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Research ArticleArticle

Role of UDP-Glucuronosyltransferase Isoforms in 13-cis Retinoic Acid Metabolism in Humans

Sophie E. Rowbotham, Nicola A. Illingworth, Ann K. Daly, Gareth J. Veal and Alan V. Boddy
Drug Metabolism and Disposition July 2010, 38 (7) 1211-1217; DOI: https://doi.org/10.1124/dmd.109.031625
Sophie E. Rowbotham
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Nicola A. Illingworth
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Ann K. Daly
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Gareth J. Veal
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Alan V. Boddy
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Abstract

13-cis Retinoic acid (13cisRA, isotretinoin) is an important drug in both dermatology, and the treatment of high-risk neuroblastoma. 13cisRA is known to undergo cytochrome P450-mediated oxidation, mainly by CYP2C8, but phase II metabolic pathways have not been characterized. In the present study, the glucuronidation activities of human liver (HLM) and intestinal microsomes (HIM), as well as a panel of human UDP-glucuronosyltransferases (UGTs) toward both 13cisRA and the 4-oxo metabolite, 4-oxo 13cisRA, were compared using high-performance liquid chromatography. Both HLM and, to a greater extent, HIM catalyzed the glucuronidation of 13cisRA and 4-oxo 13cisRA. Based on the structures of 13cisRA and 4-oxo 13cisRA, the glucuronides formed are conjugated at the terminal carboxylic acid. Further analysis revealed that UGT1A1, UGT1A3, UGT1A7, UGT1A8, and UGT1A9 were the major isoforms responsible for the glucuronidation of both substrates. For 13cisRA, a pronounced substrate inhibition was observed with individual UGTs and with HIM. UGT1A3 exhibited the highest rate of activity toward both substrates, and a high rate of activity toward 13cisRA glucuronidation was also observed with UGT1A7. However, for both substrates, Km values were above concentrations reported in clinical studies. Therefore, UGT1A9 is likely to be the most important enzyme in the glucuronidation of both substrates as this enzyme had the lowest Km and is expressed in both the intestine and at high levels in the liver.

Footnotes

  • This work was supported by Cancer Research UK.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.109.031625.

  • ABBREVIATIONS:

    ATRA
    all-trans retinoic acid
    13cisRA
    13-cis retinoic acid
    P450
    cytochrome P450
    UGT
    UDP-glucuronosyltransferase
    HPLC
    high-performance liquid chromatography
    HLM
    human liver microsomes
    HIM
    human intestinal microsomes
    UDPGA
    UDP-glucuronic acid.

  • Received December 14, 2009.
  • Accepted March 19, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (7)
Drug Metabolism and Disposition
Vol. 38, Issue 7
1 Jul 2010
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Research ArticleArticle

Role of UDP-Glucuronosyltransferase Isoforms in 13-cis Retinoic Acid Metabolism in Humans

Sophie E. Rowbotham, Nicola A. Illingworth, Ann K. Daly, Gareth J. Veal and Alan V. Boddy
Drug Metabolism and Disposition July 1, 2010, 38 (7) 1211-1217; DOI: https://doi.org/10.1124/dmd.109.031625

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Research ArticleArticle

Role of UDP-Glucuronosyltransferase Isoforms in 13-cis Retinoic Acid Metabolism in Humans

Sophie E. Rowbotham, Nicola A. Illingworth, Ann K. Daly, Gareth J. Veal and Alan V. Boddy
Drug Metabolism and Disposition July 1, 2010, 38 (7) 1211-1217; DOI: https://doi.org/10.1124/dmd.109.031625
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