Jump to main content
US EPA
United States Environmental Protection Agency
Search
Search
Main menu
Environmental Topics
Laws & Regulations
About EPA
Health & Environmental Research Online (HERO)
Contact Us
Print
Feedback
Export to File
Search:
This record has one attached file:
Add More Files
Attach File(s):
Display Name for File*:
Save
Citation
Tags
HERO ID
196821
Reference Type
Journal Article
Subtype
Review
Title
The influence of genetic polymorphisms on population variability in six xenobiotic-metabolizing enzymes
Author(s)
Ginsberg, G; Smolenski, S; Neafsey, P; Hattis, D; Walker, K; Guyton, KZ; Johns, DO; 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
307-333
Language
English
PMID
20183525
DOI
10.1080/10937400903158318
Web of Science Id
WOS:000271375100001
Abstract
This review provides variability statistics for polymorphic enzymes that are involved in the metabolism of xenobiotics. Six enzymes were evaluated: cytochrome P-450 (CYP) 2D6, CYP2E1, aldehyde dehydrogenase-2 (ALDH2), paraoxonase (PON1), glutathione transferases (GSTM1, GSTT1, and GSTP1), and N-acetyltransferases (NAT1 and NAT2). The polymorphisms were characterized with respect to (1) number and type of variants, (2) effects of polymorphisms on enzyme function, and (3) frequency of genotypes within specified human populations. This information was incorporated into Monte Carlo simulations to predict the population distribution and describe interindividual variability in enzyme activity. The results were assessed in terms of (1) role of these enzymes in toxicant activation and clearance, (2) molecular epidemiology evidence of health risk, and (3) comparing enzyme variability to that commonly assumed for pharmacokinetics. Overall, the Monte Carlo simulations indicated a large degree of interindividual variability in enzyme function, in some cases characterized by multimodal distributions. This study illustrates that polymorphic metabolizing systems are potentially important sources of pharmacokinetic variability, but there are a number of other factors including blood flow to liver and compensating pathways for clearance that affect how a specific polymorphism will alter internal dose and toxicity. This is best evaluated with the aid of physiologically based pharmacokinetic (PBPK) modeling. The population distribution of enzyme activity presented in this series of articles serves as inputs to such PBPK modeling analyses.
Tags
OPPT REs
•
OPPT_1-Bromopropane (1-BP)_A. Summary
Cited in TSCA RE related document
•
OPPT_1-Bromopropane (1-BP)_F. Human Health
Total – title/abstract screening
On topic
Supplemental search
Home
Learn about HERO
Using HERO
Search HERO
Projects in HERO
Risk Assessment
Transparency & Integrity