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A new CYP2D6 allele with a nine base insertion in exon 9 in a Japanese population associated with poor metabolizer phenotype.

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.