Molecules (Apr 2012)

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

  • Liang Wang,
  • Jian-Ping Deng,
  • Jia-Jiu Yao,
  • Hai-Rong Li,
  • Gan Li,
  • Cui-Min Hu,
  • Zhong-Ze Fang,
  • Jun Yuan,
  • Yan-Yang Tu,
  • Yong-Sheng Zhang

DOI
https://doi.org/10.3390/molecules17054896
Journal volume & issue
Vol. 17, no. 5
pp. 4896 – 4903

Abstract

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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, <em>in vitro</em> 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 <em>O</em>-glucuronidation, and the inhibition kinetic parameters (K<sub>i</sub>) 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 (K<sub>i</sub>) 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.

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