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Effect of UDP-glucuronosyltransferase 2B15 polymorphism on bisphenol A glucuronidation
Nobumitsu Hanioka1, Hiroyuki Oka, Kenjiro Nagaoka
1Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Kita-ku, Okayama, Japan. nhanioka@cc.okayama-u.ac.jp
Archives of Toxicology
|March 16, 2011
Summary
The D85Y substitution in UDP-glucuronosyltransferase 2B15 (UGT2B15) significantly reduces its ability to metabolize Bisphenol A (BPA). This finding highlights how UGT2B15 genetic variations impact BPA metabolism and potential toxicity.
Area of Science:
- Biochemistry
- Pharmacogenetics
- Toxicology
Background:
- Bisphenol A (BPA) is an endocrine-disrupting chemical.
- Human metabolism of BPA primarily involves UDP-glucuronosyltransferase 2B15 (UGT2B15).
- Several allelic variants of UGT2B15 exist across diverse populations.
Purpose of the Study:
- To investigate the impact of UGT2B15 genetic variants on BPA glucuronidation.
- To determine the kinetic parameters (Km, Vmax, CLint) for BPA metabolism by wild-type and variant UGT2B15 enzymes.
- To correlate UGT2B15 genetic variations with potential alterations in BPA metabolism and toxicity.
Main Methods:
- Recombinant UGT2B15 enzymes (wild-type UGT2B15.1 and variants UGT2B15.2-7) were expressed in insect (Sf9) cells.
- Enzymatic assays were performed to measure BPA glucuronidation kinetics.
- Kinetic parameters (Km, Vmax, CLint) were determined for each enzyme variant.
Main Results:
- The D85Y substitution in UGT2B15.2 and UGT2B15.5 markedly reduced Vmax and CLint values for BPA glucuronidation compared to UGT2B15.1.
- UGT2B15 variants with L86S, T352I, and/or K523T substitutions (UGT2B15.3, UGT2B15.4, UGT2B15.6, UGT2B15.7) showed comparable kinetic parameters to UGT2B15.1.
- No significant differences in Km values were observed between wild-type and variant UGT2B15 enzymes.
Conclusions:
- The D85Y substitution in UGT2B15 significantly impairs its enzymatic function in BPA metabolism.
- Polymorphic alleles of UGT2B15 are closely associated with variations in BPA metabolism and toxicity.
- Findings aid in the in vivo extrapolation for assessing the toxicity of endocrine-disrupting chemicals like BPA.
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