Tuntaterdtum S, Chaudhary I P, Cibull M, Robertson L W, Blouin R A
Graduate Center for Toxicology, University of Kentucky, Lexington 40536-0082.
Toxicol Appl Pharmacol. 1993 Dec;123(2):219-25. doi: 10.1006/taap.1993.1240.
The effect of phenobarbital (PB) and beta-naphthoflavone (beta-NF) on acetaminophen (APAP)-induced hepatotoxicity was evaluated in obese and lean Zucker rats. In addition, the consequences of APAP overdose on hepatic CYP2B1/2B2 enzyme activities following PB treatment were assessed. A single oral dose of APAP 3 g/kg (total body weight) was administered to both littermates 24 hr after the last dose of PB or beta-NF. Histologic evidence of hepatocellular necrosis and serum hepatic aminotransferase enzymes 48 hr after APAP administration was utilized to evaluate hepatic damage. Hepatic microsomal total cytochrome P450 concentrations, alkoxyresorufin O-dealkylase activities, and 16 beta-testosterone hydroxylase activities were determined to evaluate the effect of APAP overdose on cytochrome P450 enzyme-substrate activities in the presence and absence of PB treatment. APAP overdose produced lower hepatotoxicity in the obese Zucker rat compared to lean controls. A similar trend was observed in animals treated with PB prior to APAP administration. In contrast, beta-NF treatment produced potentiation of APAP toxicity and/or death of both obese and lean Zucker rats. Generally, APAP overdose produced reduction of hepatic cytochrome P450 enzyme-substrate activities. However, obese Zucker rats retained a higher percentage of their pre-APAP-treated enzyme activities which is consistent with the observation that obese Zucker rats are less affected by the hepatotoxic effects of APAP overdosage.
在肥胖和瘦的 Zucker 大鼠中评估了苯巴比妥（PB）和β-萘黄酮（β-NF）对乙酰氨基酚（APAP）诱导的肝毒性的影响。此外，还评估了 PB 治疗后 APAP 过量对肝脏 CYP2B1/2B2 酶活性的影响。在最后一剂 PB 或β-NF 给药 24 小时后，给同窝出生的大鼠均口服单剂量的 APAP 3 g/kg（总体重）。利用 APAP 给药后 48 小时肝细胞坏死的组织学证据和血清肝氨基转移酶来评估肝损伤。测定肝微粒体总细胞色素 P450 浓度、烷氧基试卤灵 O-脱烷基酶活性和 16β-睾酮羟化酶活性，以评估在有或无 PB 治疗的情况下 APAP 过量对细胞色素 P450 酶-底物活性的影响。与瘦对照组相比，APAP 过量在肥胖 Zucker 大鼠中产生的肝毒性较低。在 APAP 给药前用 PB 治疗的动物中也观察到类似趋势。相反，β-NF 治疗使肥胖和瘦的 Zucker 大鼠的 APAP 毒性增强和/或导致死亡。一般来说，APAP 过量会导致肝脏细胞色素 P450 酶-底物活性降低。然而，肥胖 Zucker 大鼠在 APAP 治疗前保留了较高百分比的酶活性，这与肥胖 Zucker 大鼠受 APAP 过量肝毒性影响较小的观察结果一致。
