@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{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{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{lee_usmani_chanas_ghanayem_t._e._h. w._goldstein_2003, title={Genetic findings and functional studies of human CYP3A5 single nucleotide polymorphisms in different ethnic groups}, volume={13}, DOI={10.1097/01.fpc.0000054117.14659.ac}, number={8}, journal={Pharmacogenetics}, author={Lee, S. J. and Usmani, K. A. and Chanas, B. and Ghanayem, B. and T., Hodgson and E., Mohrenweiser and H. W. and Goldstein, J. A.}, year={2003}, pages={461–472} }
 @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{usmani_knowles_2001, title={DEF sensitive esterases in homogenates of larval and adult Helicoverpa zea, Spodoptera frugiperda, and Agrotis ipsilon (Lepidoptera : Noctuidae)}, volume={94}, ISSN={["0022-0493"]}, DOI={10.1603/0022-0493-94.4.884}, abstractNote={Abstract Homogenates of Helicoverpa zea (Boddie), Agrotis ipsilon (Hufnagle), and Spodoptera frugiperda (J. E. Smith) third instars and adults contained S,S,S-tri-n-butyl phosphorotrithioate (DEF)-sensitive enzymes that hydrolyzed trans-cypermethrin and two known esterase substrates, α-naphthyl acetate and β-naphthyl acetate. Except for H. zea with α-naphthyl acetate, larval preparations were more active than those of adults, and no marked sex differences were apparent. The hydrolysis of trans-cypermethrin in noctuid preparations were inhibited by DEF, with pI50 values ranging from 4.5 to 6.7. DEF was a potent inhibitor of the degradation of general carboxylesterase substrates α-naphthyl acetate and β-naphthyl acetate in some cases. Electrophoretic studies confirmed the presence in noctuid gut homogenates of one or more DEF-sensitive esterases that hydrolyzed α-naphthyl acetate and β-naphthyl acetate and that were completely inhibited by dichlorvos.}, number={4}, journal={JOURNAL OF ECONOMIC ENTOMOLOGY}, author={Usmani, KA and Knowles, CO}, year={2001}, month={Aug}, pages={884–891} }
 @article{usmani_knowles_2001, title={Pharmacokinetic mechanisms associated with synergism by DEF of cypermethrin toxicity in larval and adult Helicoverpa zea, Spodoptera frugiperda, and Agrotis ipsilon (Lepidoptera : Noctuidae)}, volume={94}, ISSN={["0022-0493"]}, DOI={10.1603/0022-0493-94.4.874}, abstractNote={Abstract Penetration, metabolism, and excretion of radiocarbon were observed after topical treatment of Helicoverpa zea (Boddie), Spodoptera frugiperda (J. E. Smith), and Agrotis ipsilon (Hufnagle) larvae and adults with cypermethrin-14C. These pharmacokinetic events usually were higher with trans-cypermethrin-14C than with cis-cypermethrin-14C. They also were generally higher with H. zea and S. frugiperda than with A. ipsilon, and they were higher in larvae than in adults. No marked sex differences in the degradation of trans-cypermethrin were apparent. Pretreatment of H. zea, S. frugiperda, and A. ipsilon larvae and adults with S,S,S-tri-n-butyl phosphorotrithioate (DEF) 30 min before application of cypermethrin resulted in a perturbation of trans-cypermethrin pharmacokinetics manifested primarily by a lower rate of pyrethroid metabolism as compared with that in the absence of DEF. Appreciably higher internal levels of the toxic parent pyrethroid were often observed in the presence of DEF than in the absence of DEF in most cases. Suppression of cypermethrin penetration and elimination also was usually detected. Inhibition by DEF of the enzymatic degradation of cypermethrin may account for the synergy observed between these two compounds.}, number={4}, journal={JOURNAL OF ECONOMIC ENTOMOLOGY}, author={Usmani, KA and Knowles, CO}, year={2001}, month={Aug}, pages={874–883} }
 @article{shearer_usmani_2001, title={Sex-related response to organophosphorus and carbamate insecticides in adult Oriental fruit moth, Grapholita molesta}, volume={57}, ISSN={["1526-498X"]}, DOI={10.1002/ps.367}, abstractNote={Abstract}, number={9}, journal={PEST MANAGEMENT SCIENCE}, author={Shearer, PW and Usmani, KA}, year={2001}, month={Sep}, pages={822–826} }
 @article{usmani_shearer_2001, title={Susceptibility of male Oriental fruit moth (Lepidoptera : Tortricidae) populations from New Jersey apple orchards to azinphosmethyl}, volume={94}, ISSN={["0022-0493"]}, DOI={10.1603/0022-0493-94.1.233}, abstractNote={Abstract Toxicological responses to azinphosmethyl of male Oriental fruit moth, Grapholita molesta (Busck), from five commercial orchards in which control failures had occurred were examined for azinphosmethyl resistance and for potential resistance mechanisms by using topical pheromone trap bioassay and compared with a reference population that had no history of control failure and had received little selection pressure. The 1998 field survey indicated moderate level of resistance to azinphosmethyl (2.7–4.1-fold); slopes of regressions lines (2.47–2.76) indicate genetically heterogeneous populations. An approximate twofold decline was observed between the fourth flight of 1998 and the first flight of 1999, suggesting the presence of unstable resistance in moths collected from these study sites. The 1999 field surveys indicated lower levels of tolerance to azinphosmethyl. The resistance ratios ranged from 1.17 to 1.86 during the first flight of 1999 and 1.24–2.64 during the fourth flight of 1999. Steep slopes of the concentration–response lines during 1999 season indicated the presence of genetically homogeneous populations with some exceptions. A 1.5–2.0-fold increase was observed between the first and fourth flights of 1999, indicating that resistance can build up during the growing season. S,S,S,-tri-n-butyl phosphorotrithioate (DEF), but not piperonyl butoxide, significantly enhanced the toxicity of azinphosmethyl, suggesting that enhanced metabolism by esterases is involved in the tolerance of azinphosmethyl in moths collected from these study sties.}, number={1}, journal={JOURNAL OF ECONOMIC ENTOMOLOGY}, author={Usmani, KA and Shearer, PW}, year={2001}, month={Feb}, pages={233–239} }
 @article{usmani_knowles_2001, title={Toxicity of pyrethroids and effect of synergists to larval and adult Helicoverpa zea, Spodoptera frugiperda, and Agrotis ipsilon (Lepidoptera : Noctuidae)}, volume={94}, ISSN={["0022-0493"]}, DOI={10.1603/0022-0493-94.4.868}, abstractNote={Abstract Based on 48 h LD50 estimates from topical bioassays, cypermethrin was more toxic than permethrin to Helicoverpa zea (Boddie) larvae and adults; however, the two pyrethroids did not differ significantly in their relative toxicities to Spodoptera frugiperda (J. E. Smith) and Agrotis ipsilon (Hufnagle). Larvae of each species generally were more susceptible to cypermethrin and permethrin than respective adults. The only exception to this generalization occurred with H. zea where slight overlap of the 95% confidence intervals with larvae and adult males was observed with cypermethrin. Respective males and females of the three species usually did not differ significantly in their susceptibility to either cypermethrin or to permethrin; however, with A. ipsilon, females were more susceptible to permethrin than to cypermethrin. Several instances of greater than additive toxicity were noted when insects were treated with piperonyl butoxide, S,S,S-tri-n-butyl phosphorotrithioate (DEF), or amitraz 30 min before cypermethrin. DEF exhibited the broadest spectrum of synergistic activity.}, number={4}, journal={JOURNAL OF ECONOMIC ENTOMOLOGY}, author={Usmani, KA and Knowles, CO}, year={2001}, month={Aug}, pages={868–873} }
 @article{usmani_shearer_2000, title={Azinphosmethyl resistance in populations of male Oriental fruit moth (Lepidoptera: Tortricidae) from New Jersey apple orchards}, volume={11}, ISBN={1061-7795}, number={1}, journal={Resistant Pest Management}, author={Usmani, K. A. and Shearer, P. W.}, year={2000}, pages={8} }
 @article{usmani_knowles_2000, title={Cypermethrin pharmacokinetics in laboratory and field strains of Helicoverpa zea (Lepidoptera: Noctuidae)}, volume={11}, ISBN={1061-7795}, number={1}, journal={Resistant Pest Management}, author={Usmani, K. A. and Knowles, C. O.}, year={2000}, pages={13} }