Drug toxicity mechanisms in human hepatoma HepG2 cells: cyclosporin A and tamoxifen.
1. Mechanisms of drug toxicity operating in human HepG2 hepatoma cells have been assessed using cyclosporin A (CsA) and tamoxifen as examples. 2. Either 150 microM CsA or 50 microM tamoxifen caused approximately 50% loss of HepG2 cell viability. alpha-Tocopherol (32 microM) almost completely prevented cell death due to either CsA or tamoxifen. Tamoxifen stimulated malondialdehyde formation. The toxicity of CsA but not tamoxifen was increased by the glutathione synthesis inhibitor, buthionine-S,R-sulphoximine, and decreased by the glutathione precursor, L-cysteine. Thus, while both CsA and tamoxifen toxicities involved lipid peroxidation, reduced glutathione (or sulphydryl groups) protected against CsA but not tamoxifen. 3. CsA was metabolized to M1 and/or M17 in HepG2 cells. The effects of the cytochrome P450 inhibitors, ketoconazole and metyrapone, indicated that P450 played a role in the toxicity of CsA but not tamoxifen. The effects of superoxide dismutase and cytochrome c indicated that tamoxifen toxicity involved superoxide formation. 4. These results show that several oxidative mechanisms of drug toxicity operate in HepG2 cells.
Duthie
S J
SJ
Department of Biomedical Sciences, University of Aberdeen, Marischal College, UK.
Melvin
W T
WT
Burke
M D
MD
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000378:metabolism / Q000633:toxicity*; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D016572:Cyclosporine / Q000378:metabolism / Q000633:toxicity*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008054:Lipid Peroxides / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D008315:Malondialdehyde / Q000378:metabolism; D013629:Tamoxifen / Q000378:metabolism / Q000633:toxicity*; D014407:Tumor Cells, Cultured; D014810:Vitamin E / Q000494:pharmacology
D018931:Antineoplastic Agents, Hormonal; D002273:Carcinogens; D065607:Cytochrome P-450 Enzyme Inhibitors; D008054:Lipid Peroxides; D013629:Tamoxifen; D014810:Vitamin E; D008315:Malondialdehyde; D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System; D005978:Glutathione