Mechanisms of hepatocellular toxicity associated with new psychoactive synthetic cathinones. (15th July 2017)

• Record Type: Journal Article
• Authors: Luethi, Dino; Liechti, Matthias E.; Krähenbühl, Stephan
• Is Part Of: Toxicology. Volume 387(2017)
• Page Start: 57
• Page End: 66
• Publication Date: 2017-07-15
• Subjects: ADP adenosine-diphosphate -- AK adenylate kinase -- BSO buthionine sulfoximine -- CYP cytochrome P450 -- DMEM Dulbecco's Modified Eagle Medium -- DTNB 5, 5′-dithio-bis(2-nitrobenzoic acid) -- FCCP trifluoromethoxy carbonylcyanide phenylhydrazone -- FCS fetal calf serum -- GR glutathione reductase -- GSH glutathione (reduced) -- GSSG glutathione (oxidized) -- KPE potassium phosphate buffer -- MDMA 3, 4-methylenedioxymethamphetamine -- MDPV 3, 4-methylenedioxypyrovalerone -- O2− superoxide -- OCR oxygen consumption rate -- PBS phosphate-buffered saline -- PCA perchloric acid -- SRB sulforhodamine B -- TMRM tetramethylrhodamine methyl ester -- tGSH glutathione (total) -- β-NADPH β-nicotinamide adenine dinucleotide 2′-phosphate -- Δψm mitochondrial membrane potential; New psychoactive substances -- Cathinones -- Liver injury -- Mitochondria -- Electron transport chain -- ROS; Toxicology -- Periodicals; Chemicals -- Physiological effect -- Periodicals; 615.9005
• DOI: 10.1016/j.tox.2017.06.004
• Languages: English
• ISSNs: 0300-483X

Abstract

Abstract: Synthetic cathinones are a new class of psychostimulant substances. Rarely, they can cause liver injury but associated mechanisms are not completely elucidated. In order to increase our knowledge about mechanisms of hepatotoxicity, we investigated the effect of five frequently used cathinones on two human cell lines. Bupropion was included as structurally related drug used therapeutically. In HepG2 cells, bupropion, MDPV, mephedrone and naphyrone depleted the cellular ATP content at lower concentrations (0.2–1 mM) than cytotoxicity occurred (0.5–2 mM), suggesting mitochondrial toxicity. In comparison, methedrone and methylone depleted the cellular ATP pool and induced cytotoxicity at similar concentrations (≥2 mM). In HepaRG cells, cytotoxicity and ATP depletion could also be demonstrated, but cytochrome P450 induction did not increase the toxicity of the compounds investigated. The mitochondrial membrane potential was decreased in HepG2 cells by bupropion, MDPV and naphyrone, confirming mitochondrial toxicity. Bupropion, but not the other compounds, uncoupled oxidative phosphorylation. Bupropion, MDPV, mephedrone and naphyrone inhibited complex I and II of the electron transport chain, naphyrone also complex III. All four mitochondrial toxicants were associated with increased mitochondrial ROS and increased lactate production, which was accompanied by a decrease in the cellular total GSH pool for naphyrone and MDPV. In conclusion, bupropion, MDPV, mephedrone and naphyrone are mitochondrial toxicants impairing the function of the electron transport chain and depleting cellular ATP stores. Since liver injury is rare in users of these drugs, affected persons must have susceptibility factors rendering them more sensitive for these drugs.