Genetic Polymorphism in Cytochrome P450 2D6 (CYP2D6): Population Distribution of CYP2D6 Activity

Abstract

Cytochrome P-450 2D6 (CYP2D6) is involved in the metabolism of many therapeutic drugs even though the enzyme represents a small proportion of the total CYP content of human liver. In vivo phenotyping with probe drug substrates such as debrisoquine and dextromethorphan showed a clear separation between poor metabolizers (PM) and extensive metabolizers (EM). This polymorphism may affect susceptibility to environmental disease, as suggested by molecular epidemiologic studies that found an association between CYP2D6 metabolizer phenotype and cancer risk; however, this association is not consistent. There are only a few examples of CYP2D6 involvement in toxicant mechanism of action, but this has not been extensively studied. Gene probe studies documented a number of genetic polymorphisms that underlie CYP2D6 metabolizer phenotypes. The EM group carries the wild-type (*1) or active (*2) variant alleles, while the PM group carries the *3, *4, *5, or *6 alleles, all of which code for a protein that has lower or null CYP2D6 activity. The current analysis characterizes (a) influence of genotype on phenotype based upon in vivo metabolism studies of probe drugs and (b) frequency of the major genotypes in different population groups is also characterized. These data were then incorporated into Monte Carlo modeling to simulate population distributions of CYP2D6 activity. This analysis reproduced the bimodal distributions commonly seen in phenotyping studies of Caucasians and found extensive population variability in enzyme activity, as indicated by the 9- to 56-fold difference between the PM modal median and the total population median CYP2D6 activity. This substantial degree of interindividual variability in CYP function indicates that assessments involving CYP2D6 substrates need to consider the full distribution of enzyme activity in refining estimates of internal dose in health assessments of xenobiotics.

Analgesia and Opioids: A Pharmacogenetics Shortlist for Implementation in Clinical Practice

“…In the Asian population, CYP2D6 PMs are less common, but IMs are more common, with up to 20% of the Japanese population carrying the *10 decreased activity allele (6 ). In the African population, the frequently occurring *17 and *29 alleles also lead to an IM phenotype.…”

“…In the African population, the frequently occurring *17 and *29 alleles also lead to an IM phenotype. These alleles are virtually absent in the white population (6 ). Several case reports have described severe and even lethal adverse events in individuals with genetically impaired CYP2D6 metabolism who are treated with codeine and tramadol (8 ).…”

“…This phase-I liver enzyme is involved in the biological activation of codeine into morphine and tramadol into 5 (6 ). Over 100 different alleles have been discovered, of which approximately 25% lead to total loss of activity in vivo and 6% result in decreased activity (7 ).…”

Trapping of cis-2-Butene-1,4-dial to Measure Furan Metabolism in Human Liver Microsomes by Cytochrome P450 Enzymes

“…Therefore, this enzyme is not likely to contribute significantly to human liver metabolism of furan. CYP2D6 is also a minor liver P450, but genetic variants of this protein lead to high activity (Neafsey et al, 2009b), indicating that this enzyme could contribute to liver furan metabolism in some individuals. CYP3A4 protein levels are much higher than those of CYP2E1 (Shimada et al, 1994); therefore, CYP3A4 may play a role in furan metabolism in human liver.…”

In Vitro Functional Assessment of 22 Newly Identified CYP2D6 Allelic Variants in the Chinese Population

“…For Eastern Asians, only 1-2% of individuals have been found to be poor metabolizers (PMs), and approximately 57% of the Chinese population are intermediate metabolizers (IMs) [9,10]. Polymorphic studies have revealed that the IM allele CYP2D6*10 is predominant in Asian populations with frequencies ranging from 30% to 50% [7,11].…”