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Citation
Tags
HERO ID
196808
Reference Type
Journal Article
Subtype
Review
Title
Genetic polymorphism in cytochrome P450 2D6 (CYP2D6): Population distribution of CYP2D6 activity
Author(s)
Neafsey, P; Ginsberg, G; Hattis, D; Sonawane, B
Year
2009
Is Peer Reviewed?
1
Journal
Journal of Toxicology and Environmental Health, Part B: Critical Reviews
ISSN:
1093-7404
EISSN:
1521-6950
Volume
12
Issue
5
Page Numbers
334-361
Language
English
PMID
20183526
DOI
10.1080/10937400903158342
Web of Science Id
WOS:000271375100002
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.
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