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Abstract
1. 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.
Acknowledgements
The authors thank Dr Bingfang Yan of University of Rhode Island for donating the DEC1 antibody and constructs.
Declaration of interest
The authors declare that there are no conflicts of interest.
This study was supported by the Natural Science Foundation of China (Nos. 81173128, 81373443, 81102457, 81302855), the Major Project of Jiangsu Provincial Department of Education (No. 13KJA310003), the Ministry and Education of PRC (20123234110005), and Natural Science Foundation of Jiangsu Province, China (No. BK2012446).