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Published on: June 9, 2017
Nrf2 in liver toxicology
Keiko Taguchi1, Thomas W Kensler2
1Department of Medical Biochemistry, Graduate School of Medicine, Tohoku University, 2-1 Seiryo-machi, Aoba, Sendai, 980-8575, Japan. keiko@med.tohoku.ac.jp.
Abstract:
Liver plays essential roles in the metabolism of many endogenous chemicals and exogenous toxicants. Mechanistic studies in liver have been at the forefront of efforts to probe the roles of bioactivation and detoxication of environmental toxins and toxicants in hepatotoxicity. Moreover, idiosyncratic hepatoxicity remains a key barrier in the clinical development of drugs. The now vast Nrf2 field emerged in part from biochemical and molecular studies on chemical inducers of hepatic detoxication enzymes and subsequent characterization of the modulation of drug/toxicant induced hepatotoxicities in mice through disruption of either Nrf2 or Keap1 genes. In general, loss of Nrf2 increases the sensitivity to such toxic chemicals, highlighting a central role of this transcription factor and its downstream target genes as a modifier to chemical stress. In this review, we summarize the impact of Nrf2 on the toxicology of multiple hepatotoxicants, and discuss efforts to utilize the Nrf2 response in predictive toxicology.
Insights
The Nrf2 pathway protects the liver from toxic chemicals. This review summarizes Nrf2
Area of Science:
- Toxicology and Molecular Biology
- Hepatotoxicity and Drug Development
Background:
- The liver is crucial for metabolizing endogenous and exogenous compounds.
- Understanding chemical bioactivation and detoxification is key to preventing liver injury.
- Idiosyncratic hepatotoxicity hinders drug development.
Purpose of the Study:
- To review the role of the Nrf2 pathway in liver toxicology.
- To explore the impact of Nrf2 on hepatotoxicant effects.
- To discuss using the Nrf2 response for predictive toxicology.
Main Methods:
- Literature review of mechanistic studies on Nrf2, Keap1, and hepatic detoxication.
- Analysis of studies involving Nrf2 or Keap1 gene disruption in mice.
- Examination of Nrf2's role in modulating drug/toxicant-induced hepatotoxicity.
Main Results:
- The Nrf2 pathway is central to defending against chemical stress in the liver.
- Loss of Nrf2 function generally increases sensitivity to hepatotoxic chemicals.
- Nrf2 activation influences the toxicity of various hepatotoxicants.
Conclusions:
- Nrf2 plays a critical role in mitigating chemical-induced liver injury.
- Targeting the Nrf2 response holds promise for predictive toxicology and drug safety.
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