TY - JOUR T1 - Two Novel <em>CYP2D6*10</em> Haplotypes As Possible Causes of a Poor Metabolic Phenotype in Japanese JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 699 LP - 701 DO - 10.1124/dmd.108.026096 VL - 37 IS - 4 AU - Masayuki Matsunaga AU - Hiroshi Yamazaki AU - Kazuma Kiyotani AU - Shunsuke Iwano AU - Jyunji Saruwatari AU - Kazuko Nakagawa AU - Akiko Soyama AU - Shogo Ozawa AU - Jun-Ichi Sawada AU - Eiji Kashiyama AU - Moritoshi Kinoshita AU - Tetsuya Kamataki Y1 - 2009/04/01 UR - http://dmd.aspetjournals.org/content/37/4/699.abstract N2 - During the course of sequencing for the CYP2D6 gene, we found a novel single nucleotide polymorphism of g.3318G&gt;A (E383K) associated with CYP2D6*10, termed as CYP2D6*72. We also found a g.1611T&gt;A (F120I) in the CYP2D6*49, which was previously identified as a CYP2D6*10-associated allele in an independent Japanese population. To clarify the effects of these novel CYP2D6*10 haplotypes on the functions of CYP2D6, kinetic analysis for dextromethorphan O-demethylation was performed using the Escherichia coli expression system and human liver microsomes. The Vmax/Km values for dextromethorphan O-demethylation catalyzed by recombinant CYP2D6 forms encoded by CYP2D6*10, CYP2D6*49, and CYP2D6*72 were 3.0, 0.5, and 1.3%, respectively, compared with that catalyzed by CYP2D6.1. Liver microsomes from a human subject genotyped as CYP2D6*10/*49 also showed a reduced dextromethorphan O-demethylase activity. CYP2D6.49 formed a 7-hydroxydextromethorphan, with a roughly similar Vmax/Km value to that of O-demethylation. These results suggest that these two CYP2D6*10 haplotypes are possible causes of interindividual variation in the activities and the substrate specificity of CYP2D6. The American Society for Pharmacology and Experimental Therapeutics ER -