Holme J A, Søderlund E
Mutat Res. 1986 Jun;164(3):167-75. doi: 10.1016/0165-1161(86)90007-5.
The cytotoxic and genotoxic effects of phenacetin and paracetamol were examined in monolayer cultures of hepatocytes isolated from the mouse, hamster, rat and guinea pig. No marked increase in unscheduled DNA synthesis (UDS) after exposing hepatocytes from any of the species to phenacetin was observed. At cytotoxic concentrations of paracetamol, an increased UDS in mouse hepatocytes in vitro was observed. Pretreatment of the mice by inducers of drug-metabolizing enzymes, such as 3-methylcholanthrene and Aroclor 1254, lowered the concentration threshold for the toxic responses. With rat hepatocytes only a minor increase in UDS was noted, while with hepatocytes from hamsters and guinea pigs in fact a decrease was seen. The narrow range observed between the cytotoxic and genotoxic effects of paracetamol makes it difficult to predict whether the initial DNA damage could lead to a mutation or whether the cells will die before the mutation is expressed. With respect to the cytotoxic effects, hamster hepatocytes were found to be most susceptible to paracetamol, followed by mouse, while rat and guinea pig were less affected. These data were in accordance with in vivo findings (Davis et al., 1974), indicating the potential value of hepatocyte culture when screening for possible liver toxic substances.
对从小鼠、仓鼠、大鼠和豚鼠分离的肝细胞单层培养物中，检查了非那西丁和对乙酰氨基酚的细胞毒性和遗传毒性作用。未观察到将任何物种的肝细胞暴露于非那西丁后，其非预定DNA合成（UDS）有明显增加。在对乙酰氨基酚的细胞毒性浓度下，观察到体外培养的小鼠肝细胞中UDS增加。用药物代谢酶诱导剂（如3-甲基胆蒽和多氯联苯混合物Aroclor 1254）对小鼠进行预处理，降低了毒性反应的浓度阈值。对于大鼠肝细胞，仅观察到UDS略有增加，而对于仓鼠和豚鼠的肝细胞，实际上观察到UDS下降。对乙酰氨基酚的细胞毒性和遗传毒性作用之间观察到的狭窄范围，使得难以预测最初的DNA损伤是否会导致突变，或者细胞是否会在突变表达之前死亡。关于细胞毒性作用，发现仓鼠肝细胞对对乙酰氨基酚最敏感，其次是小鼠，而大鼠和豚鼠受影响较小。这些数据与体内研究结果一致（Davis等人，1974年），表明肝细胞培养在筛选可能的肝脏毒性物质时具有潜在价值。
