Hepatic CYP3A expression is attenuated in obese mice fed a high-fat diet
Hepatic CYP3A expression is attenuated in obese mice fed a high-fat diet
复制标题
DOI：
10.1007/s11095-006-0071-6
复制
发表时间：
2006-06-01
影响因子：
3.7
通讯作者：
Miwa, Masao
中科院分区：
文献类型：
--
作者：
Yoshinari, Kouichi;Takagi, Shunsuke;Miwa, Masao
目的：生理、病理生理和/或营养条件的变化通常会改变药物代谢酶的表达。在这项研究中，我们使用营养性肥胖小鼠研究了肥胖引起的肝细胞色素 P450 (P450) 水平的变化。方法：为了诱导肥胖，给小鼠喂食高脂肪饮食或用金硫葡萄糖治疗，这会损害腹内侧下丘脑。从这些小鼠的肝脏中制备总 RNA 以及微粒体和核蛋白，并测定 P450 和转录因子的 mRNA 和蛋白质水平。 结果：在检查的 P450 中，营养诱导的肥胖导致 CYP3As 的 mRNA 和蛋白质水平的组成型表达均急剧减少。一周的高脂肪饮食也可以降低肝脏 CYP3As 水平。然而，参与 CYP3A 基因转录调控的核受体的变化与 CYP3A 的变化无关。金硫葡萄糖诱导的肥胖小鼠表现出不同的肝脏P450s表达谱，而CYP3As没有显着变化。结论：高脂饮食诱导的能量代谢变化最终导致肥胖，调节肝脏P450s表达谱，特别是CYP3As。或者，高脂肪饮食中某种成分的积累可能会直接减弱 CYP3A 的表达，表明临床上重要的药物-饮食相互作用。
Purpose: Changes in physiological, pathophysiological, and/or nutritional conditions often alter the expression of drug-metabolizing enzymes. In this study, we investigated obesity-induced changes in hepatic cytochrome P450 (P450) levels using nutritionally obese mice.Methods: To induce obesity, mice were fed a high-fat diet or treated with gold thioglucose, which impairs ventromedial hypothalamus. Total RNAs and microsomal and nuclear proteins were prepared from the liver of these mice, and mRNA and protein levels of P450s and transcription factors were determined.Results: Among P450s examined, the constitutive expression of CYP3As was drastically reduced at both mRNA and protein levels by nutrition-induced obesity. One-week administration of a high-fat diet also reduced hepatic CYP3As. However, changes in nuclear receptors involved in the transcriptional regulation of CYP3A genes were not correlated with that of CYP3As. Obese mice induced by gold thioglucose exhibited a different expression profile of hepatic P450s with no significant change in CYP3As.Conclusion: High-fat diet-induced changes in energy metabolism, which eventually result in obesity, modulate the hepatic expression profile of P450s, particularly CYP3As. Alternatively, the accumulation of a certain component in a high-fat diet may directly attenuate the CYP3A expression, suggesting a clinically important drug-diet interaction.