Involvement of mitochondrial-mediated caspase-3 activation and lysosomal labilization in acrylamide-induced liver toxicity

Acrylamide (ACR) is a chemical frequently used in both industrial and synthetic processes and may be produced during food processing. ACR at very high concentrations is postulated to exert its toxicity through the stimulation of an oxidative stress. ACR in excessive doses induces the central nervous system, reproduction, and genetic toxicity. However, ACR effects on the liver, a major organ of drug metabolism, have not been adequately explored. In addition, the role of mitochondria in an ACR-mediated hepatotoxicity is still unclear. The aim of this study was to investigate the cytotoxic mechanisms attributed to ACR using isolated rat hepatocytes. Hepatocytes were isolated by the collagenase perfusion method and incubated with an EC502hr concentration of ACR for 3 hr. The EC502 hr of ACR on isolated rat hepatocytes was determined to be 1 mM. Based on our results, hepatocytes cytotoxicity of ACR (1 mM) was mediated by a reactive oxygen species formation and lipid peroxidation. Incubation of hepatocytes with ACR produced rapid hepatocyte glutathione depletion which is another marker of the cellular oxidative stress. ACR cytotoxicity was also associated with mitochondrial injury as evidenced by the decline of mitochondrial membrane potential and lysosomal membrane leakiness. Our results also showed that ACR induced caspase-3 activation, the final mediator of apoptosis signaling. These findings contribute to a better understanding underlying mechanisms involved in ACR hepatotoxicity originating from the oxidative stress and ending in mitochondrial/lysosomal damage and cell death signaling.

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