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Abegg 2024 Toxicol Lett

From Bioblast
Publications in the MiPMap
Abegg VF, Panajatovic MV, Mancuso RV, Allard JA, Duthaler U, Odermatt A, Krähenbühl S, Bouitbir J (2024) Mechanisms of hepatocellular toxicity associated with the components of St. John's Wort extract hypericin and hyperforin in HepG2 and HepaRG cells.

» Toxicol Lett [Epub ahead of print]. PMID: 38219807 Open Access

Abegg Vanessa Fabienne, Panajatovic Miljenko Valentin, Mancuso Riccardo Vincenzo, Allard Julien Arthur, Duthaler Urs, Odermatt Alex, Kraehenbuehl Stephan, Bouitbir Jamal (2024) Toxicol Lett

Abstract: St. John's Wort preparations are used for the treatment of mild to moderate depression. They are usually well tolerated but can cause adverse reactions including liver toxicity in rare cases. To date, the mechanism(s) underlying the hepatotoxicity of St. John's Wort extracts are poorly investigated. We studied the hepatocellular toxicity of hypericin and hyperforin as the two main ingredients of St. John's Wort extracts in HepG2 cells and HepaRG cells and compared the effects to citalopram (a synthetic serotonin uptake inhibitor) with a special focus on mitochondrial toxicity and oxidative stress. In HepG2 cells, hypericin was membrane-toxic at 100µM and depleted ATP at 20µM. In HepaRG cells, ATP depletion started at 5µM. In comparison, hyperforin and citalopram were not toxic up to 100µM. In HepG2 cells, hypericin decreased maximal respiration starting at 2µM and mitochondrial ATP formation starting at 10µM but did not affect glycolytic ATP production. Hypericin inhibited the activity of complex I, II and IV of the electron transfer system and caused mitochondrial superoxide accumulation in cells. The protein expression of mitochondrial superoxide dismutase 2 (SOD2) and thioredoxin 2 (TRX2) and total and reduced glutathione decreased in cells exposed to hypericin. Finally, hypericin diminished the mitochondrial DNA copy number and caused cell necrosis but not apoptosis. In conclusion, hypericin, but not hyperforin or citalopram, is a mitochondrial toxicant at low micromolar concentrations. This mechanism may contribute to the hepatotoxicity occasionally observed in susceptible patients treated with St. John's Wort preparations. Keywords: Hepatotoxicity, Hypericin, Mitochondrial function, Necrosis, Oxidative stress, St. John’s Wort Bioblast editor: Plangger M O2k-Network Lab: CH Basel Kraehenbuehl S

Labels: MiParea: Respiration, Pharmacology;toxicology 

Organism: Human  Tissue;cell: Liver  Preparation: Permeabilized cells, Intact cells 

Coupling state: LEAK, ROUTINE, OXPHOS, ET  Pathway: N, S, DQ, CIV, ROX  HRR: Oxygraph-2k