Induced hepatocytes as a metabolic activation system for the mouse-lymphoma assay

We have developed methods for the coculture of hepatocytes and mouse lymphoma cells and have shown that this system can be used for evaluating promutagens from several chemical classes (Brock et al., 1987). In the present study we investigated the use of hepatocytes isolated from rats pretreated with a cytochrome P-450 inducer (PB) or a P-448 inducer (BNF). CP-induced mutagenicity was higher in the presence of PB-induced hepatocytes than in control hepatocytes. Control and BNF-induced hepatocytes were evaluated with B(a)P, B(l)A, and BA. A dose-related positive response was observed with B(a)P and B(l)A both in the presence of control or induced hepatocytes; however, somewhat higher mutant frequencies were obtained in the presence of BNF-induced hepatocytes. BA induced a very weak positive response (approx. 2 X b.g.) in the presence of control hepatocytes and was weakly positive in the presence of BNF-induced hepatocytes. Benzene was tested using control and both PB- and BNF-induced hepatocytes. Neither of these approaches were successful in activating benzene to a mutagenic metabolite. These studies indicate that for some chemicals the mutagenic response of mouse lymphoma cells can be increased by inducing hepatocytes prior to isolation and cocultivation, and expands the use of hepatocytes for research evaluating chemicals requiring metabolic activation.