Age-associated changes of cytochrome P450 and related phase-2 gene/proteins in livers of rats
Age-associated changes of cytochrome P450 and related phase-2 gene/proteins in livers of rats
复制标题
大鼠肝脏细胞色素 P450 及相关 2 相基因/蛋白的年龄相关变化
DOI：
10.7717/peerj.7429
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发表时间：
2019-08-02
期刊：
影响因子：
2.7
通讯作者：
Liu, Jie
中科院分区：
文献类型：
--
作者：
Xu, Shang-Fu;Hu, An-Ling;Liu, Jie
细胞色素P450s （CYPs）是一类i相代谢酶，在药物代谢、膳食化学物质和内源性分子中发挥重要作用。年龄是影响P450s表达的关键因素。因此，我们检测了CYP 1-4家族和胆汁酸稳态相关CYP、相应的核受体和少数ii期基因的年龄相关变化。收集雄性Sprague-Dawley大鼠胎儿（-2 d）、新生儿（1,7和14 d）、断奶（21 d）、青春期（28和35 d）、成年（60和180 d）和衰老（540和800 d）的肝脏，进行qPCR分析。同时提取14、28、60、180、540和800日龄的肝脏蛋白，采用western blot方法进行选择蛋白分析。总体上有三种表达模式：部分药物代谢酶及相关核受体在胎儿和新生儿期较低，随着肝脏成熟而升高，衰老后迅速下降（AhR、Cyp1a1、Cyp2b1、Cyp2b2、Cyp3a1、Cyp3a2、Ugt1a2）；大多数p450 （Cyp1a2, Cyp2c6, Cyp2c11, Cyp2d2, Cyp2e1， CAR， PXR， FXR, Cyp7a1, Cyp7b1）。Cyp8b1、Cyp27a1、Ugt1a1、Sult1a1、Sult1a2)在成年期保持较高水平，在800日龄时下降；有些在7 - 14天出现早期高峰（CAR、PXR、PPAR α、Cyp4a1、Ugt1a2）。CYP1A2、CYP2B1、CYP2E1、CYP3A1、CYP4A1、CYP7A1的蛋白表达与mRNA的变化趋势相对应。综上所述，本研究确定了16种CYP、5种核受体和4种ii期基因在大鼠肝脏发育和衰老过程中的三种表达模式，增加了我们对年龄相关CYP表达变化和年龄相关疾病的认识。
Cytochrome P450s (CYPs) are phase-I metabolic enzymes playing important roles in drug metabolism, dietary chemicals and endogenous molecules. Age is a key factor influencing P450s expression. Thus, age-related changes of CYP 1-4 families and bile acid homeostasis-related CYPs, the corresponding nuclear receptors and a few phase-II genes were examined. Livers from male Sprague-Dawley rats at fetus (-2 d), neonates (1, 7, and 14 d), weanling (21 d), puberty (28 and 35 d), adulthood (60 and 180 d), and aging (540 and 800 d) were collected and subjected to qPCR analysis. Liver proteins from 14, 28, 60, 180, 540 and 800 days of age were also extracted for selected protein analysis by western blot. In general, there were three patterns of their expression: Some of the drug-metabolizing enzymes and related nuclear receptors were low in fetal and neonatal stage, increased with liver maturation and decreased quickly at aging (AhR, Cyp1a1, Cyp2b1, Cyp2b2, Cyp3a1, Cyp3a2, Ugt1a2); the majority of P450s (Cyp1a2, Cyp2c6, Cyp2c11, Cyp2d2, Cyp2e1, CAR, PXR, FXR, Cyp7a1, Cyp7b1. Cyp8b1, Cyp27a1, Ugt1a1, Sult1a1, Sult1a2) maintained relatively high levels throughout the adulthood, and decreased at 800 days of age; and some had an early peak between 7 and 14 days (CAR, PXR, PPAR alpha, Cyp4a1, Ugt1a2). The protein expression of CYP1A2, CYP2B1, CYP2E1, CYP3A1, CYP4A1, and CYP7A1 corresponded the trend of mRNA changes. In summary, this study characterized three expression patterns of 16 CYPs, five nuclear receptors, and four phase-II genes during development and aging in rat liver, adding to our understanding of age-related CYP expression changes and age-related disorders.