THE CYP2D6 GENETIC POLYMORPHISM

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The debrisoquine/sparteine genetic polymorphism is due to mutant or null alleles encoding the cytochrome P450 CYP2D6. This polymorphism is most prevalent in Caucasians in which 7 to 10% possess two null alleles and are incapable of metabolizing a large number of therapeutically-important drugs. Several null alleles have been sequenced and PCR assays developed for diagnostic purposes. Over 95% of deficient metabolizers can be diagnosed by PCR. Interethnic variation of drug metabolism has also been described and detailed studies have been conducted comparing a number of enzymes. The debrisoquine/sparteine polymorphism exhibits markedly different characteristics in Oriental subjects. In Japanese and Chinese, the frequency of deficient individuals ranges from 0 to a maximum of 2.3%, depending on the target population and the drug used for phenotyping. A most intriguing observation is that the average rate of metabolism among the normal metabolizers differ between ethnic groups; Oriental subjects have, on average, a slower metabolism than Caucasians when sparteine, a CYP2D6 substrate, was used as the probe drug to investigate this difference. Several CYP2D6 alleles were sequenced from a population of Japanese subjects and a new variant allele, designated CYP2D6v1 was uncovered that contains two amino acid changes that might confer lower rates of metabolism. In addition several CYP2D6D null alleles and two CYP2D6B mutants were found. The latter finding indicates that the CYP2D6B allele is not exclusive to Caucasians.