Cytotoxic response profiles of cultured rat hepatocytes to selected aromatic hydrocarbons.
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abstract
Cultured rat hepatocytes were challenged with benzo[a]pyrene (BaP; 0.3-30 mum), naphthalene (NAPH; 0.1-100 mum), 2-methylnaphthalene (2-MNAPH; 0.1-100 mum), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; 0.001-1 nM), 2,3,7,8-tetrachlorodibenzofuran (TCDF; 0.005-5 nM) or pentachlorophenol (PCP; 0.1-100 mum) for 4-24 hr to define class-specific differences in hepatotoxic potential. Mitochondrial fragility and GSH status were monitored as indices of hepatocyte injury. A 4-hr challenge with BaP and PCP increased mitochondrial fragility in a concentration-dependent manner, while TCDD and TCDF elicited erratic increases, and NAPH and 2-MNAPH were without effect. Pretreatment of hepatocytes with 250 muM diamide enhanced the mitochondrial toxicity of BaP. The aryl hydrocarbon receptor agonists upregulated hepatocyte GSH levels by 24 hr, a response which in the case of BaP was preceded by varying degrees of GSH depletion between 6 to 16 hr. NAPH and 2-MNAPH transiently decreased hepatocyte GSH levels at 12 hr, but were without effect at later time points, while PCP did not modulate hepatocyte GSH levels. Modulation of hepatocyte GSH by BaP and TCDD was antagonized by 10 muM alpha-naphthoflavone. These data implicate oxidative mechanisms and aryl hydrocarbon receptor signalling in aromatic hydrocarbon hepatotoxicity.
