Genetic analysis of the interethnic difference between Chinese and Caucasians in the polymorphic metabolism of debrisoquine and codeine.
The Far Eastern and Caucasian populations are strikingly different with respect to the debrisoquine/sparteine hydroxylation polymorphism. The number of poor metabolizers, as defined for Caucasians, is very low among Chinese and Japanese. We investigated the molecular basis for this difference by analysis of the CYP2D6 gene in 115 Chinese subjects, combined with phenotypic classification of codeine and debrisoquine metabolism. A correlation between the rates of metabolism of these two drugs and genotype, as analyzed by RFLP using XbaI, was observed among the Chinese. A high frequency (37%) of alleles indicative of gene insertions (reflected by XbaI 44kb fragments) was recorded in the Chinese, but was not associated with the poor metabolizer phenotype, as it is in Caucasians. PCR amplification of part of the CYP2D6 gene with mutation specific primers for CYP2D6A (29A) and CYP2D6B (29B) allelic variants revealed that the XbaI 44kb fragment in Chinese apparently contains a functional CYP2D6 gene, in contrast to the situation among Caucasians. The results provide a molecular explanation of the interethnic difference in the metabolism of drugs affected by the debrisoquine hydroxylation polymorphism.
Department of Physiological Chemistry, Karolinska Institute, Stockholm, Sweden.
I
I
Johansson
Q Y
QY
Yue
M L
ML
Dahl
M
M
Heim
J
J
Säwe
L
L
Bertilsson
U A
UA
Meyer
F
F
Sjöqvist
M
M
Ingelman-Sundberg
D000293:Adolescent; D000328:Adult; D000483:Alleles; D044466:Asian People / Q000235:genetics*; D015139:Blotting, Southern; D002681:China; D003061:Codeine / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System; D003647:Debrisoquin / Q000378:metabolism*; D005260:Female; D005784:Gene Amplification / Q000187:drug effects*; D006801:Humans; D006900:Hydroxylation; D007564:Japan; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D044465:White People / Q000235:genetics*
D003577:Cytochrome P-450 Enzyme System; D003061:Codeine; D003647:Debrisoquin