Abstract
Relationship between hepatotoxicity and erythrocyte membrane effect of clinically used drugs was investigated and the present studies were undertaken to clarify whether these methods are a useful model for screening of hepatotoxicity.
Isolated rat hepatocytes were prepared using collagenase. Cytotoxicity to isolated rat hepatocytes of various drugs was determined by the leakage of GOT, GPT and OCT into the surrounding media. Inhibition of hypotonic hemolysis of rat erythrocytes was measured as hemoglobin concentration.
The drugs such as tricyclic antidepressant and local anesthetics (dibucaine), which have both a membrane stabilizing effect on erythrocytes in lower concentrations and a hemolytic effect in higher concentrations, induced enzyme leakage from hepatocytes. The drugs such as iproniazid which only have a hemolytic effect or drugs such as β-blocker which only have a membrane stabilizing effect on erythrocytes, did not produce any direct hepatic cell damage. Iproniazid, isoniazid and their metabolite, acetylhydrazine did not induce enzyme leakage from hepatocytes. Aspirin and indomethacin caused only a slight enzyme leakage at the concentration of 1 × 10-3M. β-blockers did not have a direct damaging effect on hepatocyte membrane at the concentration of 1 × 10-3M. The order of membrane stabilizing and lytic potency of tricyclic antidepressants was chlorimipramine>amitriptyline>desipramine>imipramine. The agents, which have a membrane stabilizing effect on erythrocytes in lower concentrations and also have a hemolytic effect in higher concentrations, caused hepatic cell damage. These results suggest that membrane effects on erythrocytes of various drugs are useful for screening of hepatotoxicity in vitro.
