}, pages={231–243} }
 @article{cherrington_falls_rose_clements_philpot_levi_hodgson_1998, title={Molecular cloning, sequence, and expression of mouse flavin-containing monooxygenases 1 and 5 (FMO1 and FMO5)}, volume={12}, DOI={10.1002/(sici)1099-0461(1998)12:4<205::aid-jbt2>3.3.co;2-4}, abstractNote={Full-length cDNA clones encoding FMO1 and FMO5 have been isolated from a library constructed with mRNA from the liver of a female CD-1 mouse. The derived sequence of FMO1 contains 2310 bases: 1596 in the coding region, 301 in the 5′-flanking region, and 413 in the 3′-flanking region. The sequence for FMO5 consists of 3168 bases; 1599 in the coding region, 812 in the 5′-flanking region, and 757 in the 3′-flanking region. The sequence of FMO1 encodes a protein of 532 amino acids with a predicted molecular weight of 59.9 kDa and shows 83.3% identity to human FMO1 and 83–94% identity to other FMO1 homologs. FMO5 encodes a protein of 533 amino acids with a predicted molecular weight of 60.0 kDa and 84.1% identity to human FMO5 and 83–84% identity to other FMO5 orthologs. Two GxGxxG putative pyrophosphate binding domains exist beginning at positions 9 and 191 for FMO1, and 10 and 192 for FMO5. Mouse FMO1 and FMO5 were expressed in E. coli and show similar mobility to the native proteins as determined by SDS-PAGE. The expressed FMO1 protein showed activity toward methimazole, and FMO5 was active toward n -octylamine. In addition, FMO1 was shown to metabolize radiolabeled phorate, whereas FMO5 showed no activity toward phorate. © 1998 John Wiley & Sons, Inc. J Biochem Toxicol 12: 205–212, 1998}, number={1998}, journal={Journal of Biochemical and Molecular Toxicology}, author={Cherrington, N. J. and Falls, J. G. and Rose, R. L. and Clements, K. M. and Philpot, R. M. and Levi, P. E. and Hodgson, E.}, year={1998}, pages={205–212} }
 @article{cherrington_cao_cherrington_rose_hodgson_1998, title={Physiological factors affecting protein expression of flavin-containing monooxygenases 1, 3 and 5}, volume={28}, ISSN={["0049-8254"]}, DOI={10.1080/004982598239254}, abstractNote={1. The mouse and rat exhibit substantial differences in the gender expression of flavin-containing monooxygenase (FMO) forms. Hepatic FMO1 is gender-dependent in both species, selective to the male in rat, female in mouse. Human FMO1 is nearly undetectable. FMO3 in mouse is gender-specific to the female, but gender-independent in rat and man. FMO5 is gender-independent for mouse, rat and man. 2. Gender differences in substrate metabolism do not reflect overall FMO or isoform differences. Methimazole, imipramine and thiobenzamide are much better substrates for FMO1 than for FMO3 or FMO5. 3. Activities of microsomal samples toward these substrates reflect the relative abundance of FMO1. Hepatic samples show a 3-fold greater activity toward methimazole in the female mouse and male rat. Human microsomal samples show minimal activity. 4. Developmentally, FMO1 and FMO5 are expressed in foetuses as early as gestation days 15 and 17 and equally between genders until puberty. FMO3 is not found until 2 weeks post-partum and is found equally in the male and female until 6 weeks post-partum when it becomes undetectable in the male. 5. An event takes place after birth but before puberty that confers the ability to produce FMO3. The developmental pattern observed for mouse FMO3 is similar to human FMO3.}, number={7}, journal={XENOBIOTICA}, author={Cherrington, NJ and Cao, Y and Cherrington, JW and Rose, RL and Hodgson, E}, year={1998}, month={Jul}, pages={673–682} }
 @article{rose_goh_thompson_verma_heckel_gahan_roe_hodgson_1997, title={Cytochrome P450 (CYP)9A1 in Heliothis virescens: The first member of a new CYP family}, volume={27}, ISSN={["1879-0240"]}, DOI={10.1016/S0965-1748(97)00036-2}, abstractNote={A novel cytochrome P450 cDNA with its complete coding sequence and part or all of the 3' (77 nucleotides) and 5' (87 nucleotides) non-coding sequence was isolated from the tobacco budworm, Heliothis virescens (F). The 1763 nucleotide sequence encodes a protein of 532 amino acids which includes a hydrophobic N-terminal region and the highly conserved heme binding regions typical of P450s. Low sequence similarity to other P450 sequences and the presence of a thromboxane synthase-like insertion upstream from the I helix resulted in its assignment as the first member of family 9, i.e. CYP9A1. CYP9A1 is most similar to CYP3A1 from the rat (34.7% identity), but is also similar to the insect P450s from family 6, including CYP6B1v1 from Papilio polyxenes (33.3%), CYP6A2A from Drosophila melanogaster (32.4%), CYP6A3 from Musca domestica (31.7%) and CYP6B2 from Helicoverpa armigera (30.1%). Comparative Western and Northern blot studies indicate that expression of CYP9A1 in thiodicarb selected populations of tobacco budworm is associated with insecticide resistance. The pattern of restriction fragment length polymorphism (RELP) variation in offspring of single-pair matings demonstrated autosomal inheritance of CYP9A1 and enabled its assignment to linkage group 7. The coding region of CYP9A1 occupies no more than 10 kb in the tobacco budworm genome.}, number={6}, journal={INSECT BIOCHEMISTRY AND MOLECULAR BIOLOGY}, author={Rose, RL and Goh, D and Thompson, DM and Verma, KD and Heckel, DG and Gahan, LJ and Roe, RM and Hodgson, E}, year={1997}, month={Jun}, pages={605–615} }
 @article{falls_cherrington_clements_philpot_levi_rose_hodgson_1997, title={Molecular cloning, sequencing, and expression in Escherichia coli of mouse flavin-containing monooxygenase 3 (FMO3): Comparison with the human isoform}, volume={347}, ISSN={["0003-9861"]}, DOI={10.1006/abbi.1997.0322}, abstractNote={The sequence of mouse flavin-containing monooxygenase 3 (FMO3) was obtained from several clones isolated from a mouse liver cDNA library. The nucleotide sequence of mouse FMO3 was 2020 bases in length containing 37 bases in the 5' flanking region, 1602 in the coding region, and 381 in the 3' flanking region. The derived protein sequence consisted of 534 amino acids including the putative flavin adenine dinucleotide and NADP+ pyrophosphate binding sites (characteristic of mammalian FMOs) starting at positions 9 and 191, respectively. The mouse FMO3 protein sequence was 79 and 82% identical to the human and rabbit FMO3 sequences, respectively. Mouse FMO3 was expressed in Escherichia coli and compared to E. coli expressed human FMO3. The FMO3 proteins migrated with the same mobility ( approximately 58 kDa) as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotting. The expressed FMO3 enzymes (mouse and human forms) were sensitive to heat and reacted in a similar manner toward metal ions and detergent. Catalytic activities of mouse and human FMO3 were high toward the substrate methimazole; however, in the presence of trimethylamine and thioacetamide, FMO-dependent methimazole oxidation by both enzymes was reduced by greater than 85%. Other substrates which inhibited methimazole oxidation were thiourea and thiobenzamide and to a lesser degree N,N-dimethylaniline. When probed with mouse FMO3 cDNA, FMO3 transcripts were detected in hepatic mRNA samples from female mice, but not in samples from males. FMO3 was detected in mRNA samples from male and female mouse lung, but FMO3 message was not detected in mouse kidney sample from either gender. Results of immunoblotting confirmed the tissue- and gender-dependent expression of mouse FMO3.}, number={1}, journal={ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS}, author={Falls, JG and Cherrington, NJ and Clements, KM and Philpot, RM and Levi, PE and Rose, RL and Hodgson, E}, year={1997}, month={Nov}, pages={9–18} }
 @article{ryu_levi_hodgson_1997, title={Regulation of hepatic CYP1A isozymes by piperonyl butoxide and acenaphthylene in the mouse}, volume={105}, ISSN={["1872-7786"]}, DOI={10.1016/S0009-2797(97)00035-5}, abstractNote={The regulation of CYP1A1 and CYP1A2 isozymes by piperonyl butoxide (PBO) and acenaphthylene (ACN) was studied in the liver of male C57BL/6 and DBA/2 mice. These two cytochrome P450 genes are known to be regulated by the aromatic hydrocarbon-responsive receptor (AHR); however, it has been suggested that CYP1A2 is also induced by an AHR-independent mechanism. In this study, PBO induced hepatic CYP1A1 considerably more in C57BL/6 (Ahrb-I) than in DBA/2 (Ahrd) mice. In addition, the superinduction of CYP1A1 in wildtype hepa1c1c7 cells, which is AHR-dependent, resulted from PBO and cycloheximide treatment of the cells. In other studies in this laboratory using AHR knock-out (AHR-/-) mice, a hybrid of 129/SV and C57BL/6 strains, no induction of CYP1A1 occurred with PBO or ACN. [D.-Y. Ryu, P.E. Levi, P. Fernandez-Salguero, F.J. Gonzalez, E. Hodgson, Mol. Pharmacol., 50 (1996) 443-446.] ACN, however, did not induce CYP1A1 under the experimental conditions used. These results suggest that PBO, but not ACN, induces CYP1A1 through a weak activation of AHR. On the other hand, hepatic CYP1A2 mRNA and hnRNA were induced by PBO in both C57BL/6 and DBA/2 strains, but were not induced by ACN, a strong inducer of CYP1A2 in the B6C3F1 strain. However, both PBO and ACN induced CYP1A2 in AHR-/- mice. It is assumed, therefore, that the transcriptional induction of CYP1A2 by PBO and ACN is AHR-independent. In addition, the induction of CYP1A2 by ACN depends upon the strain of mice. Immunohistochemical studies for CYP1A1/CYP1A2 apoproteins showed that PBO induced CYP1A1/CYP1A2 around the central veins as did 3-methylcholanthrene (3-MC). The induction of CYP1A1/CYP1A2 by ACN, however, was not observed, consistent with the northern blot results.}, number={1}, journal={CHEMICO-BIOLOGICAL INTERACTIONS}, author={Ryu, DY and Levi, PE and Hodgson, E}, year={1997}, month={Jun}, pages={53–63} }
 @article{falls_ryu_cao_levi_hodgson_1997, title={Regulation of mouse liver flavin-containing monooxygenases 1 and 3 by sex steroids}, volume={342}, ISSN={["0003-9861"]}, DOI={10.1006/abbi.1997.9965}, abstractNote={Based on enzyme activity, protein levels, and mRNA levels, we have previously demonstrated the female-predominant, female-specific, and gender-independent expression in mouse liver of FMO forms 1, 3, and 5, respectively. This study investigated the roles of testosterone, 17 beta-estradiol, and progesterone in the regulation of hepatic FMOs. FMO expression was examined in gonadectomized CD-1 mice, normal CD-1 mice receiving hormonal implants, and gonadectomized mice receiving various hormonal treatments. Following castration of males, hepatic FMO activity levels were significantly increased and serum testosterone levels significantly decreased; however, administration of physiological levels of testosterone to castrated animals returned FMO activity and testosterone concentrations to control levels. When sexually intact and ovariectomized female mice were treated with testosterone, their hepatic FMO activity levels were reduced to those of their male counterparts, concomitant with high serum testosterone levels. In males, castration dramatically increased FMO3 and FMO1 expression, and testosterone replacement to castrated males resulted in ablation of FMO3 expression. In addition, testosterone administration to females (sexually intact and gonadectomized animals) reduced FMO1 expression and obviated FMO3 expression. In females, ovariectomy alone slightly reduced FMO activity, indicative of a possible stimulatory role of female sex steroids; however, female FMO isozyme expression was relatively unchanged, and hormone replacement therapy to ovariectomized females had no discernible effect. In males and females, FMO5 levels were unaffected by gonadectomy or hormone administration, thus indicating a sex hormone-independent mechanism of regulation for this isoform. Interestingly, FMO1 protein levels were increased in sexually intact males following treatment with 17 beta-estradiol; however, only a slight increase in FMO3 protein level was observed. No positive hormone effectors of female FMO expression were identified.}, number={2}, journal={ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS}, author={Falls, JG and Ryu, DY and Cao, Y and Levi, PE and Hodgson, E}, year={1997}, month={Jun}, pages={212–223} }
 @book{hodgson_levi_1997, title={Textbook of modern toxicology}, ISBN={0838588875}, publisher={Stamford, Conn.: Appleton & Lange}, author={Hodgson, E. and Levi, P. E.}, year={1997} }
 @misc{roe_hodgson_rose_1996, title={Insecticide resistance associated cytochrome 450}, volume={5,516,674}, number={1996 May 14}, publisher={Washington, DC: U.S. Patent and Trademark Office}, author={Roe, R. and Hodgson, E. and Rose, R.}, year={1996} }
 @article{hodgson_rose_ryu_falls_blake_levi_1995, title={Pesticide-metabolizing enzymes}, volume={82-3}, ISSN={["0378-4274"]}, DOI={10.1016/0378-4274(95)03469-2}, abstractNote={Pesticides are known to function as substrates, inhibitors and inducers of drug-metabolizing enzymes, with the same compound frequently acting in more than one of these roles. Current studies of phase I metabolism of pesticides include cytochrome P450 (P450) and the flavin-containing monooxygenase (FMO), with particular reference to individual isozymes. In mouse liver, the level of FMO1 is gender dependent, FMO3 is gender specific, while FMO5 appears to be gender independent. The isozyme specificity of methylenedioxyphenyl synergists for induction of P450 in mouse liver involves P450s 1A1, 1A2 and 2B10, including a non-Ah receptor-dependent mechanism for 1A2 induction. The substrate specificity of mouse and human P450 and FMO isozymes is discussed.}, journal={TOXICOLOGY LETTERS}, author={Hodgson, E and Rose, RL and Ryu, DY and Falls, G and Blake, BL and Levi, PE}, year={1995}, month={Dec}, pages={73–81} }
 @article{venkatesh_levi_inman_monteiroriviere_misra_hodgson_1992, title={ENZYMATIC AND IMMUNOHISTOCHEMICAL STUDIES ON THE ROLE OF CYTOCHROME-P450 AND THE FLAVIN-CONTAINING MONOOXYGENASE OF MOUSE SKIN IN THE METABOLISM OF PESTICIDES AND OTHER XENOBIOTICS}, volume={43}, ISSN={["1095-9939"]}, url={http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=ORCID&SrcApp=OrcidOrg&DestLinkType=FullRecord&DestApp=WOS_CPL&KeyUT=WOS:A1992HV42800007&KeyUID=WOS:A1992HV42800007}, DOI={10.1016/0048-3575(92)90019-V}, abstractNote={The cytochrome P450 (P450) content, the cytochrome c reductase activity, the metabolism of a variety of P450 substrates, and the presence and role of flavin-containing monooxygenase (FMO) in xenobiotic metabolism were studied in skin microsomes and compared to those of liver. The cytochrome P450 content of skin as determined by CO-dithionite-reduced minus CO-oxidized spectra was approximately 6.8% of the liver P450 content. By comparison, cytochrome c reductase activity in skin microsomes was high, being equivalent to approximately one-third of the liver microsomal enzyme activity. Skin microsomes metabolized several known P450 substrates and, depending upon the substrate used, the specific activity ranged from 2.5 to 13.4% of the corresponding rates seen in liver microsomes. Skin microsomes exhibited the highest enzymatic activity with benzo[a]pyrene and ethoxyresorufin, moderate activity with parathion and aldrin, and low activity with benzphetamine and ethoxycoumarin. Skin microsomes also metabolized the triazine herbicides atrazine, simazine, and terbutryn, with the activity being 2 to 5% of the liver microsomal activity. FMO activity in skin microsomes with thiobenzamide and methimazole as substrates ranged from 10 to 20% of the liver FMO activity. Immunohistochemical studies using antibodies to mouse liver FMO showed localization primarily in the epidermis. Additional studies using pig skin showed a similar distribution pattern. Antibodies developed to mouse liver FMO and the constitutive liver P450 isozyme, 1A2, showed cross-reactivity on Western blots with proteins in skin microsomes that appeared identical to the cross-reacting proteins present in liver microsomes. The relative contribution of P450 and FMO in mouse skin to the sulfoxidation of phorate was investigated and compared to that of liver microsomes. Several procedures were employed to selectively inhibit either P450 or FMO to determine the role of each monooxygenase system in the absence of the other system. In liver microsomes, P450 was responsible for 68 to 85% of the phorate sulfoxidation activity. In contrast, in skin microsomes 66 to 69% of the phorate sulfoxidation activity was due to FMO, while P450 was responsible for the remainder of the activity. Thus, although the overall phorate sulfoxidation rate in mouse skin microsomes was only 3 to 4% of the rate seen in liver, FMO appears to assume a greater relative role to P450 in the metabolic processes in skin.}, number={1}, journal={PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY}, author={VENKATESH, K and LEVI, PE and INMAN, AO and MONTEIRORIVIERE, NA and MISRA, R and HODGSON, E}, year={1992}, month={May}, pages={53–66} }
 @inbook{hodgson_motoyama_evered_collins_1984, title={Biochemical mechanisms of resistance to insecticides}, ISBN={9780272797495}, booktitle={Origins and development of adaptation}, publisher={London: Pitman}, author={Hodgson, E. and Motoyama, N. and Evered, D. and Collins, G. M.}, year={1984}, pages={167} }
 @inbook{hodgson_kulkarni_georghiou_saito_1983, title={Characterization of cytochrome P-450 in studies of insecticide resistance}, ISBN={0306412462}, booktitle={Pest resistance to pesticides}, publisher={New York: Plenum Press}, author={Hodgson, E. and Kulkarni, A. P. and Georghiou, G. P. and Saito, T.}, editor={Georghiou, G. P. and Saito, T.Editors}, year={1983}, pages={207} }
 @misc{hodgson_1983, title={THE SIGNIFICANCE OF CYTOCHROME-P-450 IN INSECTS}, volume={13}, ISSN={["0020-1790"]}, DOI={10.1016/0020-1790(83)90044-6}, abstractNote={Cotton bollworm, Helicoverpa armigera (Hübner) (Lepidoptera: Noctuidae), is a polyphagous lepidopteran pest distributed worldwide with a broad spectrum of host plants. However, the mechanism of H. armigera adaptation to various insecticides and defensive allelochemicals in its host plants is not fully understood. Therefore, this study examined the influence of consumption of plant allelochemicals on larval tolerance to methomyl and chlorpyrifos insecticides in H. armigera and its possible mechanism. Twelve plant allelochemicals were screened to evaluate their effects on larval sensitivity to methomyl. Of which flavone, coumarin, DIMBOA (2,4-Dihydroxy-7-methoxy-1,4-benzoxazin-3-one) and visnagin significantly reduced larval sensitivity to methomyl. Application of cytochrome P450 inhibitor piperonyl butoxide (PBO) significantly increased the mortality of methomyl-treated larvae. In contrast, PBO addition significantly decreased the mortality of chlorpyrifos-treated larvae. Moreover, allelochemical consumption enhanced the activities of glutathione S-transferase, carboxylesterase, cytochrome P450 and acetylcholinesterase in the midgut and fat body. The qRT-PCR analysis confirms that P450 genes, CYP6B2, CYP6B6 and CYP6B7 were induced by the four allelochemicals in the midguts and the fat bodies. In conclusion, the generalist H. armigera can take benefit of plant allelochemicals from its host plants to elaborate its defense against insecticides.}, number={3}, journal={INSECT BIOCHEMISTRY}, author={HODGSON, E}, year={1983}, pages={237–246} }
 @article{hodgson_ligon_rock_1977, title={SUBSTITUTION OF CHOLINE BY RELATED COMPOUNDS IN DIET OF ARGYROTAENIA-VELUTINANA AND HELIOTHIS-VIRESCENS}, volume={23}, ISSN={["0022-1910"]}, DOI={10.1016/0022-1910(77)90002-6}, abstractNote={Abstract Argyrotaenia velutinana, the red-banded leaf roller, and Heliothis virescens, the tobacco budworm, both require choline for growth and development when reared on semisynthetic diets. The optimum level for A. velutinana is 50 mg 100 g of diet whereas that for H. virescens exceeds 100 mg 100 g of diet. No choline analog tested can adequately replace choline in the diet. One compound, dimethylethylcholine, will permit some adut emergence but development is slower and mortality is greater than on the corresponding diet containing choline. This is in sharp contrast to a number of Diptera in which mary choline analogs can not only replace choline in the diet but are also incorporated into phospholipids analogous to phosphatidylcholine. In A. velutinana, dimethylisopropylcholine and β-methylcholine, although inadequate as choline replacements, can spare the dietary choline requirement, Isopropylethanolamine is a growth inhibitor for A. velutinana but not for H. virescens.}, number={7}, journal={JOURNAL OF INSECT PHYSIOLOGY}, author={HODGSON, E and LIGON, BG and ROCK, GC}, year={1977}, pages={801–804} }
 @article{hodgson_tate_kulkarni_plapp_1974, title={MICROSOMAL CYTOCHROME-P-450 - CHARACTERIZATION AND POSSIBLE ROLE IN INSECTICIDE RESISTANCE IN MUSCA-DOMESTICA}, volume={22}, ISSN={["0021-8561"]}, DOI={10.1021/jf60193a027}, abstractNote={ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTMicrosomal cytochrome P-450. Characterization and possible role in insecticide resistance in Musca domesticaErnest. Hodgson, Lawrence G. Tate, Arun P. Kulkarni, and Frederick W. PlappCite this: J. Agric. Food Chem. 1974, 22, 3, 360–366Publication Date (Print):May 1, 1974Publication History Published online1 May 2002Published inissue 1 May 1974https://doi.org/10.1021/jf60193a027RIGHTS & PERMISSIONSArticle Views38Altmetric-Citations42LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (890 KB) Get e-Alerts Get e-Alerts}, number={3}, journal={JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY}, author={HODGSON, E and TATE, LG and KULKARNI, AP and PLAPP, FW}, year={1974}, pages={360–366} }