Chaudhary I P, Tuntaterdtum S, McNamara P J, Robertson L W, Blouin R A
Division of Pharmacology and Experimental Therapeutics, College of Pharmacy, University of Kentucky, Lexington.
J Pharmacol Exp Ther. 1993 Jun;265(3):1333-8.
The effect of genetic obesity and phenobarbital treatment on hepatic conjugation pathways was evaluated in the obese Zucker rat. Acetaminophen pharmacokinetic parameters were examined in vivo after a 30-mg/kg acetaminophen intravenous bolus dose in the presence and absence of phenobarbital treatment. Glucuronidation and glutathione conjugation pathways were studied in vitro in obese and lean Zucker rats after phenobarbital treatment. Obese Zucker rats demonstrated a higher glucuronidation capacity as evidenced by a higher formation clearance of acetaminophen glucuronide and greater UDP-glucuronosyltransferase (UDPGT) activity toward acetaminophen and p-nitrophenol compared with lean controls. Sulfate and glutathione conjugation pathways were not affected by genetic obesity. Obese Zucker rats possessed a higher total hepatic glutathione content due to greater liver weight. Phenobarbital treatment enhanced glucuronidation of acetaminophen and structurally related compounds (i.e., p-nitrophenol) similarly in both phenotypes, but the treatment failed to induce morphine UDPGT in the obese Zucker rat. No effect of phenobarbital was observed on sulfate conjugation, gamma-glutamyl cysteine synthetase activity or hepatic glutathione content in obese or lean Zucker rats. Similar increases in glutathione transferase activities were observed in animals of both phenotypes after phenobarbital treatment. This study demonstrates that glucuronidation is enhanced in genetically obese rats, whereas phenobarbital causes normal induction of several enzymes of the glucuronidation and glutathione conjugation pathways in the obese Zucker rat. However, morphine UDPGT was not induced by phenobarbital, suggesting that obese Zucker rats may possess a defect in the induction of this enzyme similar to that already described for the CYP2B gene in this strain.
在肥胖的Zucker大鼠中评估了遗传性肥胖和苯巴比妥治疗对肝脏结合途径的影响。在给予或不给予苯巴比妥治疗的情况下，静脉注射30mg/kg对乙酰氨基酚大剂量推注后，在体内检测对乙酰氨基酚的药代动力学参数。在苯巴比妥治疗后，对肥胖和瘦的Zucker大鼠的葡萄糖醛酸化和谷胱甘肽结合途径进行体外研究。与瘦对照相比，肥胖的Zucker大鼠表现出更高的葡萄糖醛酸化能力，这表现为对乙酰氨基酚葡萄糖醛酸苷的形成清除率更高，以及对乙酰氨基酚和对硝基苯酚的尿苷二磷酸葡萄糖醛酸基转移酶（UDPGT）活性更高。硫酸盐和谷胱甘肽结合途径不受遗传性肥胖的影响。由于肝脏重量更大，肥胖的Zucker大鼠的肝脏总谷胱甘肽含量更高。苯巴比妥治疗在两种表型中均类似地增强了对乙酰氨基酚和结构相关化合物（即对硝基苯酚）的葡萄糖醛酸化，但该治疗未能在肥胖的Zucker大鼠中诱导吗啡UDPGT。在肥胖或瘦的Zucker大鼠中，未观察到苯巴比妥对硫酸盐结合、γ-谷氨酰半胱氨酸合成酶活性或肝脏谷胱甘肽含量有影响。苯巴比妥治疗后，在两种表型的动物中观察到谷胱甘肽转移酶活性有类似增加。这项研究表明，遗传性肥胖大鼠的葡萄糖醛酸化增强，而苯巴比妥在肥胖的Zucker大鼠中可正常诱导葡萄糖醛酸化和谷胱甘肽结合途径的几种酶。然而，苯巴比妥未诱导吗啡UDPGT，这表明肥胖的Zucker大鼠可能在该酶的诱导方面存在缺陷，类似于该品系中已经描述的CYP2B基因的缺陷。
