Inhibition of human hepatic cytochrome p450s and steroidogenic CYP17 by nonylphenol

Effect of nonylphenol on aminopyrine N-demethylase activity, a typical drug-metabolizing enzyme activity, by ten kinds of human hepatic cytochrome P450s (CYP) and on progesterone 17alpha-hydroxylase activity by steroidogenic CYP17 was investigated. When determined at 2 mm substrate concentration, nonylphenol (1 mm) most efficiently inhibited aminopyrine N-demethylation by CYP2C9 and CYP2C19, by 61% and 59%, respectively, followed by CYP2D6, CYP1A2, CYP2C18 and CYP2C8 (46-51%), whereas inhibition of the activities by other CYPs was less than 27%. Additionally, nonylphenol competitively inhibited diclofenac 4'-hydroxylation by CYP2C9 and S-mephenytoin 4'-hydroxyIation by CYP2C19 with K-i values of 5.3 and 37 muM, respectively. Furthermore, nonylphenol exhibited a competitive inhibition of progesterone 17alpha-hydroxylase activity by CYP17 with K-i value of 62 muM. These results suggest that nonylphenol inhibits human hepatic CYPs, especially CYP2C9 and CYP2C19, and steroidogenic CYP17 activities.