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Epoxide hydrolase--polymorphism and role in toxicology
C J Omiecinski1, C Hassett, V Hosagrahara
1Department of Environmental Health, University of Washington, 4225 Roosevelt Way NE, #100, Seattle, WA, USA. cjo@u.washington.edu
Toxicology Letters
|March 18, 2000
Summary
Genetic variations in microsomal epoxide hydrolase (mEH) show minimal impact on enzyme activity in vivo. Studies using purified enzymes and liver microsomes reveal subtle differences, suggesting modest effects of mEH polymorphisms on biotransformation.
Area of Science:
- Biochemistry
- Pharmacogenomics
- Enzymology
Background:
- Microsomal epoxide hydrolase (mEH) is a key enzyme in xenobiotic metabolism.
- Genetic polymorphisms in mEH, such as Y113/H and H139/R, can alter enzyme structure.
- Understanding the functional consequences of these polymorphisms is crucial for assessing their in vivo relevance.
Purpose of the Study:
- To investigate the enzymatic activity of wild-type and variant microsomal epoxide hydrolase (mEH) proteins.
- To evaluate the impact of structural genetic polymorphisms on mEH catalytic function.
- To compare enzymatic activity using purified proteins versus human liver microsomes.
Main Methods:
- Expression of purified mEH proteins using a baculovirus system.
- Enzymatic assays using benzo[a]pyrene-4,5-oxide and cis-stilbene oxide as substrates.
- Analysis of mEH activity in human liver microsomal preparations from individuals with homozygous allelic status.
Main Results:
- Purified wild-type mEH exhibited approximately two-fold higher reaction velocity compared to variant forms.
- Maximal velocities among variant mEH proteins in human liver microsomes were not statistically different.
- Enzymatic activity differences observed with purified enzymes were not replicated in microsomal preparations.
Conclusions:
- Structural variations in mEH due to genetic polymorphisms may have a limited impact on enzyme specific activity in vivo.
- The functional significance of mEH genetic variants might be context-dependent.
- Further research is needed to fully elucidate the in vivo implications of mEH polymorphisms.
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