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The endoplasmic reticulum participated in drug metabolic toxicity

Qingcai Huang1, Youwen Chen1, Zhengjia Zhang1

  • 1School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China.

Cell Biology and Toxicology
|January 18, 2022
PubMed

Insights

Drug metabolic activation generates reactive metabolites that bind macromolecules, causing toxicity. The endoplasmic reticulum (ER) is a key site for this activation and is targeted, leading to ER stress, cell death, and inflammation.

Area of Science:

  • Pharmacology
  • Toxicology
  • Cell Biology

Background:

  • Drug metabolic activation can produce reactive metabolites.
  • Covalent binding of these metabolites to macromolecules is a known cause of drug toxicity.
  • Emerging evidence implicates the endoplasmic reticulum (ER) in drug metabolism and toxicity.

Purpose of the Study:

  • To summarize the generation and mechanisms of reactive metabolites during ER stress.
  • To review the associated cell death and inflammatory pathways.
  • To discuss the modulation of adaptive pathways, including the unfolded protein response (UPR).

Main Methods:

  • Literature review and synthesis of recent studies.
  • Analysis of mechanisms underlying ER stress and reactive metabolite formation.
  • Examination of cellular responses to ER stress and reactive metabolites.

Main Results:

  • Reactive metabolites are generated during drug metabolic activation within the ER.
  • The ER serves as a primary target for these reactive metabolites.
  • ER stress triggers cell death and inflammatory cascades, modulated by UPR pathways.

Conclusions:

  • The endoplasmic reticulum plays a critical role in drug-induced toxicity via reactive metabolite generation.
  • Understanding ER stress and UPR pathways is crucial for mitigating drug toxicity.
  • Targeting ER stress responses may offer therapeutic strategies against drug-induced adverse effects.
Keywords:
ApoptosisDrug metabolic toxicityEndoplasmic reticulumInflammationReactive metabolitesUnfolded protein response

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