Title: Elucidation of the genetic basis of the common ‘intermediate metabolizer’ phenotype for drug oxidation by CYP2D6
Abstract: 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.
Publication Year: 2000
Publication Date: 2000-10-01
Language: en
Type: article
Indexed In: ['crossref', 'pubmed']
Access and Citation
Cited By Count: 188
AI Researcher Chatbot
Get quick answers to your questions about the article from our AI researcher chatbot