Retinoids activate the RXR/SXR-mediated pathway and induce the endogenous CYP3A4 activity in Huh7 human hepatoma cells

Toxicological Sciences : an Official Journal of the Society of Toxicology
Kun WangYu-Jui Yvonne Wan

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 eight 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 ...Continue Reading

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Jul 12, 2008·Archives of Toxicology·Olavi PelkonenHannu Raunio
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