Rodrigues A D, Machinist J M
Drug Metabolism Department, Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois 60064, USA.
Toxicol Appl Pharmacol. 1996 Apr;137(2):193-201. doi: 10.1006/taap.1996.0072.
The effects of zileuton, a 5-lipoxygenase inhibitor, on hepatic peroxisomal enzyme activity as well as hepatic drug metabolizing activity in male and female CD-1 mice were assessed after oral administration of the drug (50, 150, or 450 mg/kg/day) for 14 days. The effects were compared to those in mice receiving clofibrate (CLOF;462 mg/kg/day, po) or sodium phenobarbital (PB; 50 mg/kg/day, po). Zileuton pretreatment caused hepatomegaly and elevated liver peroxisomal KCN-insensitive palmitoyl CoA oxidase activity in a dose-dependent manner. However, these changes were marginal (< or = 121% increase), when compared to those elicited by CLOF (approximately 370% increase). In both sexes, zileuton pretreatment also caused a dose-dependent increase in the levels of liver microsomal cytochrome P450 2B and cytochrome P450 4A (CYP4A) proteins, and their associated monoxygenase activity. In the case of CYP4A, the induction of lauric acid 12-hydroxylase activity by zileuton was more pronounced in female (maximal 851% increase) than in male mice (maximal 111% increase). Based on the dose normalized response observed in CD-1 mice, zileuton can be considered a relatively weak inducer of peroxisome enzyme activities (cf.CLOF) and a moderate inducer of cytochromes P450. Moreover, zileuton exhibits characteristics of both a PB- and a CLOF-type hepatic enzyme inducer, especially in the female mice.
在雄性和雌性CD - 1小鼠口服齐留通（一种5 - 脂氧合酶抑制剂，剂量为50、150或450 mg/kg/天）14天后，评估其对肝脏过氧化物酶体酶活性以及肝脏药物代谢活性的影响。将这些影响与接受氯贝丁酯（CLOF；462 mg/kg/天，口服）或苯巴比妥钠（PB；50 mg/kg/天，口服）的小鼠的影响进行比较。齐留通预处理以剂量依赖的方式导致肝肿大并提高肝脏过氧化物酶体对氰化钾不敏感的棕榈酰辅酶A氧化酶活性。然而，与氯贝丁酯引起的变化（约370%的增加）相比，这些变化较小（增加≤121%）。在两性中，齐留通预处理还导致肝脏微粒体细胞色素P450 2B和细胞色素P450 4A（CYP4A）蛋白水平及其相关的单加氧酶活性呈剂量依赖性增加。就CYP4A而言，齐留通对月桂酸12 - 羟化酶活性的诱导在雌性小鼠中（最大增加851%）比在雄性小鼠中（最大增加111%）更明显。基于在CD - 1小鼠中观察到的剂量标准化反应，齐留通可被认为是过氧化物酶体酶活性的相对弱诱导剂（与氯贝丁酯相比）和细胞色素P450的中度诱导剂。此外，齐留通表现出PB型和CLOF型肝脏酶诱导剂的特征，尤其是在雌性小鼠中。
