Inhibition of Human Hepatic Cytochrome P450s and Steroidogenic CYP17 by Nonylphenol

Abstract

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 17α-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′-hydroxylation by CYP2C19 with K_i values of 5.3 and 37 µM, respectively. Furthermore, nonylphenol exhibited a competitive inhibition of progesterone 17α-hydroxylase activity by CYP17 with K_i value of 62 µM. These results suggest that nonylphenol inhibits human hepatic CYPs, especially CYP2C9 and CYP2C19, and steroidogenic CYP17 activities.