TY - JOUR T1 - CYP2A6 IS A PRINCIPAL ENZYME INVOLVED IN HYDROXYLATION OF 1,7-DIMETHYLXANTHINE, A MAIN CAFFEINE METABOLITE, IN HUMANS JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1361 LP - 1366 DO - 10.1124/dmd.105.004796 VL - 33 IS - 9 AU - Miyuki Kimura AU - Hiroshi Yamazaki AU - Masaki Fujieda AU - Kazuma Kiyotani AU - Goro Honda AU - Junji Saruwatari AU - Kazuko Nakagawa AU - Takashi Ishizaki AU - Tetsuya Kamataki Y1 - 2005/09/01 UR - http://dmd.aspetjournals.org/content/33/9/1361.abstract N2 - In a caffeine test previously performed with healthy Japanese volunteers, we found that the CYP1A2 index defined as urinary {5-acetylamino-6-amine-3-methyluracil (AAMU) + 1-methylxanthine (1X) + 1-methyluric acid (1U)}/1,7-dimethyluric acid (17U) was affected by the whole deleted allele of CYP2A6 (CYP2A6*4). Since the high value of the CYP1A2 index could be caused by a low urinary concentration of 17U, we postulated that CYP2A6 was responsible for the 1,7-dimethylxanthine (17X) metabolism to generate 17U (17X 8-hydroxylation). Thus, the role of CYP2A6 in the 17X 8-hydroxylation was fully examined in the present study. Among 10 isoforms of human cytochrome P450 (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, or CYP3A5) expressed in Escherichia coli cells, CYP2A6 and CYP1A2 showed high catalytic activities for the 17X 8-hydroxylation. The 17X 8-hydroxylase activities significantly associated with coumarin 7-hydroxylase activities (r = 0.67, p < 0.01) in liver microsomes from 17 individuals, but not with ethoxyresorufin O-deethylase activities. Tranylcypromine, an inhibitor of CYP2A6, reduced the 17X 8-hydroxylase activities of human liver microsomes. The 17X 8-hydroxylase activities of CYP2A6.7, CYP2A6.10, and CYP2A6.11 expressed in E. coli cells were 12, 13, and 22% of that of CYP2A6.1, respectively. The 17X 8-hydroxylase activities were found to be low in liver microsomes from individuals possessing the deletion or mutations in the CYP2A6 gene. Based on these data, we conclude that CYP2A6 is a main 17X 8-hydroxylase and that the catalytic activities for the 17X 8-hydroxylation are reduced by the genetic polymorphisms of the CYP2A6 gene. The American Society for Pharmacology and Experimental Therapeutics ER -