Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity

Abstract

CYP2D6 is of great importance for the metabolism of clinically used drugs and about 20-25% of those are metabolised by this enzyme. In addition, the enzyme utilises hydroxytryptamines as endogenous substrates. The polymorphism of the enzyme results in poor, intermediate, efficient or ultrarapid metabolisers (UMs) of CYP2D6 drugs. It is plausible that the UM genotype, where more than one active gene on one allele occurs, is the outcome of selective dietary selection in certain populations in North East Africa. The UM phenotype affects 5.5% of the population in Western Europe. A hypothesis for the evolutionary basis behind selection for CYP2D6 gene duplications is presented in relation to selection for Cyp6 variants in insecticide resistant Drosophila strains. The polymorphism of CYP2D6 significantly affects the pharmacokinetics of about 50% of the drugs in clinical use, which are CYP2D6 substrates. The consequences of the polymorphism at ordinary drug doses can be either adverse drug reactions or no drug response. Examples are presented where CYP2D6 polymorphism affects the efficacy and costs of drug treatment. Predictive CYP2D6 genotyping is estimated by the author to be beneficial for treatment of about 30-40% of CYP2D6 drug substrates, that is, for about 7-10% of all drugs clinically used, although prospective clinical studies are necessary to evaluate the exact benefit of drug selection and dosage based on the CYP2D6 genotype.

Is CYP2D6 phenotype predictable from CYP2D6 genotype?

“…The liver samples were CYP2D6-genotyped for the most frequent allelic variants occurring in Caucasian populations. The allele frequencies for CYP2D6*3, *4, *5, *6, *10 and *41 were concordant with previously reported data except for the prevalence of gene duplications (Table 3) [9,24], which was substantially higher (19.9%) than it was reported in Caucasian populations (2-5%). We were unable to correlate the elevated frequency of CYP2D6 duplication to any available clinical information about the donors.…”

“…According to the present knowledge, the expression of CYP2D6 gene is not inducible by any known xenobiotics in contrast to other drug metabolizing CYP enzymes [24,25]. Since CYP2D6 gene is remarkably polymorphic, the main factor that determines the enzyme activity is thought to be the genetic variations.…”

Global meta-analysis of the C-11377G alteration in the ADIPOQ gene indicates the presence of population-specific effects: challenge for global health initiatives

“…A possible explanation for this variable pattern of disease risk is the fact that these populations have experienced very different environments during their evolution. 48 It has been determined that adaptation affects the functioning of metabolism by natural selection within the genome of a cytoplasmic organelle. 38 Similar effects must be at play within the nuclear environment, which alters the profile of disease risk of a specific alteration dependent upon the genomic background upon which an alteration is expressed.…”

Pharmacogenetics and pharmacogenomics: origin, status, and the hope for personalized medicine

“…12 Key events that created interest in pharmacogenetics in the clinic were the discoveries of genetic variation of the metabolism of debrisoquine 13 (based on Dr Smith's, the author, personal suffering, 14 ) and of sparteine; 15 subsequent observations revealed that functional absence of the cytochrome liver enzyme CYP2D6 was responsible for both deficiencies, and that this enzyme was responsible for the metabolism of approximately 60 drugs. 16 As recently described, 17 detailed studies revealed that there were many different genetic changes of the enzyme, which altered its functional characteristics. For instance, the enzyme could be completely inactive, or some variant would selectively not metabolize a particular drug, which was normally metabolized by the enzyme; regulatory variants may lead to a large increase of an enzyme's activity.…”