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.