Toxicity of vanadium on isolated rat liver mitochondria: a new mechanistic approach

Abstract

Vanadium as a trace element is considered essential for animals; however it has not yet been recognized as a micronutrient for humans. Most of the information on the biological effects of vanadium was related to metal's insulin-like, anti-hyperlipidemic and anticancer properties in low concentrations. According to the previous literature, mitochondria were proposed as an important target for vanadium cytotoxicity. In this study, the mitochondrial toxicity mechanisms of sodium metavanadate (vanadium V or V⁵⁺) were investigated in the isolated mitochondria obtained from rat liver by differential centrifugation and mitochondrial toxicity endpoints as well as mitochondrial sources of ROS formation were determined in both in vivo and in vitro using specific substrates and inhibitors. Single injection of V⁵⁺ into Wistar rat (10, 20 and 40 mg kg⁻¹, i.p.) caused a significant increase in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Isolated mitochondria from the V⁵⁺-treated rat liver showed a marked elevation in oxidative stress parameters accompanied by mitochondrial membrane potential (MMP) collapse as compared to a control group. On the other hand, our in vitro results with isolated mitochondria showed that different concentrations of V⁵⁺ (25–200 μM) induced significant (P < 0.05) progress in mitochondrial ROS formation, ATP depletion, GSH oxidation, mitochondrial outer membrane rupture, mitochondrial swelling and cytochrome c release before the mitochondrial potential collapse ensued. We also showed that the V⁵⁺ interaction with respiratory complex III is the major source of V⁵⁺-induced ROS formation. In general, our in vivo and in vitro data strongly supported that the V⁵⁺-induced liver toxicity is a result of the metal disruptive effect on the mitochondrial respiratory complexes I, II and III which are the obvious causes of metal-induced ROS formation and ATP depletion in liver cells which leads to cell death signalling via MPT pore opening and cytochrome c release.