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The inhibition of UDP-glucuronosyltransferases (UGTs) by vitamin A

Xin Liu1, Yun-Feng Cao2,3, Pei-Pei Dong4

  • 1a First Affiliated Hospital of Liaoning Medical University , Jinzhou , Liaoning , China.

Xenobiotica; the Fate of Foreign Compounds in Biological Systems
|July 1, 2016
PubMed

Insights

High vitamin A levels can cause adverse effects by inhibiting UDP-glucuronosyltransferases (UGTs). This study reveals vitamin A competitively inhibits key UGT isoforms, offering new insights into toxicity mechanisms.

Area of Science:

  • Pharmacology
  • Biochemistry
  • Toxicology

Background:

  • Elevated plasma vitamin A levels can result from inadvertent or clinical use.
  • The precise mechanisms underlying vitamin A's adverse effects remain incompletely understood.
  • Investigating vitamin A's impact on drug-metabolizing enzymes offers a novel perspective on its toxicity.

Purpose of the Study:

  • To investigate the inhibitory effects of vitamin A on UDP-glucuronosyltransferase (UGT) activity.
  • To elucidate the mechanism by which vitamin A may cause adverse effects through UGT inhibition.
  • To provide a new understanding of vitamin A toxicity at high exposure levels.

Main Methods:

  • In vitro incubation systems using UGT supersomes to assess enzyme activity.
  • Probe reactions with 4-methylumbelliferone (4-MU), trifluoperazine (TFP), and cotinine to evaluate UGT inhibition.
  • In silico molecular docking to explore the interaction between vitamin A and UGT2B7.

Main Results:

  • Vitamin A significantly inhibited all tested UGT isoforms at 100 μM concentration.
  • Competitive inhibition was observed for UGT1A1, UGT2B4, UGT2B7, and UGT2B15, with calculated Ki values.
  • Molecular docking indicated hydrogen bonds and hydrophobic interactions contribute to UGT2B7 inhibition by vitamin A.

Conclusions:

  • Vitamin A inhibits the activity of critical phase II drug-metabolizing enzymes, the UGTs.
  • This inhibition provides a potential mechanism for the adverse effects observed with high vitamin A exposure.
  • The findings offer a new perspective on vitamin A toxicity and drug metabolism interactions.
Keywords:
Enzyme inhibitionUDP-glucuronosyltransferases (UGTs)vitamin A

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