Poulsen H E, Thomsen P
Department of Medicine A2152, Rigshospitalet, Copenhagen, Denmark.
Liver. 1988 Jun;8(3):151-6. doi: 10.1111/j.1600-0676.1988.tb00984.x.
The effect of dosing paracetamol, 4.25 g/kg BW, twice weekly for 18 weeks was assessed in female Wistar rats 24 h after the last dose. Hepatic function, estimated as the prothrombin index, was more depressed in rats given one paracetamol dose than in chronically treated rats. Cytochrome P-450 and protein concentrations in liver homogenate and microsomes were higher in chronically treated rats. Urinary excretion of paracetamol glucuronide and mercapturate was higher and paracetamol sulfate unchanged after the chronic treatment. Hepatic glutathione was identically depleted after one dose and chronic paracetamol treatment. Histological examination of livers from chronically treated animals showed varying degrees of centrilobular necrosis. We conclude that long-term treatment with paracetamol in toxic doses leads to partial maintenance of the well-known protective effect after a few toxic doses. Signs of chronic toxicity consisted of weight loss, progressing to death. We suggest this chronic toxicity to be due to methionine/cysteine deficiency since urinary excretion of sulfur-containing paracetamol metabolites closely corresponds to calculated dietary intake of sulfur-containing amino acids.
在末次给药24小时后，对雌性Wistar大鼠评估了以4.25克/千克体重的剂量每周两次给予扑热息痛，持续18周的效果。以凝血酶原指数评估的肝功能，在单次给予扑热息痛的大鼠中比在长期治疗的大鼠中更受抑制。长期治疗的大鼠肝脏匀浆和微粒体中的细胞色素P - 450和蛋白质浓度更高。长期治疗后，扑热息痛葡萄糖醛酸苷和巯基尿酸的尿排泄量更高，而硫酸扑热息痛未发生变化。单次给药和长期给予扑热息痛后，肝脏谷胱甘肽均同样耗竭。对长期治疗动物的肝脏进行组织学检查显示有不同程度的小叶中心坏死。我们得出结论，长期给予中毒剂量的扑热息痛会导致在几次中毒剂量后部分维持众所周知的保护作用。慢性毒性的迹象包括体重减轻，直至死亡。我们认为这种慢性毒性是由于蛋氨酸/半胱氨酸缺乏，因为含硫扑热息痛代谢物的尿排泄量与计算得出的含硫氨基酸饮食摄入量密切相关。
