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ToxSci Advance Access published online on April 21, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfj207
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received December 21, 2005
Accepted April 19, 2006

Biotransformation and Toxicokinetics

Retinoids Activate the RXR/SXR-mediated Pathway and Induce the Endogenous CYP3A4 Activity in Huh7 Human Hepatoma Cells

Kun Wang 1 *, Alphonse J. Mendy 1 *, Guoli Dai 1, Huai-Rong Luo 1, He Lin 1, and Yu-Jui Yvonne Wan 1 *

1 Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160

* To whom correspondence should be addressed.
Yu-Jui Yvonne Wan, E-mail: ywan{at}kumc.edu


  Abstract

Steroid and xenobiotic receptor (SXR) or human pregnane X receptor (hPXR) dimerizes with retinoid X receptor (RXR) and regulates the transcription of genes encoding xenobiotic-metabolizing enzymes such as CYP3A4. Rifampin, the classical activator of CYP3A4, binds to SXR directly. It is unclear whether various natural and synthetic retinoids can regulate the expression of CYP3A4. To evaluate the effects of retinoids on the RXR/SXR-mediated pathway, transient transfection assays were performed on both CV-1 and human hepatoma Huh7 cells using a reporter construct containing multiple RXR/SXR consensus binding elements (an everted repeat with a 6-nucleotide spacer, ER-6). The results revealed that 8 out of 13 retinoids screened significantly induced the RXR/SXR-mediated pathway in Huh7 cells. At an equal molar concentration, the acid forms (9-cis-RA, 13-cis-RA, and all-trans-RA) or aldehyde, the direct precursor of acid (9-cis-retinal and 13-cis-retinal), exhibited a greater or similar potency than rifampin. Depending on the ligands, RXR may serve as a silent or an active partner of SXR.

Additionally, retinoids can increase CYP3A4 enzyme activity in Huh7 cells. To further evaluate the potential drug-drug interactions, which may caused by retinoids, Huh7 cells were pretreated with 9-cis-RA and followed by acetaminophen. We showed that 9-cis-RA enhanced the covalent binding of N-acetyl-p-quinoneimine, a toxic intermediate of acetaminophen produced by phase I enzymes oxidation. This result suggested that drug-drug interaction might occur between 9-cis-RA and acetaminophen in human liver cells. Taken together, retinoids activate the RXR/SXR-mediated pathway and regulate the expression of CYP3A4. Thus, retinoids potentially can cause drug-drug interactions when they are administered with other CYP3A4 substrates.

Keywords: retinoids; retinoid X receptor; steroid and xenobiotic receptor; CYP3A4, liver, drug-drug interaction.

*Kun Wang and Alphonse J. Mendy contributed equally to this work and should be considered as first authors.


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