The relationship among microsomal enzyme induction, liver weight and histological change in rat toxicology studies
The relationship among microsomal enzyme induction, liver weight and histological change in rat toxicology studies
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DOI：
10.1016/s0278-6915(98)00066-0
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发表时间：
1998-09-01
影响因子：
4.3
通讯作者：
Burkhardt, JE
中科院分区：
文献类型：
--
作者：
Amacher, DE;Schomaker, SJ;Burkhardt, JE
本研究的目的是确定在临床前毒理学研究中给予高剂量治疗剂的大鼠中伴随肝脏肿大和微粒体酶诱导的组织学变化（如果有的话）。这是通过评估数据库来实现的，该数据库源自对大鼠进行的一系列 11 项诱导研究，其中包括 5 种治疗类别的 10 种新型化合物。对血清酶化学分析、总器官重量变化和肝切片组织学分析的结果进行评估，并与肝细胞色素 P450 诱导的幅度和程度进行比较。在研究期间，所有化合物均通过口腔插管每天一次，使用多次剂量，每次剂量根据体重按比例给药。在这些研究过程中，记录了血清临床化学数据和临床观察结果。尸检后，进行组织病理学观察，并测定肝微粒体的细胞色素 P450 含量和相关药物代谢酶。在某些情况下，还测定了棕榈酰辅酶 A 的氰化物不敏感 β 氧化。肝脏重量增加 20% 或以上与肥大的组织学证据相关，但肥大的严重程度和肝脏重量增加的幅度与药物代谢酶升高的幅度无关。单独的肥大与血清酶的增加无关。虽然肝脏重量增加的发生率与微粒体酶诱导之间存在相关性，但这些增加的幅度并不相关。血清甘油三酯降低通常与肝过氧化物酶体增殖导致的β-氧化升高有关。结论是，虽然偶尔观察到轻微的 ALT 升高，但肝微粒体酶诱导通常不伴随显着的形态变化或被认为表明肝损伤的血清酶水平升高。 (C) 1998 Elsevier Science Ltd. 保留所有权利。
The purpose of this study was to determine what histological changes, if any, accompany liver enlargement and microsomal enzyme induction in rats administered high doses of therapeutic agents in preclinical toxicology studies. This was accomplished by evaluating a database derived from a series of 11 induction studies in rats with 10 novel compounds comprising five therapeutic classes. Results from serum enzyme chemistry analyses, gross organ weight changes, and histological analyses of the liver sections were evaluated and compared with the magnitude and extent of hepatic cytochrome P450 induction. All compounds were administrated via oral intubation once a day for the duration of the study using multiple doses, each proportionally based on body weight. During the course of these studies, serum clinical chemistry data and clinical observations were recorded. After necropsy, histopathology observations were made, and hepatic microsomes were assayed for cytochrome P450 content and associated drug-metabolizing enzymes. In some cases, cyanide-insensitive beta-oxidation of palmitoyl CoA was also assayed. Liver weight increases of 20% or greater were associated with histological evidence of hypertrophy, but neither the severity of hypertrophy nor the magnitude of liver weight increase correlated with the magnitude of drug-metabolizing enzyme elevations. Hypertrophy alone was not associated with serum enzyme increases. While there was a correlation between the incidence of increased liver weights and microsomal enzyme induction, the magnitudes of these increases were not related. Decreased serum triglycerides were often associated with elevated beta-oxidation attributed to hepatic peroxisome proliferation. It was concluded that, while slight ALT elevations occasionally were observed, hepatic microsomal enzyme induction was generally not accompanied by substantial morphological changes or elevated serum enzyme levels considered indicative of liver injury. (C) 1998 Elsevier Science Ltd. All rights reserved.