Poulsen H E, Lerche A, Pedersen N T
Pharmacology. 1985;30(2):100-8. doi: 10.1159/000138057.
Rats were pretreated with phenobarbital to induce hepatic cytochrome P-450. Compared to noninduced rats, a similar relation between the dose of acetaminophen and mortality, and between dose and changes in liver function (prothrombin index) and identical time courses, was found. The urinary excretion of acetaminophen mercapturate and acetaminophen cysteine was identical in induced and noninduced rats. The metabolism of acetaminophen in terms of blood levels and excreted metabolites was not influenced by phenobarbital induction. At the same dose level, hepatic necrosis was accelerated (maximum 24 h) compared to noninduced animals (maximum 72 h), but no difference in the maximum extent was found. These data cannot support the concept that induction of cytochrome P-450 leads to greater formation of the hypothetical toxic metabolite of acetaminophen, or that induction enhances its hepatotoxicity, in the rat. Several factors may contribute to accelerate the necrotic changes which make it possible to histologically identify cell damage and death. In that case, functional studies are more relevant than morphological evaluation in quantitative assessment of liver damage.
用苯巴比妥对大鼠进行预处理以诱导肝细胞色素P - 450。与未诱导的大鼠相比，发现对乙酰氨基酚剂量与死亡率之间、剂量与肝功能变化（凝血酶原指数）之间存在相似关系，且时间进程相同。对乙酰氨基酚巯基尿酸盐和对乙酰氨基酚半胱氨酸的尿排泄量在诱导和未诱导的大鼠中相同。就血药浓度和排泄代谢物而言，对乙酰氨基酚的代谢不受苯巴比妥诱导的影响。在相同剂量水平下，与未诱导的动物相比（最大72小时），肝坏死加速（最大24小时），但在最大程度上未发现差异。这些数据不支持细胞色素P - 450的诱导会导致对乙酰氨基酚假设的有毒代谢物形成增加，或诱导会增强其在大鼠中的肝毒性这一概念。有几个因素可能导致坏死变化加速，从而能够在组织学上识别细胞损伤和死亡。在这种情况下，在肝脏损伤的定量评估中，功能研究比形态学评估更具相关性。
