DNA haplotype-dependent differences in the amino acid sequence of debrisoquine 4-hydroxylase (CYP2D6): evidence for two major allozymes in extensive metabolisers.
The molecular basis for DNA haplotype-dependent debrisoquine 4-hydroxylase (CYP2D6) expression was explored by sequencing all of the nine exons of the CYP2D6 gene. Two distinct exon sequence frameworks of the CYP2D6 gene were found, each associated with specific BamHI-defined DNA haplotypes of the CYP2D cluster. They corresponded to Arg296/Cys296 and Ser486/Thr486 amino acid polymorphisms in the CYP2D6 enzyme, and occurred in almost equal frequency among the Caucasians examined. These two major allozymes with amino acid differences in the presumed substrate recognition region and in the vicinity of the heme binding site could be the source of the observed DNA haplotype-dependent variation in phenotypic expression.
Panserat
S
S
INSERM U120, Hôpital Robert Debré, Paris, France.
Mura
C
C
Gérard
N
N
Vincent-Viry
M
M
Galteau
M M
MM
Jacqz-Aigrain
E
E
Krishnamoorthy
R
R
D000483:Alleles; D000595:Amino Acid Sequence; D001483:Base Sequence; D019389:Cytochrome P-450 CYP2D6; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004247:DNA / Q000032:analysis*; D017931:DNA Primers; D005091:Exons; D006239:Haplotypes; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D006899:Mixed Function Oxygenases / Q000235:genetics*; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length
D017931:DNA Primers; D007527:Isoenzymes; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019389:Cytochrome P-450 CYP2D6