DRUG TOXICITY MECHANISMS IN HUMAN HEPATOMA HEPG2 CELLS - CYCLOSPORINE-A AND TAMOXIFEN

1. Mechanisms of drug toxicity operating in human HepG2 hepatoma cells have been assessed using cyclosporin A (CsA) and tamoxifen as example s. 2. Either 150 mu M CsA or 50 mu M tamoxifen caused approximately 50 % loss of HepG2 cell viability. alpha-Tocopherol (32 mu M) almost comp letely prevented cell death due to either CsA or tamoxifen. Tamoxifen stimulated malondialdehyde formation. The toxicity of CsA but not tamo xifen was increased by the glutathione synthesis inhibitor, buthionine -S,R-sulphoximine, and decreased by the glutathione precursor, L-cyste ine. Thus, while both CsA and tamoxifen toxicities involved lipid pero xidation, reduced glutathione (or sulphydryl groups) protected against CsA but not tamoxifen. 3. CsA was metabolized to M1 and/or M17 in Hep G2 cells. The effects of the cytochrome P450 inhibitors, ketoconazole and metyrapone, indicated that P450 played a role in the toxicity of C sA but not tamoxifen. The effects of superoxide dismutase and cytochro me c indicated that tamoxifen toxicity involved superoxide formation. 4. These results show that several oxidative mechanisms of drug toxici ty operate in HepG2 cells.