氟西汀通过降低HepG2细胞中孕烷X受体（PXR）并增加DEC1的表达，从而降低羧酸酯酶1（CES1）、羧酸酯酶2（CES2）和细胞色素P450 3A4（CYP3A4）的表达。
Fluoxetine reduces CES1, CES2, and CYP3A4 expression through decreasing PXR and increasing DEC1 in HepG2 cells.
作者信息
Shang Wei, Liu Jie, Chen Ruini, Ning Rui, Xiong Jing, Liu Wei, Mao Zhao, Hu Gang, Yang Jian
机构信息
a Department of Pharmacology , Nanjing Medical University , Nanjing , China and.
b Jinling Hospital, Nanjing Medical University , Nanjing , China.
出版信息
Xenobiotica. 2016;46(5):393-405. doi: 10.3109/00498254.2015.1082209. Epub 2015 Sep 4.
Abstract
- This study investigated the mechanisms of the decreases of carboxylesterases (CES) and cytochrome P4503A4 (CYP3A4) and the enzymatic activities induced by fluoxetine (FLX) in HepG2 cells. We found that FLX decreased the carboxylesterase 1 (CES1) and carboxylesterase 2 (CES2) expression and the hydrolytic activity. 2. FLX decreased the pregnane X receptor (PXR) expression which regulated the target genes such as CYP3A4, whereas increased the differentiated embryonic chondrocyte-expressed gene 1 (DEC1) expression. 3. FLX repressed the PXR at transcriptional level. 4. Overexpression of PXR alone increased the expression of CES1, CES2, and CYP3A4 and attenuated the decreases of CES1, CES2, and CYP3A4 induced by FLX. On the contrary, knockdown of PXR alone decreased the expression of CES1, CES2, and CYP3A4 and almost abolished the decreases of CES1, CES2, and CYP3A4 induced by FLX. 5. Knockdown of DEC1 alone increased the expression of PXR and CYP3A4 and almost abolished the decreases of CES1, CES2, and CYP3A4 induced by FLX. 6. Taken together, the decreases of CES and CYP3A4 expression and enzymatic activities induced by FLX are through decreasing PXR and increasing DEC1 in HepG2 cells.
摘要
- 本研究调查了氟西汀（FLX）诱导HepG2细胞中羧酸酯酶（CES）和细胞色素P4503A4（CYP3A4）降低及其酶活性降低的机制。我们发现FLX降低了羧酸酯酶1（CES1）和羧酸酯酶2（CES2）的表达以及水解活性。2. FLX降低了调节CYP3A4等靶基因的孕烷X受体（PXR）的表达，而增加了分化胚胎软骨细胞表达基因1（DEC1）的表达。3. FLX在转录水平上抑制PXR。4. 单独过表达PXR增加了CES1、CES2和CYP3A4的表达，并减弱了FLX诱导的CES1、CES2和CYP3A4的降低。相反，单独敲低PXR降低了CES1、CES2和CYP3A4的表达，并且几乎消除了FLX诱导的CES1、CES2和CYP3A4的降低。5. 单独敲低DEC1增加了PXR和CYP3A4的表达，并且几乎消除了FLX诱导的CES1、CES2和CYP3A4的降低。6. 综上所述，FLX诱导的CES和CYP3A4表达及酶活性降低是通过降低HepG2细胞中的PXR并增加DEC1实现的。
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