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Research ArticleArticle

Glucuronidation of all-trans-Retinoic Acid and 5,6-Epoxy-all-trans-retinoic Acid

Activation of Rat Liver Microsomal UDP-Glucuronosyltransferase Activity by Alamethicin

Joanna M. Little, Paul A. Lehman, Susan Nowell, Victor Samokyszyn and Anna Radominska
Drug Metabolism and Disposition January 1997, 25 (1) 5-11;
Joanna M. Little
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Paul A. Lehman
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Susan Nowell
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Victor Samokyszyn
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Anna Radominska
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Activation of Rat Liver Microsomal UDP-Glucuronosyltransferase Activity by Alamethicin

Abstract

The effects of detergent, alamethicin (a channel-forming peptide), and the inducers phenobarbital and 3-methylcholanthrene on glucuronidation of all-trans-retinoic acid (atRA) and 5,6-epoxy-atRA have been investigated using liver microsomes from Sprague-Dawley and Fischer 344 rats. Conditions for enzymatic glucuronidation were optimized for substrate concentration, protein, and time by using atRA and Sprague-Dawley microsomes. With detergent-activated Sprague-Dawley microsomes, 5,6-epoxy-atRA was shown to be a significantly better substrate than atRA for microsomal glucuronidation (263 vs. 116 pmol/mg/min for 5,6-epoxy-atRA and atRA, respectively). The product of incubation of microsomes with atRA and UDP-glucuronic acid was identified as a glucuronide by β-glucuronidase hydrolysis and by HPLC analysis. Alamethicin was shown to be a highly effective activator of glucuronidation activity; atRA and 5,6-epoxy-atRA glucuronidation rates were increased 2- and 3-fold, respectively, compared with detergent activation. Alamethicin (but not detergent) significantly increased retinoid glucuronidation by microsomes from Fischer 344 rats treated with phenobarbital and 3-methylcholanthrene, compared with untreated controls. The two compounds were equally effective inducers of activity, although 5,6-epoxy-atRA was again the better substrate. The same control and induced Fischer rat microsomes were photolabeled with [32P]5-azido-UDP-glucuronic acid in the absence or presence of detergent, two concentrations of alamethicin, and a 10-fold molar excess of unlabeled UDP-glucuronic acid. Photoincorporation into microsomal proteins from detergent-disrupted induced microsomes was 2–3 times greater than that of controls. Alamethicin increased photoincorporation of the probe into UDP-glucuronosyltransferase proteins an additional 1.5–2-fold in control and induced microsomes, compared with the respective detergent-activated samples.

Footnotes

  • Send reprint requests to: Joanna M. Little, Division of Gastroenterology, University of Arkansas for Medical Sciences, 4301 W. Markham, Slot 567, Little Rock, AR 72205.

  • This work was supported by National Institutes of Health Grant DK45123 (A.R.).

  • Abbreviations used are::
    UDP-GlcUA
    UDP-glucuronic acid
    UGT
    UDP-glucuronosyltransferase
    atRA
    all-trans-retinoic acid
    atRAG
    all-trans-retinoyl-β-glucuronide
    RA
    retinoic acid
    RAG
    retinoyl-β-glucuronide
    3-MC
    3-methylcholanthrene
    PB
    phenobarbital
    • Received April 10, 1996.
    • Accepted October 1, 1996.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition
Vol. 25, Issue 1
1 Jan 1997
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Research ArticleArticle

Glucuronidation of all-trans-Retinoic Acid and 5,6-Epoxy-all-trans-retinoic Acid

Joanna M. Little, Paul A. Lehman, Susan Nowell, Victor Samokyszyn and Anna Radominska
Drug Metabolism and Disposition January 1, 1997, 25 (1) 5-11;

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Research ArticleArticle

Glucuronidation of all-trans-Retinoic Acid and 5,6-Epoxy-all-trans-retinoic Acid

Joanna M. Little, Paul A. Lehman, Susan Nowell, Victor Samokyszyn and Anna Radominska
Drug Metabolism and Disposition January 1, 1997, 25 (1) 5-11;
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