TY - JOUR T1 - Inhibition and Inactivation of Human Cytochrome P450 Isoforms by Phenethyl Isothiocyanate JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1110 LP - 1113 VL - 29 IS - 8 AU - Miki Nakajima AU - Ryoko Yoshida AU - Noriaki Shimada AU - Hiroshi Yamazaki AU - Tsuyoshi Yokoi Y1 - 2001/08/01 UR - http://dmd.aspetjournals.org/content/29/8/1110.abstract N2 - The inhibition and mechanism-based inactivation potencies of phenethyl isothiocyanate (PEITC) for human cytochrome P450 (CYP) activities were investigated using microsomes from baculovirus-infected insect cells expressing specific human CYP isoforms. PEITC competitively inhibited phenacetin O-deethylase activity catalyzed by CYP1A2 (Ki = 4.5 ± 1.0 μM) and coumarin 7-hydroxylase activity catalyzed by CYP2A6 (Ki = 18.2 ± 2.5 μM). Benzyloxyresorufin O-dealkylase activity catalyzed by CYP2B6 was most strongly and noncompetitively inhibited (Ki = 1.5 ± 0.0 μM). Paclitaxel 6α-hydroxylase activity catalyzed by CYP2C8 was not affected by PEITC up to 100 μM. PEITC noncompetitively inhibitedS-warfarin 7-hydroxylase activity catalyzed by CYP2C9 (Ki = 6.5 ± 0.9 μM),S-mephenytoin 4′-hydroxylase activity catalyzed by CYP2C19 (Ki = 12.0 ± 3.2 μM), bufuralol 1′-hydroxylase activity catalyzed by CYP2D6 (Ki = 28.4 ± 7.9 μM), and chlorzoxazone 6-hydroxylase activity catalyzed by CYP2E1 (Ki = 21.5 ± 3.4 μM). The inhibition for testosterone 6β-hydroxylase activity catalyzed by CYP3A4 was a mixed-type of competitive (Ki = 34.0 ± 6.5 μM) and noncompetitive (Ki = 63.8 ± 12.5 μM) inhibition. Furthermore, PEITC is a mechanism-based inactivator of human CYP2E1. The kinact value was 0.339 min−1 and Ki was 9.98 μM. Human CYP1A2, CYP2A6, CYP2B6, CYP2D6, and CYP3A4 were not inactivated. The present study directly proved that the chemopreventive effects of PEITC for nitrosamine-induced carcinogenesis are due to the inhibition of CYP by an in vitro study. The possibility that PEITC would affect the pharmacokinetics of clinically used drugs that are metabolized by these CYP isoforms was also suggested. The American Society for Pharmacology and Experimental Therapeutics ER -