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Myeloperoxidase-Mediated Metabolic Activation of Aristolochic Acid I Aggravates Liver Injury Under Inflammatory

Yudi Jia1, Yanjia Zhao1, Xinxin Deng1

  • 1Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning110016, P. R. China.

Journal of Agricultural and Food Chemistry
|July 21, 2026
PubMed

Insights

Inflammation worsens aristolochic acid I (AAI) liver injury by increasing protein damage. Myeloperoxidase (MPO) mediates this activation, forming reactive metabolites that bind to proteins, contributing to AAI toxicity.

Area of Science:

  • Toxicology
  • Biochemistry
  • Immunology

Background:

  • Aristolochic acid I (AAI) is a nephrotoxic and carcinogenic compound.
  • Inflammation is known to exacerbate drug-induced liver injury.
  • The role of myeloperoxidase (MPO) in AAI-induced hepatotoxicity is not fully understood.

Purpose of the Study:

  • To investigate the role of inflammation and MPO in AAI-induced liver injury.
  • To identify reactive metabolites of AAI formed under inflammatory conditions.
  • To elucidate the mechanism of MPO-mediated AAI metabolic activation.

Main Methods:

  • Murine models of acetaminophen-induced inflammation and MPO-knockout mice were used.
  • Hepatic AAI-protein adduction was quantified.
  • Incubation studies with leukocytes and hypochlorous acid were performed to identify reactive intermediates.
  • LC-MS/MS was used to identify and characterize AAI-protein adducts.

Main Results:

  • Acetaminophen-induced inflammation significantly exacerbated AAI hepatotoxicity and protein adduction in mice.
  • MPO-knockout mice showed reduced liver injury and AAI-protein adducts.
  • A reactive intermediate, ALI-chloride (ALI-Cl), was identified as a key mediator of AAI activation by MPO.
  • ALI-Cl formed conjugates with cysteine and N-acetylcysteine, and with cellular proteins, matching adducts found in AAI-exposed mouse livers.

Conclusions:

  • Inflammation potentiates AAI hepatotoxicity through MPO-mediated metabolic activation.
  • MPO plays a critical role in generating reactive metabolites of AAI, leading to protein adduction and liver injury.
  • Understanding these mechanisms is crucial for managing AAI toxicity, especially in inflammatory contexts.
Keywords:
aristolactam I-chloride intermediatearistolochic acid Iinflammationmetabolic activationmyeloperoxidase

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