title: A new CYP2D6 allele with a nine base insertion in exon 9 in a Japanese population associated with poor metabolizer phenotype.
abstract: The CYP2D6 gene of a Japanese sparteine poor metabolizer (PM, proband) showing a urinary sparteine metabolic ratio of 31.6 was analysed, and a heterozygous CYP2D6(D), a deletional type, was found by restriction fragment length polymorphism analysis with Xba I enzyme. The PM did not have any other previously described mutations in the CYP2D6 gene causing the loss of catalytic activity of the CYP2D6 enzyme. Thus, a possible new allele(s) responsible for the PM phenotype was analysed. The results indicated that the PM possessed a new 9-base insertion in exon 9, designated CYP2D6(J9). The CYP2D6(J9) and CYP2D6(D) alleles were clarified to be inherited from the mother [2D6(W)/2D6(J9)] and the father [2D6(W)/2D6(D)], respectively. The 9-base insertion caused a large increase in the apparent K(m) value for bufuralol 1'-hydroxylation as examined by expression of the enzyme protein in yeast. Four of 300 Japanese carried a heterozygous CYP2D6(J9) allele (0.7%, 4/600 chromosomes) as determined by a polymerase chain reaction analysis.
authors.affiliation: Division of Drug Metabolism, Faculty of Pharmaceutical Sciences, Hokkaido University, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yokoi
authors.forename: Y
authors.initials: Y
authors.lastname: Kosaka
authors.forename: M
authors.initials: M
authors.lastname: Chida
authors.forename: K
authors.initials: K
authors.lastname: Chiba
authors.forename: H
authors.initials: H
authors.lastname: Nakamura
authors.forename: T
authors.initials: T
authors.lastname: Ishizaki
authors.forename: M
authors.initials: M
authors.lastname: Kinoshita
authors.forename: K
authors.initials: K
authors.lastname: Sato
authors.forename: F J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: T
authors.initials: T
authors.lastname: Kamataki
mesh_terms: D000483:Alleles; D044466:Asian People / Q000235:genetics*; D015139:Blotting, Southern; D019389:Cytochrome P-450 CYP2D6 / Q000096:biosynthesis / Q000235:genetics*; D003577:Cytochrome P-450 Enzyme System; D005091:Exons / Q000235:genetics; D005787:Gene Frequency; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D007564:Japan; D006899:Mixed Function Oxygenases; D016254:Mutagenesis, Insertional; D009154:Mutation; D012150:Polymorphism, Restriction Fragment Length; D011994:Recombinant Proteins / Q000096:biosynthesis; D012441:Saccharomyces cerevisiae / Q000235:genetics; D017422:Sequence Analysis, DNA; D013034:Sparteine / Q000378:metabolism* / Q000652:urine
chemical_list: D011994:Recombinant Proteins; D013034:Sparteine; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019389:Cytochrome P-450 CYP2D6; C043872:bufuralol 1'-hydroxylase