Evidence for a new variant CYP2D6 allele CYP2D6J in a Japanese population associated with lower in vivo rates of sparteine metabolism.
A group of Japanese subjects were phenotyped for CYP2D6 activity by administration of sparteine and determination of urine metabolic ratios (MR). The CYP2D6 alleles from two subjects having a high MR, characteristic of slower rates of sparteine metabolism, were cloned in lambda EMBL3 and subjected to sequence analysis. One individual possessed a CYP2D6B allele, typically found in Caucasians, that is inactive due to an altered 3' splice recognition site and other potentially disruptive mutations. The second allele from this individual was identical to the wild type normal Caucasian CYP2D6 allele except for C188T and G4268C base differences in exons 1 and 9, respectively, that result in P34S and S486T amino acid substitutions. This allele was designated CYP2D6J. The second individual possessed two CYP2D6J alleles. PCR assays were performed to detect this allele and other alleles from a group of subjects exhibiting low rates of sparteine metabolism, i.e. with MRs > 1.5. Eleven CYP2D6J alleles were detected in 14 subjects exhibiting low rates of metabolism and including four individuals who were homozygous for this variant and had very low rates of sparteine metabolism (MRs > 2.5). In contrast, only two CYP2D6J alleles were found in 14 subjects having MRs of < 1.0. These data suggest that CYP2D6J encodes an enzyme having lower rates of sparteine metabolism.
Yokota
H
H
Laboratory of Molecular Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Tamura
S
S
Furuya
H
H
Kimura
S
S
Watanabe
M
M
Kanazawa
I
I
Kondo
I
I
Gonzalez
F J
FJ
D000483:Alleles; D044466:Asian People / Q000235:genetics; D001483:Base Sequence; D019389:Cytochrome P-450 CYP2D6; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D005091:Exons; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007564:Japan; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D013034:Sparteine / Q000378:metabolism
D017931:DNA Primers; D013034:Sparteine; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019389:Cytochrome P-450 CYP2D6