Genetic and metabolic criteria for the assignment of debrisoquine 4-hydroxylation (cytochrome P4502D6) phenotypes.
A randomly selected population of 73 volunteers, together with 22 previously established poor metabolisers of debrisoquine, were phenotyped for their ability to 4-hydroxylate debrisoquine and were also analysed for a number of mutations in the CYP2D6 gene. Genotyping was performed using both restriction fragment length polymorphism with the restriction enzyme Xba I, together with two separate polymerase chain reaction assays. Together, these assays detected 98% of mutant alleles in the poor metaboliser group which corresponded to positive identification of 95% of this group. The most common mutant allele detected as the 29B which comprised 75% of total alleles in the poor metaboliser group, whereas the 29A had a frequency of 0.11. Two other allelic variants, which were detectable by restriction fragment length polymorphism analysis occurred at frequencies of 0.07 and 0.05. In the volunteer group, 2.7% of subjects were genotypically poor metabolisers, 35.6% heterozygous extensive metabolisers and 61.7% homozygous extensive metabolisers, on the basis of the genotyping assays used. A good correlation between debrisoquine metabolic ratio and genotype was obtained particularly for subjects genotyped as homozygous extensive metabolisers.
Department of Pharmacological Sciences, University of Newcastle upon Tyne, Medical School, UK.
A K
AK
Daly
M
M
Armstrong
S C
SC
Monkman
M E
ME
Idle
J R
JR
Idle
D000483:Alleles; D001483:Base Sequence; D019389:Cytochrome P-450 CYP2D6; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism*; D004247:DNA / Q000097:blood / Q000235:genetics / Q000302:isolation & purification; D003647:Debrisoquin / Q000378:metabolism*; D015252:Deoxyribonucleases, Type II Site-Specific; D005091:Exons; D005260:Female; D005838:Genotype; D006720:Homozygote; D006801:Humans; D007962:Leukocytes / Q000201:enzymology; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D009838:Oligodeoxyribonucleotides; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction / Q000379:methods; D012150:Polymorphism, Restriction Fragment Length
D009838:Oligodeoxyribonucleotides; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019389:Cytochrome P-450 CYP2D6; C025580:endodeoxyribonuclease XBAI; D015252:Deoxyribonucleases, Type II Site-Specific; D003647:Debrisoquin