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

Several environmental chemicals are disruptive to the reproductive and endo crine systems of many species, including humans. Mechanisms for endocrine d isruption are presently under scrutiny. Xenobiotic inducible mammalian cyto chrome P450 (CYP) enzymes metabolize a variety of substrates including envi ronmental chemicals, pesticides, and drugs. The metabolism, and thus the ef fect, of endogenous chemicals including steroid hormones. vitamins, etc. th at are transformed by CYP enzymes can be influenced by environmental exposu re to CYP-inducing chemicals. This study demonstrated that structurally div erse environmental chemicals including mirex, 2,2-Bis(p-chlorophenyl)-1,1-d ichloroethylene (DDE), vinclozolin, and flutamide are capable of inducing s everal mouse liver CYP isozymes. As demonstrated by Western blotting, mirex induced CYP1A2, 2B10, 2E1, and 3A and vinclozolin induced 1A2 and 2B10. Th e only isoforms significantly induced by DDE and flutamide were 3A and 1A2, respectively. Since some of these isoforms are known to be involved in met abolism of endogenous hormones, we also studied the effects of these CYP in ducers on testosterone metabolism and seminal vesicle weights. Mirex and DD E treatments had profound effects on the metabolism of testosterone, result ing in 2.5- to 3-fold more hydroxylated products than controls. Lesser, but significant, increases in specific metabolites of testosterone were also o bserved following treatment with vinclozolin and flutamide. Seminal vesicle weights were lower for all treatment groups except DDE. Results of this st udy demonstrate that, due to their CYP-inducing potential, these chemicals may significantly impact testosterone metabolism and this may be a contribu ting factor in their antiandrogenic effects. (C) 2001 Academic Press.