Department of Chemistry Seminar - Roles of Inflammation and Myeloperoxidase in Aristolochic Acid I-Induced Liver Injury and Identification of Reactive Metabolites

Speaker: Dr. Hui LI

Institution: School of Pharmacy, Shenyang Pharmaceutical University, China

Hosted By: Professor Simon Wan CHAN

Abstract

Aristolochic acids (AAs) are the most prevalent phytotoxins in Aristolochiaceae plants, and humans are frequently exposed to them through medicinal and environmental sources. However, the underlying mechanism linking AA exposure, inflammation, and carcinogenesis remains largely unclear. The present study demonstrated for the first time that hepatitis (inflammation) induced by acetaminophen potentiated hepatotoxicity of AAI (the most representative AA) in mice and increased hepatic AAI-protein adduction, whereas MPO-knockout mice exhibited attenuated liver injury and fewer adducts. Further investigation revealed that MPO mediates the metabolic activation of AAI, specifically its metabolite ALI, forming a reactive ALI-chloride intermediate (ALI-Cl). ALI-Cl reacted with N-acetylcysteine or cysteine to form conjugates and also bound to cysteine residues on cellular proteins in leukocytes. Notably, the resulting ALI-protein adduct matched that found in the liver of AAI-exposed mice, indicating that this protein adduction is responsible for liver injury. This study provides mechanistic insights into AAI toxicity under inflammatory conditions