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Quantitative Analysis of Dietary Vitamin A Metabolites in Murine Ocular and Non-Ocular Tissues Using High-Performance Liquid Chromatography
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Three conazoles increase hepatic microsomal retinoic acid metabolism and decrease mouse hepatic retinoic acid levels

Pei-Jen Chen1, William T Padgett, Tanya Moore

  • 1Department of Agricultural Chemistry, National Taiwan University, Taipei, Taiwan.

Toxicology and Applied Pharmacology
|November 18, 2008
PubMed
Summary

Three conazoles, used as fungicides and pharmaceuticals, significantly altered all trans-retinoic acid (atRA) metabolism in mice. These fungicides decreased hepatic atRA levels, potentially impacting cell proliferation and tumorigenesis.

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Area of Science:

  • Toxicology and Pharmacology
  • Metabolism and Drug Interactions
  • Carcinogenesis and Cancer Prevention

Background:

  • Conazoles are widely used fungicides in agriculture and medicine.
  • Previous studies indicated triazole conazoles alter all trans-retinoic acid (atRA) metabolism, a vitamin A metabolite with cancer-preventative properties.
  • Understanding conazole effects on atRA metabolism is crucial for assessing potential health risks.

Purpose of the Study:

  • To investigate the effects of propiconazole, triadimefon, and myclobutanil on microsomal metabolism of atRA.
  • To identify hepatic cytochrome P450 (P450) enzymes involved in conazole-mediated atRA metabolism.
  • To determine the in vivo effects of these conazoles on hepatic atRA levels in mice.

Main Methods:

  • In vitro metabolism of atRA was measured in liver microsomes from mice treated with propiconazole, triadimefon, or myclobutanil.
  • Chemical and immuno-inhibition studies were used to identify involved P450 enzymes.
  • Gene expression (RT-qPCR) and protein levels (Western blot) of relevant P450s were analyzed; hepatic atRA levels were quantified.

Main Results:

  • All three conazoles significantly increased the formation of 4-hydroxy-atRA and 4-oxo-atRA in vitro.
  • Conazole treatment led to significant overexpression of Cyp2b, Cyp3a, and other P450 genes, with increased Cyp2b and Cyp3a protein levels.
  • In vivo, propiconazole, triadimefon, and myclobutanil decreased hepatic atRA levels by 45-67%.

Conclusions:

  • Propiconazole, triadimefon, and myclobutanil alter atRA metabolism by inducing specific hepatic cytochrome P450 enzymes.
  • These conazoles significantly reduce hepatic atRA levels in vivo.
  • The observed alterations in atRA metabolism and levels may have implications for cell proliferation and tumorigenesis.