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Inhibition of UDP-glucuronosyltransferases in rat liver microsomes by natural mutagens and carcinogens

K Grancharov1, H Engelberg, Z Naydenova

  • 1Institute of Molecular Biology, Bulgarian Academy of Sciences, Sofia.

Archives of Toxicology
|January 26, 2002
PubMed

Insights

Tannic acid and griseofulvin significantly inhibit UDP-glucuronosyltransferase (UGT) enzymes, which are crucial for drug metabolism. These natural compounds can block the glucuronidation of various substrates, impacting how the body processes toxins and medications.

Area of Science:

  • Pharmacology
  • Biochemistry
  • Toxicology

Background:

  • UDP-glucuronosyltransferase (UGT) enzymes are critical for the detoxification and elimination of xenobiotics and endogenous compounds.
  • Dietary compounds and drugs can modulate UGT activity, influencing drug efficacy and toxicity.
  • Understanding UGT inhibition is vital for predicting drug-drug interactions and assessing the safety of natural products.

Purpose of the Study:

  • To investigate the inhibitory potential of eight naturally occurring toxic compounds on rat liver microsomal UDP-glucuronosyltransferase (UGT) activity.
  • To characterize the inhibition kinetics of potent inhibitors, tannic acid and griseofulvin, against specific UGT substrates.

Main Methods:

  • Rat liver microsomes were used to assess UGT activity with 1-naphthol (1-NA), phenolphthalein (PPh), and 4-nitrophenol (4-NP) as substrates.
  • Inhibition assays were performed at various concentrations of tested compounds, including tannic acid and griseofulvin.
  • Kinetic studies were conducted to determine the type of inhibition and inhibition constants (Ki) for potent inhibitors.

Main Results:

  • Tannic acid and griseofulvin exhibited strong inhibition of UGT activity. At 1 mM, both compounds completely suppressed the glucuronidation of 1-NA and PPh, respectively.
  • Even at 50 microM, tannic acid caused nearly 50% inhibition of 1-NA conjugation.
  • UGT isoforms metabolizing 4-NP were generally less sensitive, except to griseofulvin. Kinetic analysis revealed uncompetitive inhibition by tannic acid and non-competitive/mixed-type inhibition by griseofulvin.

Conclusions:

  • Tannic acid and griseofulvin are potent inhibitors of specific rat liver UGT isoforms.
  • These findings highlight the potential for dietary components and certain drugs to interfere with drug metabolism via UGT inhibition.
  • Further research is warranted to assess the in vivo implications of tannic acid and griseofulvin on drug disposition and toxicity.

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