Response of isolated hepatocytes to organic and inorganic cytotoxins.

Thirty-four chemicals-diverse in structure, postulated mechanisms of action, and primary target organs--were tested for cytotoxic response in isolated hepatocyte suspensions from young male Sprague-Dawley rats. Hepatocytes were incubated in the presence and absence of the test chemicals in closed vessels fitted with side arms for serial sampling for up to 5 h at 37 degrees C with gentle shaking under an O2:CO2 (95:5) atmosphere. The parameters evaluated were glutamate-oxaloacetate transaminase and lactate dehydrogenase release from the cells, Trypan blue exclusion, cell count, urea synthesis capability, and steady-state ATP levels. All chemicals cytotoxic in animals following single or short-term repeated exposures caused statistically significant changes in one or more of these parameters in the 0.01-10-mM concentration range. Dimethylnitrosamine and thioacetamide were not as potent in the isolated cell system as expected from their in vivo hepatotoxicity, and the quantitative changes produced with thioacetamide in the hepatocytes were marginal, even at 10 mM. The solvents tested--ethanol, acetone, dimethyl sulfoxide (DMSO), and propylene glycol--were without effect. These results indicate that isolated hepatocyte suspensions are useful for the identification of cytotoxins in general and hepatotoxins in particular, but that their capability for yielding a quantitative index of cytotoxic potential for diverse chemical species remains to be demonstrated.