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Rifampicin and isoniazid increase acetaminophen and isoniazid cytotoxicity in human HepG2 hepatoma cells

Laboratoire de Biologie Cellulaire, Faculte de Medecine et de Pharmacie, 4, Place Saint-Jacques

Catherine Viollon

Laboratoire de Biologie Cellulaire, Faculte de Medecine et de Pharmacie, 4, Place Saint-Jacques

Any Regnier

Laboratoire de Biologie Cellulaire, Faculte de Medecine et de Pharmacie, 4, Place Saint-Jacques

Alain Jacqueson

Laboratoire de Toxicologie, Faculté de Médecine et de Pharmacie, 4, Place Saint-Jacques, F-25030 Besançon

Lysiane Richert

Laboratoire de Biologie Cellulaire, Faculte de Medecine et de Pharmacie, 4, Place Saint-Jacques

Acetaminophen (APAP) induced a concentration-depen dent (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 day 3-treated compared to day 1- treated HepG2 cells. A 3-day preincubation of HepG2 cells with 5 ?M 3-methylcholanthrene (3MC), 50 ?M 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 ?M 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 and INH cytotoxicity in vitro in hepatocellular cells of human origin. It is in accordance with clinical observations of severe hepatotoxicity asso ciated with APAP or INH usage in patients receiving multiple drug therapy (INH, RFP) for tuberculosis or in alcoholics.

Key Words: HepG2 • cytotoxicity/drug interactions • acetamino phen • isoniazid • rifampicin

Human & Experimental Toxicology, Vol. 16, No. 1, 28-34 (1997)
DOI: 10.1177/0960327197016001061


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