DNA haplotype dependency of debrisoquine 4-hydroxylase (CYP2D6) expression among extensive metabolisers.
Deficient debrisoquine/sparteine type oxidation is inherited as an autosomal recessive trait. Of all Caucasians, 5-10% are poor metabolisers, due to the absence of cytochrome P4502D6. Extensive metabolisers (EMs) exhibit highly variable metabolic activity. We investigated the relationship between CYP2D6 activity and genotypes of the CYP2D locus in a large set of French Caucasian families. Genotypes concern both common mutations affecting the enzyme activity and linked BamHI polymorphisms of the locus. We found, like other authors, that in EMs part of the heterogeneity is explained by a subgroup of individuals heterozygous for a mutant allele. However, a second level of heterogeneity was detected among individuals not carrying mutations, and this was related to a polymorphic BamHI-defined DNA haplotype. Different combinations of haplotypes are associated with differences in CYP2D6 metabolic activity. This finding might help to clarify the conflicting data on the relation between CYP2D6 activity and susceptibility to lung cancer.
Mura
C
C
INSERM U120, Hôpital Robert Debré, Paris, France.
Panserat
S
S
Vincent-Viry
M
M
Galteau
M M
MM
Jacqz-Aigrain
E
E
Krishnamoorthy
R
R
D000293:Adolescent; D000328:Adult; D019389:Cytochrome P-450 CYP2D6; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism*; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D003647:Debrisoquin / Q000378:metabolism; D003915:Dextromethorphan / Q000008:administration & dosage; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism*; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D011897:Random Allocation
D003915:Dextromethorphan; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019389:Cytochrome P-450 CYP2D6; D003647:Debrisoquin