Rifampicin and isoniazid increase acetaminophen and isoniazid cytotoxicity in human HepG2 hepatoma cells.
Acetaminophen (APAP) induced a concentration-dependent (0-30 mM) cytotoxic effect in human HepG2 hepatoma cells which was significantly increased when intracellular reduced glutathione (GSH) content was decreased. The cytotoxic effect of APAP (0-30 mM) was significantly lower in a day 3-treated compared to day 1-treated HepG2 cells. A 3-day preincubation of HepG2 cells with 5 microM 3-methylcholanthrene (3MC), 50 microM rifampicin (RFP) or 1 mM isoniazid (INH) significantly increased 15-30 mM APAP cytotoxicity, of about 15-20% for INH and RFP and 35-50% for 3MC. The cytotoxicity of 10 mM APAP was also increased (about 20%) by a 3-day preincubation with INH but was not affected by 3MC and RFP. INH induced a concentration-dependent (0-40 mM) cytotoxic effect in day-1 treated HepG2 cells and not significantly affected by decreases in intracellular GSH concentrations. INH was not cytotoxic in day 3-treated HepG2 cells. A 3-day preincubation of HepG2 cells with 50 mM RFP or 1 mM INH significantly increased 10-40 mM INH cytotoxicity, respectively of about 10% and 10-25%. A 3-day preincubation with 3MC did not modify the cytotoxic effect of INH at these concentrations. This is to our knowledge the first report of increases by INH and RFP of APAP of INH cytotoxicity in vitro in hepatocellular cells of human origin. It is in accordance with clinical observations of severe hepatotoxicity associated with APAP or INH usage in patients receiving multiple drug therapy (INH, RFP) for tuberculosis or in alcoholics.
Nicod
L
L
Laboratoire de Biologie Cellulaire, Faculté de Médecine et de Pharmacie, Besançon.
Viollon
C
C
Regnier
A
A
Jacqueson
A
A
Richert
L
L
D000082:Acetaminophen / Q000633:toxicity*; D018712:Analgesics, Non-Narcotic / Q000633:toxicity*; D000995:Antitubercular Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced* / Q000503:physiopathology; D002470:Cell Survival / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007538:Isoniazid / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000503:physiopathology; D008748:Methylcholanthrene / Q000494:pharmacology; D012293:Rifampin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D018712:Analgesics, Non-Narcotic; D000995:Antitubercular Agents; D000082:Acetaminophen; D008748:Methylcholanthrene; D003577:Cytochrome P-450 Enzyme System; D005978:Glutathione; D007538:Isoniazid; D012293:Rifampin