Pyrrolizidine Alkaloid-induced Hepatotoxicity by Mitochondrial Damage
Refereed conference paper presented and published in conference proceedings

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AbstractPyrrolizidine alkaloids (PAs) are naturally occurring heterocyclic compounds that can cause severe toxicities particularly in the liver. The reactive pyrroles formed by hepatic metabolic activation of toxic PAs can rapidly bind to intracellular proteins forming pyrrole-protein adducts, which is deemed to be a major trigger initiating PA-induced hepatotoxicity. Our previous proteomic study has illustrated that ATP5B, a critical subunit of ATP synthase, could be a potential target for PA-induced hepatotoxicity. The present study aimed to further investigate the direct interaction between the reactive pyrroles and ATP5B, and also to examine the subsequent cascade of hepatotoxic events after such interaction. The immunoprecipitation of ATP5B coupled with Western blot analysis using anti-pyrrole-protein antibody demonstrated that reactive pyrroles covalently bind with ATP5B to form pyrrole-ATP5B adducts in the liver of rats treated with a representative hepatotoxic PA, retrorsine, and also in the retrorsine-treated human HepaRG hepatocytes. Further study in HepaRG hepatocytes, the ATP synthase activity were significantly reduced after the treatment of retrorsine for 6 hr. Retrorsine induced mitochondrial damage demonstrated by depolarization of mitochondrial membrane potential and dose-dependent inhibition of mitochondrial aerobic respiration. Subsequently, at 18 hr after retrorsine treatment, cell apoptosis was evidenced by a significant elevation of caspase 3/7 activity and significantly increased numbers of apoptotic cells assessed by Annexin V/propidium iodide apoptosis assay. To the best of our knowledge, our results revealed for the first time that hepatotoxicity of PA was triggered, at least in part, by the direct interaction of ATP5B with the reactive metabolite of PA followed by impairing mitochondrial function.
All Author(s) ListLu Yao, Ma Jiang, Lian Wei, Fu Peter & Lin Ge
Name of ConferenceExperimental Biology 2017
Start Date of Conference22/04/2017
End Date of Conference26/04/2017
Place of ConferenceChicago
Country/Region of ConferenceUnited States of America
Proceedings TitleThe FASEB Journal
Volume Number31
Issue NumberSuppl. 1
LanguagesEnglish-United States

Last updated on 2018-20-01 at 18:38