Membrane effects of various drugs on isolated rat hepatocytes and erythrocytes

The relationship between hepatotoxicity and membrane effects of clinically used drugs on erythrocytes was investigated. The cytotoxicity of various drugs to isolated rat hepatocytes was determined by the leakage of glutamic oxalacetic transaminase (GOT) and ornithine carbamyl transferase (OCT) into the surrounding medium. Inhibition of hypotonic hemolysis of rat erythrocytes was measured as the hemoglobin concentration in the supernatant solution. Drugs such as tricyclic antidepressants, local anesthetics (dibucaine), and bile acids (chenodeoxycholic acid), which have both a membrane stabilizing effect on erythrocytes at low concentrations and a hemolytic effect at higher concentrations, induced enzyme leakage from hepatocytes. The concentration at which hemolysis occurred corresponded to the concentration which caused a marked enzyme leakage from hepatocytes. These phenomena were observed for alkyltrimethylammonium salts (C10 to C16), the order of cytotoxicity to hepatocytes and erythrocytes was C16 greater than C14 greater than C12 greater than C10. Marked enzyme leakage was observed for chenodeoxycholic acid at 1 X 10(-3) M but not for ursodeoxycholic acid. The order of membrane stabilizing and lytic potency of tricyclic antidepressants was chlorimipramine greater than amitriptyline greater than desipramine greater than imipramine. These results suggest that these membrane effects of various drugs on erythrocytes may be useful for screening for hepatocytotoxicity in vitro.