Buttar H S, Nera E A, Downie R H
Toxicology. 1976 Jun;6(1):9-20. doi: 10.1016/0300-483x(76)90003-2.
The dose- and time-related hepatotoxic effects of acetaminophen were investigated in rats using biochemical parameters as indices of hepatotoxicity supplemented by the histopathological examination of the livers. The acute or subacute (twice daily for 7 days) administration of 0.25 g/kg acetaminophen did not produce any noticeable hepatocellular damage. On the other hand, dose-dependent elevations in serum enzyme glutamic-oxaloacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT) and sorbitol dehydrogenase (SDH) activities and hepatic triglyceride (TG) levels were observed following the administration of single doses of 0.5 and lg/kg acetaminophen. Maximal hepatic damage occurred 12-18 h after acute dosing, while the hepatic function returned to control levels by 48-72 h. In contrast with the acutely treated rats, the serum enzyme activities and the hepatic TG levels remained unchanged following 7-day treatment with 0.5 or 1 g/kg acetaminophen. Also, histopathologically the degree of acetaminophen-induced hepatic necrosis was found to be far less extensive in rats given 0.5 and 1 g/kg acetaminophen twice daily for up to one week, as compared with the animals sacrificed 18 h after administering single equivalent doses of this drug. The results suggest that the liver function is reversibly impaired following acetaminophen overdosage, and that the intensity of acetaminophen-induced hepatotoxicity becomes less severe after repeated exposure to this hepatotoxin.
以生化参数作为肝毒性指标，并辅以肝脏组织病理学检查，研究了对乙酰氨基酚在大鼠体内与剂量和时间相关的肝毒性作用。0.25 g/kg对乙酰氨基酚急性或亚急性（每日两次，共7天）给药未产生任何明显的肝细胞损伤。另一方面，单次给予0.5和1 g/kg对乙酰氨基酚后，观察到血清酶谷氨酸草酰乙酸转氨酶（GOT）、谷氨酸丙酮酸转氨酶（GPT）和山梨醇脱氢酶（SDH）活性以及肝甘油三酯（TG）水平呈剂量依赖性升高。急性给药后12 - 18小时出现最大肝损伤，而肝功能在48 - 72小时恢复至对照水平。与急性处理的大鼠相比，0.5或1 g/kg对乙酰氨基酚治疗7天后血清酶活性和肝TG水平保持不变。此外，组织病理学发现，与单次给予等效剂量该药物18小时后处死的动物相比，每日两次给予0.5和1 g/kg对乙酰氨基酚长达一周的大鼠中，对乙酰氨基酚诱导的肝坏死程度要轻得多。结果表明，对乙酰氨基酚过量服用后肝功能会出现可逆性损害，并且反复接触这种肝毒素后，对乙酰氨基酚诱导的肝毒性强度会减轻。
