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Molecules 2012, 17(5), 4896-4903;

Gossypol Exhibits a Strong Influence Towards UDP-Glucuronosyltransferase (UGT) 1A1, 1A9 and 2B7-Mediated Metabolism of Xenobiotics and Endogenous Substances

Tangdu Hospital, Fourth Military Medical University, Xi’an 710038, China
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
1001 Rockville Pike, Rockville, MD 20852, USA
These authors contributed equally to this work.
Author to whom correspondence should be addressed.
Received: 19 March 2012 / Revised: 8 April 2012 / Accepted: 16 April 2012 / Published: 27 April 2012
(This article belongs to the Section Natural Products Chemistry)
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Gossypol, the polyphenolic constituent isolated from cottonseeds, has been used as a male antifertility drug for a long time, and has been demonstrated to exhibit excellent anti-tumor activity towards multiple cancer types. The toxic effects of gossypol limit its clinical utilization, and enzyme inhibition is an important facet of this. In the present study, in vitro human liver microsomal incubation system supplemented with UDPGA was used to investigate the inhibition of gossypol towards UGT1A1, 1A9 and 2B7-mediated metabolism of xenobiotics and endogenous substances. Estradiol, the probe substrate of UGT1A1, was selected as representative endogenous substance. Propofol (a probe substrate of UGT1A9) and 3'-azido-3'-deoxythimidine (AZT, a probe substrate of UGT2B7) were employed as representative xenobiotics. The results showed that gossypol noncompetitively inhibits UGT-mediated estradiol-3-glucuronidation and propofol O-glucuronidation, and the inhibition kinetic parameters (Ki) were calculated to be 34.2 and 16.4 μM, respectively. Gossypol was demonstrated to exhibit competitive inhibition towards UGT-mediated AZT glucuronidation, and the inhibition kinetic parameter (Ki) was determined to be 14.0 μM. All these results indicated that gossypol might induce metabolic disorders of endogenous substances and alteration of metabolic behaviour of co-administered xenobiotics through inhibition of UGTs’ activity. View Full-Text
Keywords: gossypol; UDP-glucuronosyltransferase (UGT); enzyme inhibition gossypol; UDP-glucuronosyltransferase (UGT); enzyme inhibition

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Zhang, Y.-S.; Yuan, J.; Fang, Z.-Z.; Tu, Y.-Y.; Hu, C.-M.; Li, G.; Wang, L.; Deng, J.-P.; Yao, J.-J.; Li, H.-R. Gossypol Exhibits a Strong Influence Towards UDP-Glucuronosyltransferase (UGT) 1A1, 1A9 and 2B7-Mediated Metabolism of Xenobiotics and Endogenous Substances. Molecules 2012, 17, 4896-4903.

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