TY - JOUR T1 - Role of CYP2C19 in Stereoselective Hydroxylation of Mephobarbital by Human Liver Microsomes JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 36 LP - 40 VL - 29 IS - 1 AU - Kaoru Kobayashi AU - Mari Kogo AU - Masayoshi Tani AU - Noriaki Shimada AU - Takashi Ishizaki AU - Satoshi Numazawa AU - Takemi Yoshida AU - Toshinori Yamamoto AU - Yukio Kuroiwa AU - Kan Chiba Y1 - 2001/01/01 UR - http://dmd.aspetjournals.org/content/29/1/36.abstract N2 - The 4-hydroxylation of mephobarbital enantiomers was investigated by using human liver microsomes from the extensive metabolizers (EM) and poor metabolizers of CYP2C19. The 4-hydroxylase activity ofR-mephobarbital in the EM microsomes was >10 times higher than that of S-mephobarbital. In the poor metabolizer microsomes, the 4-hydroxylase activity ofR-mephobarbital was much lower than that in the EM microsomes, and the ratio of 4-hydroxylase activity ofR-mephobarbital to that ofS-mephobarbital was also lower than that in the EM microsomes. Moreover, the 4-hydroxylase activity ofR-mephobarbital showed a high correlation (r = 0.985, p < 0.001) with the 4′-hydroxylase activity of S-mephenytoin in a panel of nine human liver microsomes. Anti-CYP2C antibody inhibitedR-mephobarbital 4-hydroxylase activity by 85% of the control activity. R-Mephobarbital competitively inhibited S-mephenytoin 4′-hydroxylase activity (Ki = 34 μM), whileS-mephenytoin inhibited R-mephobarbital 4-hydroxylase activity (Ki = 103 μM). Among the seven cDNA-expressed CYPs studied, only CYP2C19 catalyzedR-mephobarbital 4-hydroxylation. These findings suggest that the 4-hydroxylation of mephobarbital catalyzed by CYP2C19 is preferential for R-enantiomer in human liver microsomes. The American Society for Pharmacology and Experimental Therapeutics ER -