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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

Intrinsic versus idiosyncratic drug-induced hepatotoxicity--two villains or one?

Robert A Roth1, Patricia E Ganey

  • 1Department of Pharmacology and Toxicology, Center for Integrative Toxicology, 221 Food Safety and Toxicology Bldg., Michigan State University, East Lansing, MI 48824, USA. rothr@msu.edu

The Journal of Pharmacology and Experimental Therapeutics
|December 19, 2009
PubMed

Insights

Drug-induced liver injury reactions, both intrinsic and idiosyncratic, may share similar mechanisms. Inflammatory stress can shift dose-response curves, potentially explaining the unique characteristics of idiosyncratic drug toxicity.

Area of Science:

  • Hepatotoxicity
  • Pharmacology
  • Toxicology

Background:

  • Drug-induced liver injury (DILI) is categorized as intrinsic or idiosyncratic.
  • Intrinsic DILI is dose-dependent and reproducible in animals.
  • Idiosyncratic DILI occurs unpredictably in a minority of patients and is not reproducible in standard animal models.

Purpose of the Study:

  • To investigate the potential shared mechanisms between intrinsic and idiosyncratic drug-induced liver injury.
  • To explore the role of inflammatory stress in modulating drug hepatotoxicity.

Main Methods:

  • Review of fundamental principles of dose-response relationships in toxicology.
  • Analysis of existing studies on drug hepatotoxicity, including acetaminophen and lipopolysaccharide (LPS) models.
  • Examination of data linking inflammatory stimuli to drug-induced hepatotoxicity in rodents.

Main Results:

  • Inflammatory stress, exemplified by LPS exposure, can shift the dose-response curve for acetaminophen hepatotoxicity to the left, enhancing toxicity.
  • A similar leftward shift in the dose-response curve for hepatotoxicity, induced by sporadic inflammatory episodes, could explain the characteristics of idiosyncratic DILI.
  • Several drugs causing idiosyncratic DILI in humans were found to be hepatotoxic in rodents when combined with an inflammatory stimulus.

Conclusions:

  • Intrinsic and idiosyncratic drug-induced liver injury reactions may not be fundamentally different.
  • Inflammatory stress is a critical factor that can bridge the gap between intrinsic and idiosyncratic DILI.
  • Understanding the influence of inflammatory modulators on drug toxicity is crucial for predicting and managing DILI.

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