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'-hydroxylation by CYP2C19 with Ki values of 5.3 and 37 microM, respectively. Furthermore, nonylphenol exhibited a competitive inhibition of progesterone 17alpha-hydroxylase activity by CYP17 with Ki value of 62 microM. These results suggest that nonylphenol inhibits human hepatic CYPs, especially CYP2C9 and CYP2C19, and steroidogenic CYP17 activities.
Niwa
Toshiro
T
Division of Natural Science, Osaka Kyoiku University, Kashiwara, Japan.
Maekawa
Yumi
Y
Fujimoto
Megumi
M
Kishimoto
Kae
K
Yabusaki
Yoshiyasu
Y
Ishibashi
Fumihide
F
Katagiri
Masanao
M
D000632:Aminopyrine / Q000378:metabolism; D000633:Aminopyrine N-Demethylase / Q000037:antagonists & inhibitors; D001189:Aryl Hydrocarbon Hydroxylases; D019388:Cytochrome P-450 CYP1A2; D065731:Cytochrome P-450 CYP2C19; D065727:Cytochrome P-450 CYP2C8; D065729:Cytochrome P-450 CYP2C9; D065607:Cytochrome P-450 Enzyme Inhibitors; D004008:Diclofenac / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008099:Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors; D010636:Phenols / Q000494:pharmacology*; D039181:Steroid 16-alpha-Hydroxylase; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors*; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors
D065607:Cytochrome P-450 Enzyme Inhibitors; D010636:Phenols; D000632:Aminopyrine; D004008:Diclofenac; C025256:nonylphenol; D006899:Mixed Function Oxygenases; D013250:Steroid Hydroxylases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C504573:CYP1A2 protein, human; C045793:CYP2C19 protein, human; C450259:CYP2C8 protein, human; D019388:Cytochrome P-450 CYP1A2; D065731:Cytochrome P-450 CYP2C19; D065727:Cytochrome P-450 CYP2C8; D039181:Steroid 16-alpha-Hydroxylase; D013254:Steroid 17-alpha-Hydroxylase; D000633:Aminopyrine N-Demethylase