Vanadium induces liver toxicity through reductive activation by glutathione and mitochondrial dysfunction

Abstract

Pentavalent vanadium (V 5+) (metavanadate salt) toxicity is a challenging problem to the health professionals and has been recognized as an industrial hazard that adversely affects human and animal health, but its cytotoxic mechanisms have not yet been completely understood. In this study, we investigated the cytotoxic mechanisms of V 5+ in freshly isolated rat hepatocytes. V 5+ cytotoxicity was associated with reactive oxygen species (ROS) formation, collapse of mitochondrial membrane potential, lysosomal membrane rupture and cytochrome c release into the hepatocyte cytosol. All of the above mentioned V 5+ -induced cytotoxicity markers were significantly (p < 0.05) prevented by ROS scavengers, antioxidants and mitochondrial permeability transition (MPT) pore sealing agents. Hepatocyte glutathione (GSH) was also rapidly oxidized and GSH-depleted hepatocytes were more resistant to lithium-induced oxidative stress markers. This suggests that V 5+ is activated by GSH. Our findings also showed that the lysosomotropic agents prevented V 5+ induced mitochondrial membrane potential collapse. On the other hand, mitochondrial MPT pore sealing agents inhibited lysosomal membrane damage caused by V 5+ . It can therefore be suggested that there is probably a toxic interaction (cross-talk) between mitochondrial and lysosomal oxidative stress generating systems, which potentiates ROS formation and further damages both sub-organelles in V 5+ -induced induced hepatotoxicity. In conclusion, V 5+ -induced cytotoxicity can be attributed to oxidative stress started from glutathione mediated metal reductive activation and continued by mitochondrial/lysosomal toxic interaction.

Involvement of P38 and ERK1/2 in mitochondrial pathways independent cell apoptosis in oviduct magnum epithelial cells of layers challenged with vanadium

“…Moreover, the increase in green coloration (JC‐1 monomers) in the merged images indicates that the △ψm depolarization was severe, implying that early apoptosis was occurring, supporting our apoptosis results. A similar study reported that V induced the depolarization of △ψm in hepatic cells . Although P38 and ERK1/2 inhibitors reduced V‐induced depolarization of △ψm , the JNK inhibitor did not have this effect.…”

“…A similar study reported that V induced the depolarization of 5ψm in hepatic cells. 32 Although P38 and ERK1/2 inhibitors reduced V-induced depolarization of 5ψm, the JNK inhibitor did not have this effect. It could be argued that while P38 and ERK1/2 participate in the mitochondrial pathway that regulate apoptosis in OMECs exposed to V, JNK mediates are involved through another pathway.…”

Neuroprotective Effect of Grewia carpinifolia Extract against Vanadium Induced Behavioural Impairment

“…Vanadium toxicity have been previously reported to induce anorexia [19] leading to the reduction in daily body weights which becomes significant following chronic exposure as reported by S á n c h e z et al [38] and T o d o r i c h et al…”

Vanadium: Risks and possible benefits in the light of a comprehensive overview of its pharmacotoxicological mechanisms and multi-applications with a summary of further research trends

“…7). It has been suggested that the hepatotoxic, nephrotoxic [48,62,[68][69][70][71], cardiotoxic [72], genotoxic [73,74], neurotoxic [72,75,76], and carcinogenic [48,77] effects of this metal as well as inflammatory and fibrotic changes in the lungs [78] are associated with the pro-oxidative potential of V and its ability to intensify LPO ( Fig. 7).…”