Dietary-Induced Obesity, Hepatic Cytochrome P450, and Lidocaine Metabolism: Comparative Effects of High-Fat Diets in Mice and Rats and Reversibility of Effects With Normalization of Diet
Dietary-Induced Obesity, Hepatic Cytochrome P450, and Lidocaine Metabolism: Comparative Effects of High-Fat Diets in Mice and Rats and Reversibility of Effects With Normalization of Diet
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DOI：
10.1016/j.xphs.2019.11.007
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发表时间：
2020-02-01
影响因子：
3.8
通讯作者：
Brocks, Dion R.
中科院分区：
文献类型：
--
作者：
Al Nebaihi, Hamdah M.;Al Batran, Rami;Brocks, Dion R.
本文研究了高脂饮食对大鼠和小鼠细胞色素P450(CYP)酶基因和蛋白的影响及其对大鼠利多卡因去乙基化为其主要活性代谢物单乙基甘氨己内酯(MEGX)的影响。还评估了从高脂肪饮食到标准饮食的改变的效果。测定血浆生化、所选CYP的信使核糖核酸、蛋白质表达及利多卡因脱乙基活性。高脂饲料降低了大多数细胞色素P450(CYP1A2、CYP3A1、CYP2C11、CYP2C12和CYP2D1)的活性和表达，降低了其mRNA水平(CYP1A2和Cyp3a2)和MEGX最大形成率(Vmax)。小鼠在其细胞色素P3A和1a2的蛋白表达上表现出互补的结果。将饮食转换为标准饮食4周后，大鼠的mRNA和蛋白质表达水平恢复到正常水平，MEGX的最大形成速度也恢复到正常水平。雌性和雄性啮齿动物在CYP表达和利多卡因代谢方面表现出相似的模式，尽管雄性大鼠形成MEGX的速度更快。总而言之，饮食诱导的肥胖不仅在大鼠中引起了CYP亚型的普遍减少，在小鼠中也是如此。通过正常饮食，这种影响在大鼠身上是可逆的。(C)2020美国药剂师协会(R)。爱思唯尔公司出版，版权所有。
The effects of a high-fat diet on mRNA and protein of cytochrome P450 (CYP) enzymes in rats and mice and its impact on lidocaine deethylation to its main active metabolite, monoethylglycinexylidide (MEGX), in rats were investigated. The effect of a change in diet from high-fat to standard diet was also evaluated. Plasma biochemistry, mRNA, protein expression for selected CYP, and the activity of lidocaine deethylation were determined. The high-fat diet curtailed the activity and the expression of the majority of CYPs (CYP1A2, CYP3A1, CYP2C11, CYP2C12, and CYP2D1), mRNA levels (Cyp1a2 and Cyp3a2), and MEGX maximal formation rate (Vmax). Mice showed complementary results in their protein expressions of cyp3a and 1a2. Switching the diet back to standard chow in rats for 4 weeks reverted the expression levels of mRNA and protein back to normal levels as well as the maximum formation rates of MEGX. Female and male rodents showed similar patterns in CYP expression and lidocaine metabolism in response to the diets, although MEGX formation was faster in male rats. In conclusion, diet-induced obesity caused general decreases in CYP isoforms not only in rats but also in mice. The effects were shown to be reversible in rats by normalizing the diet. (c) 2020 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.