@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{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{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} }
 @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} }
 @article{levi_rose_adams_hodgson_1992, title={INDUCTION OF CYTOCHROME-P450-4A1 IN MOUSE-LIVER BY THE HERBICIDE SYNERGIST TRIDIPHANE}, volume={44}, ISSN={["0048-3575"]}, DOI={10.1016/0048-3575(92)90003-I}, abstractNote={The herbicide synergist tridiphane [2-(3,5-dichlorophenyl)-2-(2,2,2,-trichloroethyl) oxirane] was examined for its ability to induced cytochrome P450 in vivo. Male C57BL/6N mice were given tridiphane, 250 mg/kg ip, for 3 days. Liver weight and P450 content were increased after tridiphane treatment, and SDS-PAGE showed an increase in microsomal proteins in the 50–60 kDa range. No significant increases in enzymatic activities were observed with the substrates benzphetamine, p-nitroanisole, benzo[a]pyrene, or ethoxyresorufin. There was, however, a 10-fold elevation in microsomal hydroxylation of lauric acid, an activity specifically associated with induction of P450 4A1, Western blot analysis using an antibody specific for P450 4A1 showed a dramatic increase in P450 4A1.}, number={1}, journal={PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY}, author={LEVI, PE and ROSE, RL and ADAMS, NH and HODGSON, E}, year={1992}, month={Sep}, pages={9–14} }
 @article{levi_hollingworth_hodgson_1988, title={DIFFERENCES IN OXIDATIVE DEARYLATION AND DESULFURATION OF FENITROTHION BY CYTOCHROME-P-450 ISOZYMES AND IN THE SUBSEQUENT INHIBITION OF MONOOXYGENASE ACTIVITY}, volume={32}, ISSN={["0048-3575"]}, DOI={10.1016/0048-3575(88)90105-8}, abstractNote={The organophosphorus insecticide, fenitrothion (O,O-dimethyl O-(3-methyl-4-nitrophenyl) phosphorothioate), a substrate for the cytochrome P-450 (P-450) monooxygenase system, yields the corresponding phosphate triester (fenitroxon) by oxidative desulfuration (an activation reaction) and 4-nitro-m-cresol by oxidative dearylation (a detoxication reaction). Four constitutive P-450 isozymes and the major isozymes induced by phenobarbital (PB) and β-naphthoflavone (BNF) were incubated with [14C]fenitrothion in reconstituted monooxygenase systems. Both metabolites were formed with all isozymes, with the ratio of oxon to cresol being characteristic of the individual P-450s. Cytochrome P-450 B2 and P-450 PB formed the highest percentage of oxon, 75 and 82%, respectively; while P-450 A1, B3, and BNF produced 55 to 60% oxon. By contrast, P-450 A2 formed the least amount of oxon, 38%, with 62% of the product being 4-nitro-m-cresol. Microsomes prepared from mice treated in vivo with organophosphates, such as fenitrothion, have reduced levels of cytochrome P-450 and associated monooxygenase activities. Presumably, this reduction is due to destruction of P-450 caused by the release of active sulfur occurring during desulfuration. To determine if some P-450 isozymes were preferentially inhibited by fenitrothion, purified isozymes were incubated with fenitrothion and subsequent p-nitroanisole O-demethylase activity was determined. Inhibition studies using purified P-450 isozymes indicated close to 100% inhibition by fenitrothion of P-450 PB, while enzyme activity of P-450 BNF and P-450 A2 was inhibited 85–90%.}, number={3}, journal={PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY}, author={LEVI, PE and HOLLINGWORTH, RM and HODGSON, E}, year={1988}, month={Nov}, pages={224–231} }