Blouin R A, Dickson P, McNamara P J, Cibull M, McClain C
College of Pharmacy, University of Kentucky, Lexington.
J Pharmacol Exp Ther. 1987 Nov;243(2):565-70.
The obese Zucker rodent appears to lack a significant induction response after phenobarbital pretreatment. Induction of the hepatic cytochrome P-450 system with phenobarbital is known to enhance acetaminophen hepatotoxicity. The purpose of this study was to evaluate the influence of phenobarbital enzyme induction on acetaminophen hepatotoxicity in the obese and lean Zucker rodent. A preliminary study was performed evaluating the pharmacokinetics of acetaminophen in both the obese and lean Zucker rats. Data were utilized to calculate appropriate loading doses of acetaminophen during the subsequent hepatotoxicity study. Phenobarbital enzyme-inducing regimens were administered p.o. to achieve similar steady-state phenobarbital plasma concentrations. Control rats received appropriate placebo solutions. Serum hepatic transaminase enzymes and histologic evidence of hepatocellular necrosis were utilized to evaluate hepatic damage after p.o. administration of 1300 mg of acetaminophen to both obese and lean Zucker rats. Obese Zucker control animals had approximately 2.5 times the total hepatic glutathione content compared to their lean control (164.9 +/- 43.2 vs. 65.3 +/- 18.4 mumol/whole liver). Obese Zucker animals receiving only acetaminophen showed a trend toward a reduced incidence of hepatocellular necrosis compared to similarly treated lean littermates. Obese Zucker rodents pretreated with phenobarbital had an even more pronounced resistance to acetaminophen-induced hepatocellular necrosis (P less than .01) when compared to similarly treated lean littermates. Thus, acetaminophen hepatotoxicity is reduced in the obese Zucker rat and pretreatment with phenobarbital offers further protection against hepatocellular damage. We suggest that the previously unrecognized increase in hepatic glutathione plays a major role in the resistance of the obese Zucker rat to acetaminophen hepatotoxicity.
肥胖型 Zucker 啮齿动物在苯巴比妥预处理后似乎缺乏显著的诱导反应。已知用苯巴比妥诱导肝细胞色素 P - 450 系统会增强对乙酰氨基酚的肝毒性。本研究的目的是评估苯巴比妥酶诱导对肥胖型和瘦型 Zucker 啮齿动物对乙酰氨基酚肝毒性的影响。进行了一项初步研究，评估肥胖型和瘦型 Zucker 大鼠对乙酰氨基酚的药代动力学。利用这些数据计算后续肝毒性研究中对乙酰氨基酚的合适负荷剂量。经口服给予苯巴比妥酶诱导方案，以达到相似的苯巴比妥稳态血浆浓度。对照大鼠接受适当的安慰剂溶液。在肥胖型和瘦型 Zucker 大鼠口服 1300 mg 对乙酰氨基酚后，利用血清肝转氨酶和肝细胞坏死的组织学证据评估肝损伤。肥胖型 Zucker 对照动物的肝脏总谷胱甘肽含量约为瘦型对照动物的 2.5 倍（164.9±43.2 对 65.3±18.4 μmol/全肝）。仅接受对乙酰氨基酚的肥胖型 Zucker 动物与同样处理的瘦型同窝仔相比，肝细胞坏死发生率有降低的趋势。与同样处理的瘦型同窝仔相比，用苯巴比妥预处理的肥胖型 Zucker 啮齿动物对乙酰氨基酚诱导的肝细胞坏死具有更明显的抗性（P＜0.01）。因此，肥胖型 Zucker 大鼠对乙酰氨基酚的肝毒性降低，并且用苯巴比妥预处理可进一步保护其免受肝细胞损伤。我们认为，之前未被认识到的肝脏谷胱甘肽增加在肥胖型 Zucker 大鼠对乙酰氨基酚肝毒性的抗性中起主要作用。
