Circadian rhythm of cytochrome P4502E1 and its effect on disposition kinetics of chlorzoxazone in rats
Circadian rhythm of cytochrome P4502E1 and its effect on disposition kinetics of chlorzoxazone in rats
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DOI：
10.1016/j.ejphar.2007.06.032
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发表时间：
2007-11-21
影响因子：
5
通讯作者：
Miyamoto, Ken-ichi
中科院分区：
文献类型：
--
作者：
Khemawoot, Phisit;Nishino, Kousuke;Miyamoto, Ken-ichi
本报告的目的是研究细胞色素P4502EI （CYP2E1）的昼夜节律及其对雄性Wistar大鼠氯唑唑酮处置动力学的影响。将大鼠置于12 h光照/暗循环（9:00 - 2:00光照）下，随意进食和饮水3个月。结果发现，肝脏微粒体CYP2E1 mRNA在暗期的表达量显著低于亮期，而CYP2E1蛋白含量及其羟基化活性显著高于亮期。因此，在12:00（光相组）或24:00（暗相组）静脉给药氯唑唑酮20mg /kg，以确定对处置动力学的影响。氯唑唑酮的血浆浓度-时间曲线下面积(AUC（0-8) (h)）在两组间无显著差异。光相组氯唑唑酮在血浆中的半衰期值明显长于暗相组。6-羟基氯唑唑酮的AUC(0-8) (h)在暗期显著高于光期，是由氯唑唑酮主要由CYP2E1形成的代谢物。综上所述，大鼠微粒体CYP2E1显示出明显的昼夜变化，这与氯唑酮半衰期缩短和6-羟基氯唑酮产量增加有关。因此，对于其他主要由CYP2E1代谢的外源药物，特别是那些半衰期短的外源药物，治疗反应和毒理学效应的时间变化可能必须考虑在内。(C) 2007 Elsevier B.V.版权所有
The aim of this report is to study the circadian rhythm of cytochrome P4502EI (CYP2E1) and its effect on the disposition kinetics of chlorzoxazone in male Wistar rats. The rats were housed under a 12-h light/dark cycle (lights from 9:00 to 2 1:00) with food and water ad libitum for 3 months. It was found that the expression of microsomal CYP2E1 mRNA in the liver during the dark phase was significantly lower than during the light phase, whereas the content of CYP2E1 protein and its hydroxylation activity were significantly higher. Therefore, chlorzoxazone 20 mg/kg was intravenously administered at 12:00 (light phase group) or 24:00 (dark phase group) to determine the effect on the disposition kinetics. The value of the area under the plasma concentration-time curve from 0 to 8 It (AUC(0-8) (h)) of chlorzoxazone showed no significant difference between the two groups. However, the value of chlorzoxazone half-life in plasma of the light phase group was significant longer than the dark phase group. The AUC(0-8) (h) of 6-hydroxychlorzoxazone, a metabolite formed from chlorzoxazone mainly by CYP2E1, was significantly higher in the dark phase than in the light phase. In conclusion, microsomal CYP2E1 shows a substantial circadian variation in rats, and this was associated with a decrease of chlorzoxazone half life, and an increase of 6-hydroxychlorzoxazone production. Therefore, the temporal variations of therapeutic response and toxicological effects may have to be taken into consideration for other xenobiotics that are predominantly metabolized by CYP2E1, particularly those with a short half-life. (C) 2007 Elsevier B.V. All rights reserved.