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1749 2938 4268 Europe

1749 1934 4268 Europe

1934 4268 Europe

1749 4268 Japan

1749 4268 China

1749 4268 China

2938 4268 Africa

^Compiled from data in (45) and (46) by W. Kalow (private communication).

bThe variants 4A and 4B represent enzymes without activity. All others have reduced activity compared to the wild type.

exaggerated toxicity to agents that are activated by CYP2D6* (e.g., the analgesic codeine).

Population studies have been performed on more than 10,000 subjects since the discovery of the CYP2D6* polymorphism in the 1970s. Table 8.2 (W. Kalow, private communication) concisely describes the extent of ethnic variation of people from Africa, Asia, and Europe with 11 nucleotide changes belonging to 7 CYP2D6 allelic variants.45,46 Certain mutations (G ? C at nt 4268) are shared by people from all three continental regions suggesting the mutation probably occurred before evolutionary separation. Other mutations occur in people within particular regions such as the C ? T at nt 1127 in China, or the G ? C at nt 1726 in Africa suggesting that these mutations probably occurred after evolutionary separation.

The prevalence of CYP2D6 poor metabolizers, phenotypes (Figure 8.4)47 and ultrarapid metabolizers (Figure 8.5)48 varies considerably from one population, and subpopulation, to another. The frequency of the poor metabolizers varies from about 0.1% in Japanese and Egyptians and up 10% in Caucasians of Europe and North America, and one study reported an absence of this phenotype in Cunas Amerindians of Panama.42 In Europeans, poor metabolizers of debriso-quine are also poor metabolizers of sparteine, but among Ghanians, poor meta-bolizers of debrisoquine (and phenformin) are not poor metabolizers of sparte-ine.49 The reason for this lack of concordance has not been determined.

Individuals of the ultrarapid metabolizer phenotype possess CYP2D6L* 2, 3, 4, 5, and 13 copies of the CYP2D6L gene in one allele.50 The ethnic distribution of ultrarapid metabolizer phenotypes in Northern European populations summarized in Table 8.351 shows that Swedes and Germans possess 1-2% of the CYP2D6L ultrarapid phenotype, whereas the frequency of ultrarapid carriers in Ethiopia52 and in Saudi Arabia (20%) (not shown in Table 8.3)48 is much higher. Spaniards alsohave ahigh proportion of individuals carrying amplified CYP2D6L* genes, presumably due to the admixture of African genes.53,54

Figure 8.4 Racial differences among CYP2D6 poor metabolizer phenotypes in various ethnic populations.

German

German

Figure 8.5 Racial differences in CYP2D6 ultrarapid metabolizer phenotypes among various ethnic populations.

Table 8.3 Ethnic Distribution of CYP2D6 Ultrarapid Metabolizers51

Allele frequency (%)

Allele frequency (%)

Table 8.3 Ethnic Distribution of CYP2D6 Ultrarapid Metabolizers51

CYP2D6 Allele

Swedes

Germans

Spaniards

Ethiopians

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