@article{casabar_das_dekrey_gardiner_cao_rose_wallace_2010, title={Endosulfan induces CYP2B6 and CYP3A4 by activating the pregnane X receptor}, volume={245}, number={3}, journal={Toxicology and Applied Pharmacology}, author={Casabar, R. C. T. and Das, P. C. and DeKrey, G. K. and Gardiner, C. S. and Cao, Y. and Rose, R. L. and Wallace, A. D.}, year={2010}, pages={335–343} }
 @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{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} }
 @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{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{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{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{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{karoly_rose_2001, title={Sequencing, expression, and characterization of cDNA expressed flavin-containing monooxygenase 2 from mouse}, volume={15}, ISSN={["1099-0461"]}, DOI={10.1002/jbt.10009}, abstractNote={Abstract}, number={6}, journal={JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY}, author={Karoly, ED and Rose, RL}, year={2001}, pages={300–308} }
 @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{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{maynard_brumback_itterly_capps_rose_1999, title={Metabolism of [C-14]prometryn in rats}, volume={47}, ISSN={["0021-8561"]}, DOI={10.1021/jf981363+}, abstractNote={[14C]Prometryn, 2,4-bis(isopropylamino)-6-(methylthio)-s-triazine, was orally administered to male and female rats at approximately 0.5 and 500 mg/kg; daily urine and feces were collected. After 3 or 7 days rats were sacrificed, and blood and selected tissues were isolated. The urine and feces extracts were characterized for metabolite similarity as well as for metabolite identification. Over 30 metabolites were observed, and of these, 28 were identified mostly by mass spectrometry and/or cochromatography with available reference standards. The metabolism of prometryn was shown to occur by N-demethylation, S-oxidation, S−S dimerization, OH substitution for NH2 and SCH3, and conjugation with glutathione or glucuronic acid. Rat liver microsomal incubations of prometryn were conducted and compared to the in vivo metabolism. Both in vivo and in vitro phase I metabolisms of prometryn were similar, with S-oxidation and N-dealkylation predominating. The involvement of cytochrome P-450 and flavin-containing monoo...}, number={9}, journal={JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY}, author={Maynard, MS and Brumback, D and Itterly, W and Capps, T and Rose, R}, year={1999}, month={Sep}, pages={3858–3865} }
 @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{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} }
 @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{rose_barbhaiya_roe_rock_hodgson_1995, title={CYTOCHROME P450-ASSOCIATED INSECTICIDE RESISTANCE AND THE DEVELOPMENT OF BIOCHEMICAL DIAGNOSTIC ASSAYS IN HELIOTHIS-VIRESCENS}, volume={51}, ISSN={["0048-3575"]}, DOI={10.1006/pest.1995.1018}, abstractNote={Abstract The metabolic enzymes of a multiresistant (i.e., carbamate, organophosphate, pyrethroid) population of tobacco budworm, Heliothis virescens (F.), were compared with those of a susceptible population. The resistant Hebert population, collected from areas where control failures with cypermethrin and thiodicarb had been reported, was selected in the laboratory with thiodicarb for seven generations. Resistance ratios as determined by topical bioassays were 91- and >150-fold to cypermethrin and thiodicarb, respectively. Resistance-associated increases in metabolism were found in fifth instar larvae for monooxygenases, carboxylester hydrolases, and glutathione transferases. Cytochrome P450 content was elevated in microsomes from gut (3.7-fold), fat body (4.4-fold), and carcass (4-fold). Monooxygenase activity varied substantially among the four substrates and three tissue sources examined. For three monooxygenase substrates ( p -nitroanisole, benzo( a )pyrene, and benzphetamine) increases in metabolism varied from 3- to 33-fold. The greatest increases in metabolism were observed with methoxyresorufin, in which increases were observed in all three tissues (23-, 29-, and 58-fold in fat body, midgut, and carcass microsomes, respectively). Significant increases ranging from 3- to 5-fold were observed for two esterase substrates, while smaller differences of up to 2-fold were observed for a glutathione transferase substrate. The high metabolic activity of the resistant population suggested that homogenates of individual larvae might be used in resistance monitoring. The development of a monooxygenase-based microtiter plate assay using p -nitroanisole as substrate clearly discriminates between resistant and susceptible individuals in the third instar, suggesting that biochemical resistance monitoring can be carried out with field-collected individuals. The esterase substrate p -nitrophenyl acetate also may be a useful tool for resistance monitoring.}, number={3}, journal={PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY}, author={ROSE, RL and BARBHAIYA, L and ROE, RM and ROCK, GC and HODGSON, E}, year={1995}, month={Mar}, pages={178–191} }
 @article{rose_gould_levi_hodgson_1991, title={DIFFERENCES IN CYTOCHROME-P450 ACTIVITIES IN TOBACCO BUDWORM LARVAE AS INFLUENCED BY RESISTANCE TO HOST PLANT ALLELOCHEMICALS AND INDUCTION}, volume={99}, ISSN={["0305-0491"]}, DOI={10.1016/0305-0491(91)90334-A}, abstractNote={1. Nicotine and 2-tridecanone resistant strains of the tobacco budworm, Heliothis virescens (F), had elevated cytochrome P450 content and significant increases in metabolism of five of six monooxygenase substrates relative to two susceptible strains. 2. Resistance to quercetin did not result in an increase in cytochrome P450 content; however, significant increases in metabolism were observed for two monooxygenase substrates. 3. P450 content was significantly induced by nicotine and 2-tridecanone, but not by quercetin. 4. Patterns of substrate oxidations varied between strains and inducing agents, suggesting that different isozymes of P450 are associated with resistance and induction.}, number={3}, journal={COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY B-BIOCHEMISTRY & MOLECULAR BIOLOGY}, author={ROSE, RL and GOULD, F and LEVI, PE and HODGSON, E}, year={1991}, pages={535–540} }