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Retinoids modulate thioacetamide-induced acute hepatotoxicity.

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Toxicological Sciences : an Official Journal of the Society of Toxicology
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Lifetime hepatic retinoid stores significantly influence xenobiotic metabolism and toxicity. Mice lacking these stores (Lrat(-/-)) showed no thioacetamide (TAA) induced liver injury, unlike wild-type mice, demonstrating retinoids

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Area of Science:

  • Hepatology
  • Toxicology
  • Biochemistry

Background:

  • Retinoids and xenobiotics mutually influence each other's metabolism and actions.
  • The impact of lifelong hepatic retinoid accumulation on xenobiotic metabolism remains poorly understood.

Purpose of the Study:

  • To investigate how endogenous hepatic retinoid stores affect xenobiotic metabolism and toxicity.
  • To determine the role of retinoid availability in thioacetamide (TAA)-induced liver injury.

Main Methods:

  • Hepatotoxicity was induced using thioacetamide (TAA) in wild-type (WT) mice and lecithin:retinol acyltransferase-deficient (Lrat(-/-)) mice, which lack hepatic retinoid stores.
  • Biochemical markers of liver injury, hepatic encephalopathy, oxidative stress, and xenobiotic-metabolizing enzyme activity were assessed.
  • The effect of exogenous retinyl acetate administration on TAA-induced hepatotoxicity in Lrat(-/-) mice was evaluated.

Main Results:

  • WT mice exhibited significant liver injury, hepatic encephalopathy, altered redox balance, and increased xenobiotic metabolism after TAA administration.
  • Lrat(-/-) mice showed no TAA-induced effects, indicating retinoid stores are crucial for TAA hepatotoxicity.
  • Supplementation with retinyl acetate induced TAA hepatotoxicity in Lrat(-/-) mice, confirming the role of retinoids.

Conclusions:

  • Endogenous hepatic retinoid stores play a critical role in modulating thioacetamide (TAA) hepatotoxicity in mice.
  • The findings highlight the significant impact of accumulated retinoids on the body's response to xenobiotic exposure.