Identification and functional characterization of human soluble epoxide hydrolase genetic polymorphisms
M Sandberg1, C Hassett, E T Adman
1Department of Plant Biology, Uppsala Genetic Center, Swedish University of Agricultural Sciences, SE-750 07 Uppsala, Sweden.
The Journal of Biological Chemistry
|June 22, 2000
Summary
Genetic variations in human soluble epoxide hydrolase (sEH) impact its function. A specific arginine insertion in sEH significantly reduces its enzymatic activity, affecting epoxide metabolism and toxicity.
Area of Science:
- Biochemistry
- Pharmacogenomics
- Enzymology
Background:
- Soluble epoxide hydrolase (sEH) metabolizes endogenous and xenobiotic epoxides.
- Interindividual variation in sEH function can influence health and disease.
- Genomic characterization of sEH is crucial for understanding its functional diversity.
Purpose of the Study:
- To identify and characterize genetic variations in human soluble epoxide hydrolase (sEH).
- To investigate the functional consequences of identified sEH variants on enzyme activity.
- To explore the physiological implications of sEH allelic differences in epoxide disposition and toxicity.
Main Methods:
- RNA isolation from human liver samples and cDNA generation.
- Polymerase chain reaction amplification, sequencing, and variant identification.
- Enzyme activity assays using transient transfection and a model substrate.
Main Results:
- Eight variant loci in human sEH were identified, including two leading to altered protein sequences.
- A common variant involves an arginine to glutamine substitution at residue 287.
- A novel variant features an arginine insertion after serine 402, resulting in significantly reduced catalytic activity compared to wild-type sEH.
Conclusions:
- Human sEH exhibits functional allelic variations with distinct enzymatic profiles.
- The identified sEH variants, particularly the arginine insertion, may significantly impact the metabolism of fatty acid-derived epoxides and xenobiotic toxicity.
- Further research is warranted to elucidate the full physiological and toxicological relevance of sEH genetic polymorphisms.
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