Modulation of rat hepatic CYP3A by nonylphenol.
1. In in vitro assays, nonylphenol (NP) inhibited microsomal 5 alpha-reductase and steroid hydroxylase activities from the liver of dexamethasone-treated rats. The inhibition was specific in that 6 beta-hydroxylase was affected the most followed by 16 alpha-hydroxylase. The activity of 17 alpha-hydroxylase remained unchanged. 2. Enzyme kinetic analyses (Lineweaver Burke plots) using different NP concentrations with graded increases in the concentrations of the substrate, progesterone, showed that the inhibition was of a mixed competitive and non-competitive type. 3. In in vivo studies, treatment of rats with NP resulted in a dose dependent increase in the hepatic microsomal progesterone hydroxylase activity and CYP3A proteins as measured by Western blot analysis. 4. The mixed competitive and non-competitive nature of inhibition by NP on hepatic microsomal progesterone hydroxylase activity indirectly suggests that this compound may behave as a partial substrate of the CYP3A enzyme. More importantly, nonylphenol induces the expression of rat hepatic CYP3A which may then affect its own metabolism and that of other steroid substrates.
Lee
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Department of Pediatrics, Medical College of Wisconsin, Milwaukee 53226, USA.
Patra
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Struve
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D000367:Age Factors; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001667:Binding, Competitive; D015153:Blotting, Western; D042944:Cholestenone 5 alpha-Reductase; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D010088:Oxidoreductases / Q000187:drug effects / Q000378:metabolism; D010636:Phenols / Q000378:metabolism* / Q000494:pharmacology*; D011247:Pregnancy; D011374:Progesterone / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D039181:Steroid 16-alpha-Hydroxylase; D013254:Steroid 17-alpha-Hydroxylase / Q000187:drug effects / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000187:drug effects / Q000378:metabolism*; D013379:Substrate Specificity
D010636:Phenols; D011374:Progesterone; C025256:nonylphenol; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; D039181:Steroid 16-alpha-Hydroxylase; C025619:steroid 16-beta-hydroxylase; C022657:steroid hormone 6-beta-hydroxylase; D013254:Steroid 17-alpha-Hydroxylase; D042944:Cholestenone 5 alpha-Reductase