Molecular analysis of mechanisms leading to CYP2D6 intermediate and ultrarapid metabolizer phenotypes ; Molerkulargenetische Untersuchungen zu Mechanismen des CYP2D6 intermediären und ultraschnellen Metabolisierer-Phänotyps

Genetic polymorphisms in drug metabolizing enzymes and transporters can considerably influence an individual's ability to metabolize and eliminate drugs and other xenobiotics. The consequences are unexpected reactions of patients to drug treatment. Depending on whether the polymorphism causes reduced or increased metabolism rate the consequences of a normal dosage can be adverse reactions or reduced efficacy. CYP2D6 is one of the most important drug metabolizing enzymes in human liver showing high interindividual variability with clinical relevance for drug treatment. Four distinct phenotypes are commonly observed in Caucasian populations, namely ultrarapid metabolizer (UM), extensive metabolizer (EM), intermediate metabolizer (IM) and poor metabolizer (PM) based on their drug oxidation capacity. The research of the last 25 years showed that interindividual differences are essentially caused by genetic polymorphisms at the CYP2D gene locus on chromosome 22. The numerous known allelic variants lead to increased, normal, decreased or absent 2D6 protein and/or function. Today, the presence of null mutations on both chromosomes allows the reliable identification of individuals with PM phenotype for adjustment of drug dosing. In contrast, ultrarapid and intermediate metabolizers, who may also be at increased risk, have a considerably poorer predictivity. The intermediate metabolizer phenotype comprises 10-15 % of a distinct population subgroup characterized by impaired but detectable residual enzyme activity. Two already known alleles, 2D6*9 and 2D6*10 were shown to be associated with lower in vivo metabolic capacity but they account for not more than 10-20 % of Caucasian IMs. In attempt to elucidate the genetic basis of the IM phenotype in the major fraction, the CYP2D6*41 allele was identified in our pharmacogenetic group at the IKP Stuttgart, which was found to be the second most frequent CYP2D6 deficient allele. The *41 allele is genetically closely related to the functionally *2 allele but lacks the -1584C>G ...