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

• Published in: Chemico-biological interactions 2010-03, Vol.184 (3), p.492-501
• Main Authors: Kim, Tae Hyun, Kim, Young Woo, Shin, Sang Mi, Kim, Choon Won, Yu, Il Je, Kim, Sang Geon
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; bcl-X Protein - metabolism; Carbon tetrachloride; Carbon Tetrachloride - toxicity; Caspase 3 - metabolism; Dimethylformamide; DMF; eIF-2 Kinase - metabolism; Endoplasmic Reticulum - drug effects; Endoplasmic Reticulum - metabolism; ER stress; Formamides - toxicity; Heat-Shock Proteins - genetics; Heat-Shock Proteins - metabolism; Hepatocyte death; Hepatotoxicity; Lactate Dehydrogenases - metabolism; Liver - drug effects; Liver - pathology; Poly(ADP-ribose) Polymerases - metabolism; Rats; Rats, Sprague-Dawley; Transaminases - metabolism
• ISSN: 0009-2797; 1872-7786
• DOI: 10.1016/j.cbi.2010.01.029

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 CCl 4 (0.2 ml/kg) alone caused small increases in plasma transaminases and lactate dehydrogenase activities. However, combinatorial treatment of DMF with CCl 4 markedly increased blood biochemical changes. Histopathology confirmed the synergism in hepatotoxicity. Moreover, DMF + CCl 4 caused PARP cleavage and caspase-3 activation, but decreased the level of Bcl-xL, all of which confirmed apoptosis of hepatocytes. Consistently, DMF + CCl 4 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 CCl 4 treatment. Whereas either DMF or CCl 4 treatment alone marginally changed the expression levels of glucose-regulated protein 78 and 94 and phosphorylated PKR-like ER-localized eIF2α kinase, concomitant treatment with DMF and CCl 4 synergistically induced them with increases in glucose-regulated protein 78 and C/EBP homologous protein mRNAs. Our results demonstrate that DMF treatment in combination with CCl 4 synergistically increases hepatocyte death, which may be associated with the induction of severe ER stress.