Evolutionary pharmacogenetics of CYP2D6 in Ngawbe Guaymi of Panama: allele-specific PCR detection of the CYP2D6B allele and RFLP analysis.
Gene cluster CYP2D controls the biosynthesis of enzyme CYP2D6, which is responsible for the polymorphic oxidation of sparteine, debrisoquine and related drugs. This cluster consists of the functional gene D6 and of two pseudogenes, D7 and D8. RFLP Bam HI analysis of CYP2D in 37 unrelated and eight related Ngawbe Guaymi Amerindians of Panama showed a polymorphism characterized by the presence of two alleles: 4.7 + 7.9 and 2.3 + 6.0 (frequencies: 0.63 and 0.37, respectively, n = 35 unrelated subjects). The possible genotypes for these alleles follow the Hardy-Weinberg distribution (chi 2 = 1.76; 0.10 < p < 0.25). All PMs of sparteine or debrisoquine (n = 7) were homozygotes for the second allele, but not all homozygotes (n = 10) were PMs, so there was not an exclusive association between the Bam HI genotype and the observed phenotype. A similar analysis with the endonuclease Xba I proved to be non-informative in relation to phenotype, since all subjects (n = 40) showed only the 29 kb allele. Allele-specific PCR studies of selected subjects indicated the existence of the CYP2D6B allele (freq = 0.17; C.I.95% = 0.085, 0.29; n = 30 unrelated subjects), in addition to the wild-type. The mutant CYP2D6B allele was responsible for the enzyme deficiency present in PMs. Its presence in Amerindians suggests that this allele has a far more ancient evolutionary history than previously thought. The over-all RFLP and PCR analyses point to a diminished genetic diversity for the Ngawbe subjects, consistent with their demographic history and population genetics.
Jorge
L F
LF
College of Pharmacy, University of Panamá.
Arias
T D
TD
Griese
U
U
Nebert
D W
DW
Eichelbaum
M
M
D000483:Alleles; D005075:Biological Evolution; D019389:Cytochrome P-450 CYP2D6; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007197:Indians, Central American / Q000235:genetics*; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics*; D005810:Multigene Family; D010176:Panama; D010641:Phenotype; D012150:Polymorphism, Restriction Fragment Length; D011544:Pseudogenes
D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019389:Cytochrome P-450 CYP2D6