Limited effects of frequent CYP2D6*36-*10 tandem duplication allele on in vivo dextromethorphan metabolism in a Japanese population.
OBJECTIVE
although CYP2D6*36 was thought to be one of the alleles causing the poor metabolizer phenotype, several in vitro studies clarified that the enzyme produced by CYP2D6*36 showed enzymatic activities. However, the effects of CYP2D6*36 in tandem with CYP2D6*10 on the in vivo CYP2D6 activity have been unclear. In this study, we investigated in vivo metabolic capacities of CYP2D6 among the subjects carrying different numbers of CYP2D6*36 in tandem with CYP2D6*10.


METHODS
we measured the metabolic ratio (MR) of dextromethorphan in 98 subjects. We determined the CYP2D6 genotype of these subjects, including allelic copy number of CYP2D6*10 and CYP2D6*36 by direct sequencing, TaqMan assay, and real-time Invader assay.


RESULTS
single copies of CYP2D6*10 and tandem duplication of CYP2D6*36-*10 alleles were found at frequencies of 8.7 and 32.7%, respectively. Median dextromethorphan MRs of the subjects carrying CYP2D6*10 and CYP2D6*36-*10 were not significantly different (P = 0.24).


CONCLUSIONS
CYP2D6*36 in tandem with CYP2D6*10 plays a minor role in interindividual variation of dextromethorphan metabolism in vivo.
Kiyotani
Kazuma
K
Laboratory for Pharmacogenetics, RIKEN Center for Medicine, Yokohama 230-0045, Japan.
Shimizu
Makiko
M
Kumai
Toshio
T
Kamataki
Tetsuya
T
Kobayashi
Shinichi
S
Yamazaki
Hiroshi
H
D000328:Adult; D044466:Asian People / Q000235:genetics*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism*; D003915:Dextromethorphan / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007564:Japan; D008297:Male; D010641:Phenotype; D012016:Reference Values
D018691:Excitatory Amino Acid Antagonists; D003915:Dextromethorphan; D019389:Cytochrome P-450 CYP2D6