Elucidation of the genetic basis of the common 'intermediate metabolizer' phenotype for drug oxidation by CYP2D6.
A subgroup of 10-15% of Caucasians are termed phenotypical 'intermediate metabolizers' of drug substrates of CYP2D6 because they have severely impaired yet residual in-vivo function of this cytochrome P450. Genotyping based on the currently known CYP2D6 alleles does not predict this phenotype satisfactorily. A systematic sequencing strategy through 1.6 kb of the CYP2D6 5'-flanking sequence revealed six mutations of which three were exclusively associated with the functional CYP2D6*2 allele (-1496 C to G; -652 C to T; and -590 G to A), two were associated with the nonfunctional *4 and with the functional *10-alleles (-1338 C to T and -912 G to A) and one (-1147 A to G) was seen in all *2, *4 and *10-alleles investigated. The -1496 C to G mutation was found to be polymorphic within CYP2D6*2 alleles. In a family study, the wild-type CYP2D6 *2[-1496 C] and the novel variant [-1496 G] allele co-segregated with lower and higher CYP2D6 in-vivo function, respectively, as shown by phenotyping using sparteine as probe drug. In a representative population sample selected for genotypes comprising one CYP2D6*2 and one non-functional allele, the median urinary metabolic ratio (MRs) for sparteine oxidation was 4.4-fold reduced in individuals with the variant allele (*2[-1496 G], MRs = 0.53, n = 27) compared with individuals lacking the mutation (*2[-1496 C], MRs = 2.33, n = 12; P < 0.0001). The mutation -1496 C to G has an estimated frequency of approximately 20% in the general population and allows establishment of a genotype for the identification of over 60% of intermediate metabolizers in Caucasian populations.
Raimundo
S
S
Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
Fischer
J
J
Eichelbaum
M
M
Griese
E U
EU
Schwab
M
M
Zanger
U M
UM
D001483:Base Sequence; D019389:Cytochrome P-450 CYP2D6 / Q000493:pharmacokinetics*; D017931:DNA Primers; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D009154:Mutation; D010084:Oxidation-Reduction; D010375:Pedigree; D010641:Phenotype; D013034:Sparteine / Q000493:pharmacokinetics*
D017931:DNA Primers; D013034:Sparteine; D019389:Cytochrome P-450 CYP2D6