Suppression of the constitutive, male-specific rat hepatic cytochrome P-450 2c and its mRNA by 3,4,5,3',4',5'-hexachlorobiphenyl and 3-methylcholanthrene.
Rat liver cytochrome P-450 2c (P-450 2c) is a constitutive, male-specific enzyme that oxidatively metabolizes both steroid hormones and liphophilic foreign compounds. Exposure of adult male rats to certain xenobiotics can lead to a decrease in the expression of hepatic P-450 2c. The present studies were undertaken to examine the mechanism of this decrease. Treatment of adult male rats with 3-methylcholanthrene (3-MC) or 3,4,5,3',4',5'-hexachlorobiphenyl (HCB) (two compounds known to induce P-450c and P-450d as a consequence of their interaction with the aromatic hydrocarbon receptor) decreased hepatic content of P-450 2c and its associated steroid hormone 2 alpha- and 16 alpha-hydroxylase activities. Moreover, the present studies demonstrate that decreases in hepatic content of P-450 2c mRNA (determined by electrophoretic analysis of immunoprecipitated translational products) fully account for the effects of 3-MC and HCB on P-450 2c. HCB (50 mg/kg) produced the most striking decrease in P-450 2c and its mRNA, virtually eliminating their expression in hepatic tissue. The time course and dose-response for the decrease in P-450 2c and its mRNA differed markedly from that for induction of P-450c, indicating that the effects of HCB on the two proteins may involve different mechanisms. Additional experiments demonstrated that the sex difference in hepatic expression of P-450 2c is the result of a greater than 5-fold higher content of P-450 2c mRNA in male as compared to female rats. HCB decreased serum testosterone levels by greater than 98% at 5 days in adult male rats. However, the decrease in P-450 2c and serum testosterone levels was not accompanied by an increase in serum estradiol levels or induction of the female-specific enzyme P-450 2d. The present findings clearly establish that the decrease in P-450 2c produced by administration of HCB and 3-MC is the result of a decrease in the hepatic content of P-450 2c mRNA. These xenobiotics may decrease transcription of the mRNA for P-450 2c as a consequence of binding to the aromatic hydrocarbon receptor, or, alternatively, may interfere with the hormonal regulation of the mRNA for this male-specific P-450 enzyme.
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004794:Enzyme Repression; D007118:Immunoassay; D008099:Liver / Q000032:analysis; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000201:enzymology; D010634:Phenobarbital / Q000494:pharmacology; D011078:Polychlorinated Biphenyls / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects*; D051381:Rats; D011919:Rats, Inbred Strains; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000378:metabolism; D013739:Testosterone / Q000097:blood; D013997:Time Factors
D012333:RNA, Messenger; D013739:Testosterone; D008748:Methylcholanthrene; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; D013250:Steroid Hydroxylases; D039181:Steroid 16-alpha-Hydroxylase; C027309:3,4,5,3',4',5'-hexachlorobiphenyl; D010634:Phenobarbital