Fluoxetine reduces CES1, CES2, and CYP3A4 expression through decreasing PXR and increasing DEC1 in HepG2 cells

Xenobiotica. 2016;46(5):393-405. doi: 10.3109/00498254.2015.1082209. Epub 2015 Sep 4.

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.

Keywords: Carboxylesterase1 and 2 (CES1 and CES2); cytochrome P450 3A4 (CYP450); differentiated embryonic chondrocyte-expressed gene 1 (DEC1); fluoxetine (FLX); pregnane X receptor (PXR).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Carboxylesterase / metabolism*
  • Carboxylic Ester Hydrolases / metabolism*
  • Cytochrome P-450 CYP3A / metabolism*
  • Fluoxetine / chemistry*
  • Gene Expression Regulation / drug effects*
  • Hep G2 Cells
  • Homeodomain Proteins / metabolism*
  • Humans
  • Hydrolysis
  • Pregnane X Receptor
  • RNA Interference
  • Receptors, Steroid / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription, Genetic
  • Transfection

Substances

  • BHLHE40 protein, human
  • Basic Helix-Loop-Helix Transcription Factors
  • Homeodomain Proteins
  • Pregnane X Receptor
  • Receptors, Steroid
  • Fluoxetine
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Carboxylic Ester Hydrolases
  • CES1 protein, human
  • CES2 protein, human
  • Carboxylesterase