Obesity-induced increase of CYP2E1 activity and its effect on disposition kinetics of chlorzoxazone in Zucker rats
Obesity-induced increase of CYP2E1 activity and its effect on disposition kinetics of chlorzoxazone in Zucker rats
复制标题
DOI：
10.1016/j.bcp.2006.09.006
复制
发表时间：
2007-01-01
影响因子：
5.8
通讯作者：
Miyamoto, Ken-ichi
中科院分区：
文献类型：
--
作者：
Khemawoot, Phisit;Yokogawa, Koichi;Miyamoto, Ken-ichi
本研究旨在探讨CYP 2 E1在肥胖Zucker大鼠体内的诱导作用及其对氯唑沙宗（CZX）代谢动力学的影响。将CZX 20 mg/kg给予三组大鼠：正常饮食喂养的正常Zucker大鼠（ND）、高脂饮食喂养的正常Zucker大鼠（HF）和正常饮食喂养的遗传性肥胖Zucker大鼠（OB）。CZX的0 ~无穷大血药浓度-时间曲线下面积（AUC（infinity））大小顺序为ND > HF > OB。总6-羟基氯唑沙宗（60 HCZX-T）（被认为是CYP 2 E1代谢标志物）的AUC（无穷大）值顺序相反。ND、HF和OB大鼠的AUC（无穷大）比值（60 HCZX-T/CZX）分别约为0.2、0.3和0.4。脂肪中的CZX浓度远高于血浆、肝脏和肾脏中的浓度。OB大鼠肝脏和脂肪中CYP 2 E1蛋白的诱导作用均大于HF大鼠。肝脏和脂肪中CYP 2 E1的活性也是OB > HF > NM大鼠。这些结果表明，CYP 2 E1可能在肥胖患者的肝脏和脂肪中被诱导，从而潜在地改变CZX的处置动力学，而且还改变由CYP 2 E1代谢的其他亲脂性药物。(c)2006年爱思唯尔公司All rights reserved.
This study was designed to investigate the induction of CYP2E1 in obese Zucker rats and its effect on the disposition kinetics of chlorzoxazone (CZX). CZX 20 mg/kg was administered to three groups of rats: normal Zucker rats fed a normal diet (ND), normal Zucker rats fed a high-fat diet (HF), and genetically obese Zucker rats fed a normal diet (OB). The values of the area under the plasma concentration-time curve from 0 to infinity (AUC(infinity)) of CZX were in the order of ND > HF > OB rats. The AUC(infinity) values of total 6-hydroxychlorzoxazone (60HCZX-T), which is considered to be a CYP2E1 metabolic marker, were in the opposite order. The values of the AUC(infinity) ratio (60HCZX-T/CZX) in ND, HF and OB rats were approximately 0.2, 0.3 and 0.4, respectively. The CZX concentration in fat was much higher than the concentrations in plasma, liver and kidney in all groups. Induction of CYP2E1 protein was greater in both liver and fat of OB rats than in those of HF rats. Microsomal activity of CYP2E1 in liver and fat was also in the order of OB > HF > NM rats. These results suggest that CYP2E1 may be induced in liver and fat of obese patients, thereby potentially altering the disposition kinetics of not only CZX, but also other lipophilic drugs metabolized by CYP2E1. (c) 2006 Elsevier Inc. All rights reserved.