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Luethi 2017 Toxicology

From Bioblast
Publications in the MiPMap
Luethi D, Liechti ME, Krähenbühl S (2017) Mechanisms of hepatocellular toxicity associated with new psychoactive synthetic cathinones. Toxicology 387:57-66.

» PMID: 28645576

Luethi D, Liechti ME, Kraehenbuehl S (2017) Toxicology

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 (0.2-1mM) than cytotoxicity occurred (0.5-2mM), suggesting mitochondrial toxicity. In comparison, methedrone and methylone depleted the cellular ATP pool and induced cytotoxicity at similar concentrations (≥2mM). 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.

Copyright © 2017 Elsevier B.V. All rights reserved. Keywords: Cathinones, Electron transport chain, Liver injury, Mitochondria, New psychoactive substances, ROS, HepG2 Bioblast editor: Kandolf G O2k-Network Lab: CH Basel Kraehenbuehl S

Labels: MiParea: Respiration, Pharmacology;toxicology 

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

Regulation: Inhibitor  Coupling state: OXPHOS, ET  Pathway: N, S, DQ, CIV, NS, ROX  HRR: Oxygraph-2k 

Labels, 2017-09