The cytochrome P450 CYP2D6 allelic variant CYP2D6J and related polymorphisms in a European population.

DNA from two subjects showing anomalous CYP2D6 phenotype-genotype relationships was analysed for the presence of new CYP2D6 mutations by single strand conformational polymorphism (SSCP) analysis. One of these subjects was homozygous for polymorphisms in exon 1 and exon 9 previously detected in Oriental populations and termed the CYP2D6J allele. The frequency of these polymorphisms and their effect on phenotype was investigated in a European population with a small Chinese population as a control group. Subjects homozygous for both polymorphisms showed impaired metabolism of debrisoquine whereas subjects with the exon 9 mutation only appeared to show similar metabolism to the wild-type. The CYP2D6J allele frequency was 0.05 in the European group compared with 0.47 for the Chinese group. The relationship between the CYP2D6J allele and the exon 9 polymorphism and the presence of insertions upstream of CYP2D6 detectable by RFLP analysis with Xba I was investigated. In the Chinese group the insertion appeared to be associated with the CYP2D6J allele but in the European group no association was detected. Subjects homozygous for the CYP2D6J allele appear to show a similar debrisoquine phenotype to those heterozygous for CYP2D6-inactivating mutations but the exon 9 polymorphism or the presence of an upstream insertion without an associated CYP2D6B or CYP2D6J allele does not appear to affect enzyme activity.