Synergistic hepatotoxicity of N,N-dimethylformamide with carbon tetrachloride in association with endoplasmic reticulum stress

Abstract

N,N-Dimethylformamide (DMF) is an organic solvent extensively used in industries such as synthetic leather, fibers and films, and induces liver toxicity and carcinogenesis. Despite a series of experimental and clinical reports on DMF-induced liver failure, the mechanism of toxicity is yet unclear. This study investigated whether DMF in combination with a low dose of hepatotoxicant enhances hepatotoxicity, and if so, on what mechanistic basis. Treatment of rats with either DMF (50-500 mg/kg/day, for 3 days) or a single low dose of CCl4 (0.2 ml/kg) alone caused small increases in plasma transaminases and lactate dehydrogenase activities. However, combinatorial treatment of DMF with CCl4 markedly increased blood biochemical changes. Histopathology confirmed the synergism in hepatotoxicity. Moreover, DMF + CCl4 caused PARP cleavage and caspase-3 activation, but decreased the level of Bcl-xL, all of which confirmed apoptosis of hepatocytes. Consistently, DMF + CCl4 treatment markedly increased lipid peroxidation. By contrast, treatment of DMF in combination with lipopolysaccharide, acetaminophen or D-galactosamine caused no enhanced hepatotoxicity. Given the link between endoplasmic reticulum (ER) dysfunction and cell death, ER stress response was monitored after DMF and/or CCl4 treatment. Whereas either DMF or CCl4