4-Hydroxyretinoic acid, a novel substrate for human liver microsomal UDP-glucuronosyltransferase(s) and recombinant UGT2B7

Victor M. Samokyszyn, Walter E. Gall, Gregory Zawada, Mary Ann Freyaldenhoven, Guangping Chen, Peter I. Mackenzie, Thomas R. Tephly, Anna Radominska-Pandya

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    99 Citations (Scopus)

    Abstract

    It is suggested that formation of more polar metabolites of all-trans- retinoic acid (atRA) via oxidative pathways limits its biological activity. In this report, we investigated the biotransformation of oxidized products of atRA via glucuronidation. For this purpose, we synthesized 4-hydroxy-RA (4- OH-RA) in radioactive and nonradioactive form, 4-hydroxy-retinyl acetate (4- OH-RAc), and 5,6-epoxy-RA, all of which are major products of atRA oxidation. Glucuronidation of these retinoids by human liver microsomes and human recombinant UDP-glucuronosyltransferases (UGTs) was characterized and compared with the glucuronidation of atRA. The human liver microsomes glucuronidated 4-OH-RA and 4-OH-RAc with 6- and 3-fold higher activity than atRA, respectively. Analysis of the glucuronidation products showed that the hydroxyl-linked glucuronides of 4-OH-RA and 4-OH-RAc were the major products, as opposed to the formation of the carboxyl-linked glucuronide with atRA, 4- oxo-RA, and 5,6-epoxy-RA. We have also determined that human recombinant UGT2B7 can glucuronidate atRA, 4-OH-RA, and 4-OH-RAc with activities similar to those found in human liver microsomes. We therefore postulate that this human isoenzyme, which is expressed in human liver, kidney, and intestine, plays a key role in the biological fate of atRA. We also propose that atRA induces its own oxidative metabolism via a cytochrome P450 (CYP26) and is further biotransformed into glucuronides via UGT-mediated pathways.

    Original languageEnglish
    Pages (from-to)6908-6914
    Number of pages7
    JournalJournal of Biological Chemistry
    Volume275
    Issue number10
    DOIs
    Publication statusPublished - 10 Mar 2000

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