Mechanisms of hepatocellular toxicity associated with new psychoactive synthetic cathinones

Toxicology. 2017 Jul 15;387:57-66. doi: 10.1016/j.tox.2017.06.004. Epub 2017 Jun 20.

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.

Keywords: Cathinones; Electron transport chain; Liver injury; Mitochondria; New psychoactive substances; ROS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Alkaloids / toxicity*
  • Benzodioxoles / toxicity
  • Bupropion / toxicity
  • Chemical and Drug Induced Liver Injury / etiology*
  • Chemical and Drug Induced Liver Injury / metabolism
  • Chemical and Drug Induced Liver Injury / pathology
  • Dose-Response Relationship, Drug
  • Electron Transport Chain Complex Proteins / metabolism
  • Hep G2 Cells
  • Hepatocytes / drug effects*
  • Hepatocytes / metabolism
  • Hepatocytes / pathology
  • Humans
  • Lactic Acid / metabolism
  • Membrane Potential, Mitochondrial / drug effects
  • Methamphetamine / analogs & derivatives
  • Methamphetamine / toxicity
  • Mitochondria, Liver / drug effects
  • Mitochondria, Liver / metabolism
  • Mitochondria, Liver / pathology
  • Oxidative Phosphorylation / drug effects
  • Oxidative Stress / drug effects
  • Oxygen Consumption / drug effects
  • Pentanones / toxicity
  • Psychotropic Drugs / toxicity*
  • Pyrrolidines / toxicity
  • Reactive Oxygen Species / metabolism

Substances

  • 1-naphthalen-2-yl-2-pyrrolidin-1-ylpentan-1-one
  • 3,4-methylenedioxypyrovalerone
  • Alkaloids
  • Benzodioxoles
  • Electron Transport Chain Complex Proteins
  • Pentanones
  • Psychotropic Drugs
  • Pyrrolidines
  • Reactive Oxygen Species
  • Bupropion
  • Lactic Acid
  • Methamphetamine
  • cathinone
  • mephedrone
  • Adenosine Triphosphate