The role of enzyme induction and inhibition on cypermethrin hepatotoxicity

Cypermethrin at different concentrations (100, 200, 400 and 800 ng ml(-1)) was incubated with a primary culture of rat hepatocytes. Cypermethrin was cytotoxic to rat hepatocytes at concentrations of 200 ng ml(-1)or greater. Toxicity was measured by a decrease in cell viability and leakage of ALT and AST enzymes into the culture medium. The role of cytochrome P450 in the hepatotoxicity of cypermethrin insecticide was investigated in fresh hepatocytes isolated either from phenobarbital pretreated rats or control rats and coincubated with SKF525A. Pretreatment with phenobarbital strongly protected the hepatocytes against the cypermethrin induced loss of cell viability percentage and increased enzyme leakage percentage. Coincubation of the hepatocytes with SKF525A, a well-known cytochrome P450 inhibitor, substantially potentiated the effect of cypermethrin on cell viability and enzyme leakage. These results suggest that the cytocidal hepatotoxicity of cypermethrin in primary hepatocyte culture depends on its parent compound and phenobarbital, as a cytochrome P450 inducer, could be of therapeutic value.