Two novel CYP2D6*10 haplotypes as possible causes of a poor metabolic phenotype in Japanese.
During the course of sequencing for the CYP2D6 gene, we found a novel single nucleotide polymorphism of g.3318G>A (E383K) associated with CYP2D6*10, termed as CYP2D6*72. We also found a g.1611T>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 V(max)/K(m) 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 V(max)/K(m) 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.
Matsunaga
Masayuki
M
Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan. m_matsunaga@research.otsuka.co.jp
Yamazaki
Hiroshi
H
Kiyotani
Kazuma
K
Iwano
Shunsuke
S
Saruwatari
Jyunji
J
Nakagawa
Kazuko
K
Soyama
Akiko
A
Ozawa
Shogo
S
Sawada
Jun-Ichi
J
Kashiyama
Eiji
E
Kinoshita
Moritoshi
M
Kamataki
Tetsuya
T
D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D003915:Dextromethorphan / Q000493:pharmacokinetics; D006239:Haplotypes; D006801:Humans; D007564:Japan; D008862:Microsomes, Liver / Q000201:enzymology; D010641:Phenotype
D003915:Dextromethorphan; D019389:Cytochrome P-450 CYP2D6