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Sex differences in UDP-glucuronosyltransferase 2B17 expression and activity
Carla J Gallagher1, Renee M Balliet, Dongxiao Sun
1Department of Pharmacology, Penn State College of Medicine, 500 University Drive, CH69, Hershey, PA 17033, USA.
Drug Metabolism and Disposition: the Biological Fate of Chemicals
|September 3, 2010
Summary
Men show significantly higher UGT2B17 enzyme expression and activity compared to women. This difference in UDP-glucuronosyltransferases (UGTs) may impact carcinogen detoxification and drug metabolism differently between sexes.
Area of Science:
- Pharmacogenomics
- Enzyme kinetics
- Human physiology
Background:
- UDP-glucuronosyltransferases (UGTs) are crucial enzymes for metabolizing various endogenous and exogenous compounds.
- Previous in vitro studies suggested UGT2B gene family involvement in hormonal regulation, hinting at potential sex-based differences.
- Investigating sex-related variations in UGT2B expression and activity is important for understanding differential drug metabolism and detoxification.
Purpose of the Study:
- To determine if significant sex-based differences exist in the expression and activity of UGT2B enzymes in human liver tissues.
- To correlate UGT2B gene expression levels with actual enzyme activity in human liver microsomes (HLM).
Main Methods:
- Analysis of 103 normal human liver specimens using real-time polymerase chain reaction to quantify UGT2B gene expression.
- Measurement of in vitro glucuronidation activity in HLM using specific UGT2B17 substrates.
- Stratification of results based on UGT2B17 gene deletion genotypes (+/+, +/0, 0/0).
Main Results:
- Men exhibited approximately 4-fold higher UGT2B17 gene expression compared to women (p = 0.007).
- HLM from men showed significantly higher glucuronidation activity for UGT2B17 substrates: 3-fold for 17-dihydroexemestane (p = 0.002), 3-fold for 3-hydroxycotinine (p < 0.001), and 1.5-fold for suberoylanilide hydroxamic acid (p = 0.014).
- These patterns held true when stratified by UGT2B17 gene deletion genotype.
Conclusions:
- Men possess higher UGT2B17 gene expression and corresponding glucuronidation activity than women.
- These sex-based differences in UGT2B17 activity could influence the detoxification of carcinogens and the elimination of drugs.
- Further research is warranted to explore the clinical implications of these sex-specific metabolic variations.
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