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Research ArticleArticle

Glucuronidation of Amines and Other Xenobiotics Catalyzed by Expressed Human UDP-Glucuronosyltransferase 1A3

Mitchell D. Green, Christopher D. King, Behnaz Mojarrabi, Peter I. Mackenzie and Thomas R. Tephly
Drug Metabolism and Disposition June 1998, 26 (6) 507-512;
Mitchell D. Green
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Christopher D. King
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Behnaz Mojarrabi
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Peter I. Mackenzie
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Thomas R. Tephly
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Abstract

Glucuronide conjugation of xenobiotics containing a tertiary amine moiety represents a unique and important metabolic pathway for these compounds in humans. Previously, human UDP-glucuronosyltransferase (UGT) 1A4 was shown to be an important enzyme for the formation of quaternary ammonium-linked glucuronides. UGT1A3 is 93% identical to UGT1A4 in primary amino acid sequence. We show that human UGT1A3, transiently expressed in human embryonic kidney 293 cells, also catalyzes the N-glucuronidation of primary, secondary, and tertiary amine substrates, such as 4-aminobiphenyl, diphenylamine, and cyproheptadine. In contrast to expressed human UGT1A4, which catalyzes the glucuronidation of amines with high efficiency, glucuronidation of amines catalyzed by UGT1A3 exhibited low efficiency, suggesting that UGT1A3 makes only a limited contribution to the metabolic elimination of these compounds. The reactivity of expressed human UGT1A3 toward hydroxylated and carboxylic acid-containing compounds was also examined. In addition to amines, expressed human UGT1A3 catalyzed the glucuronidation of opioids (e.g. morphine and buprenorphine), coumarins, flavonoids (e.g. naringenin and quercetin), anthraquinones, and small phenolic compounds (e.g. 4-nitrophenol). Drugs containing a carboxylic acid moiety, such as nonsteroidal anti-inflammatory agents (e.g.naproxen and ibuprofen) and fibrates (e.g. ciprofibrate), were substrates for human UGT1A3. In contrast, compounds containing an aliphatic hydroxyl group, such as sapogenins, monoterpenoid alcohols (e.g. menthol and borneol), and androgens, were not conjugated by expressed human UGT1A3. Of the compounds tested, scopoletin, naringenin, and norbuprenorphine appeared to be the best xenobiotic substrates for human UGT1A3.

Footnotes

  • Send reprint requests to: Dr. Thomas R. Tephly, Department of Pharmacology, 2–452 Bowen Science Building, The University of Iowa, Iowa City, IA 52242.

  • This work was supported by National Institutes of Health Grant GM26221 and The Australian National Health and Medical Research Council.

  • Abbreviations used are::
    UGT
    UDP-glucuronosyltransferase
    HK293 cells
    human embryonic kidney 293 cells
    NSAID
    nonsteroidal anti-inflammatory drug
    • Received November 26, 1997.
    • Accepted February 4, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition
Vol. 26, Issue 6
1 Jun 1998
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Research ArticleArticle

Glucuronidation of Amines and Other Xenobiotics Catalyzed by Expressed Human UDP-Glucuronosyltransferase 1A3

Mitchell D. Green, Christopher D. King, Behnaz Mojarrabi, Peter I. Mackenzie and Thomas R. Tephly
Drug Metabolism and Disposition June 1, 1998, 26 (6) 507-512;

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Research ArticleArticle

Glucuronidation of Amines and Other Xenobiotics Catalyzed by Expressed Human UDP-Glucuronosyltransferase 1A3

Mitchell D. Green, Christopher D. King, Behnaz Mojarrabi, Peter I. Mackenzie and Thomas R. Tephly
Drug Metabolism and Disposition June 1, 1998, 26 (6) 507-512;
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