Induction of the hepatic CYP2B and CYP3A enzymes by the proestrogenic pesticide methoxychlor and by DDT in the rat. Effects on methoxychlor metabolism.
In earlier investigations, methoxychlor treatment did not elicit induction of hepatic P450 monooxygenases in rats, apparently due to the short half-life of methoxychlor in vivo. The current study demonstrates that multiple bidaily doses of methoxychlor to female rats produce a marked induction of the hepatic microsomal P450 2B1/2B2 and 3A proteins. There was no increase in CYP1A1 or CYP2E1 proteins, demonstrating selectivity of induction by methoxychlor. Similarly, treatment with DDT, a methoxychlor analog, increased CYP2B and 3A proteins but had no effect on CYP1A1 and 2E1. Methoxychlor moderately elevated the enzymatic activity corresponding to CYP2B and 3A catalysis. In immature rats, only the higher dose of methoxychlor (300 mg/kg), produced elevation of testosterone hydroxylation at the 16 alpha position (major product) that was statistically significant, indicative of increased catalysis by CYP2B1/2B2. Both the low (150 mg/kg) and high dose (300 mg/kg) of methoxychlor increased the 6 beta hydroxylation (major product) and 2 beta and 15 beta hydroxylation (minor products) of testosterone, indicative of increased catalysis by CYP3A. In mature female rats, both methoxychlor and DDT treatment elevated the 16 alpha and 6 beta hydroxylation and androstenedione formation. Additional indication of methoxychlor- and DDT-mediated induction of CYP2B enzymatic activity in mature and immature rats was evident from increased ring hydroxylation of methoxychlor, an activity attributed to CYP2B. These findings indicate that methoxychlor and DDT belong to the phenobarbital type of inducers and that exposure to methoxychlor can affect its own metabolism. The methoxychlor-mediated increase in CYP2B and 3A proteins was considerably larger than the increase in the corresponding enzymatic activities. The possible reasons for the lack of correlation between P450 levels and their enzymatic activities and the potential relevance of induction by methoxychlor to its metabolism and toxicity are discussed.
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Worcester Foundation for Experimental Biology, Shrewsbury, MA 01545, USA.
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D000818:Animals; D015153:Blotting, Western; D002855:Chromatography, Thin Layer; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D003634:DDT / Q000378:metabolism / Q000633:toxicity*; D004790:Enzyme Induction; D005260:Female; D006900:Hydroxylation; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008731:Methoxychlor / Q000378:metabolism / Q000633:toxicity*; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009251:NADPH-Ferrihemoprotein Reductase; D010088:Oxidoreductases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013739:Testosterone / Q000378:metabolism
D013739:Testosterone; D003577:Cytochrome P-450 Enzyme System; D003634:DDT; D010088:Oxidoreductases; D009251:NADPH-Ferrihemoprotein Reductase; D008731:Methoxychlor