Nicod L, Viollon C, Regnier A, Jacqueson A, Richert L
Laboratoire de Biologie Cellulaire, Faculté de Médecine et de Pharmacie, Besançon.
Hum Exp Toxicol. 1997 Jan;16(1):28-34. doi: 10.1177/0960327197016001061.
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.
对乙酰氨基酚（APAP）在人肝癌HepG2细胞中诱导出浓度依赖性（0 - 30 mM）的细胞毒性效应，当细胞内还原型谷胱甘肽（GSH）含量降低时，这种效应显著增强。与第1天处理的HepG2细胞相比，第3天处理的细胞中，APAP（0 - 30 mM）的细胞毒性效应显著降低。用5 μM 3 - 甲基胆蒽（3MC）、50 μM利福平（RFP）或1 mM异烟肼（INH）对HepG2细胞进行3天预孵育，可显著增强15 - 30 mM APAP的细胞毒性，INH和RFP增强约15 - 20%，3MC增强35 - 50%。用INH进行3天预孵育也可使10 mM APAP的细胞毒性增加（约20%），但3MC和RFP对其无影响。INH在第1天处理的HepG2细胞中诱导出浓度依赖性（0 - 40 mM）的细胞毒性效应，且不受细胞内GSH浓度降低的显著影响。INH对第3天处理的HepG2细胞无细胞毒性。用50 mM RFP或1 mM INH对HepG2细胞进行3天预孵育，分别使10 - 40 mM INH的细胞毒性显著增加约10%和10 - 25%。在这些浓度下，用3MC进行3天预孵育不会改变INH的细胞毒性效应。据我们所知，这是首次报道INH和RFP在体外增加人源肝细胞中APAP或INH的细胞毒性。这与在接受结核病联合药物治疗（INH、RFP）的患者或酗酒者中，APAP或INH使用相关的严重肝毒性的临床观察结果一致。
