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Human Liver Microphysiological System for Assessing Drug-Induced Liver Toxicity In Vitro
11:06

Human Liver Microphysiological System for Assessing Drug-Induced Liver Toxicity In Vitro

Published on: January 31, 2022

Proteomic identification of potential susceptibility factors in drug-induced liver disease

Kevin D Welch1, Bo Wen, David R Goodlett

  • 1Molecular and Cellular Toxicology Section, Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA. WelchKD@nhlbi.nih.gov

Chemical Research in Toxicology
|June 21, 2005
PubMed

Insights

Understanding drug-induced liver injury (DILI) is crucial. Comparing resistant and susceptible mice revealed novel protective factors and mitochondrial dysfunction in DILI, offering new insights into disease mechanisms.

Area of Science:

  • Hepatology
  • Proteomics
  • Toxicology

Background:

  • Drug-induced liver disease (DILD) poses significant health risks and hinders drug development.
  • Predicting DILD susceptibility and identifying risk factors remain challenging.
  • Previous studies linked factors like COX-2, IL-6, and IL-10 to DILD, but no single factor is absolute.

Purpose of the Study:

  • To elucidate the multifactorial basis of DILD by comparing hepatic proteomes of resistant and susceptible mouse strains.
  • To identify novel hepatoprotective factors and understand mechanisms underlying acetaminophen-induced liver injury (AILD).

Main Methods:

  • Comparative proteomic analysis using solution-based isotope-coded affinity tag (ICAT) liquid chromatography mass spectrometry.
  • Analysis of hepatic proteomes in SJL (resistant) and C57Bl/6 (susceptible) mouse strains subjected to APAP challenge.

Main Results:

  • Identification of novel proteins, including those involved in stress response, cell proliferation, and protein modification, with higher expression in resistant SJL mice.
  • Discovery of a selective loss of mitochondrial proteins in susceptible C57Bl/6 mice, suggesting mitochondrial dysfunction in AILD.
  • Implication of identified proteins as potential hepatoprotective factors against DILD.

Conclusions:

  • Comparative hepatic proteomic analysis is a valuable global approach for identifying DILD risk factors and mechanistic pathways.
  • Novel hepatoprotective factors and mitochondrial dysfunction are implicated in the differential susceptibility to DILD.
  • Findings pave the way for better prediction and prevention strategies for drug-induced liver injury.

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