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Retinoids induce cytochrome P450 3A4 through RXR/VDR-mediated pathway
Kun Wang1, Shiyong Chen, Wen Xie
1Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, 2146 W 39th Avenue, Kansas City, KS 66160, United States.
Biochemical Pharmacology
|April 11, 2008
Summary
Retinoids, including 9-cis-retinoic acid, activate RXR/VDR pathways to induce CYP3A4 expression and activity in liver and intestinal cells. This suggests retinoids may impact drug metabolism by increasing CYP3A4 levels.
Area of Science:
- Molecular Pharmacology
- Drug Metabolism
- Nutritional Biochemistry
Background:
- Cytochrome P450 3A4 (CYP3A4) is crucial for metabolizing many drugs and endogenous compounds.
- Retinoids are essential for various physiological processes, but their role in drug-metabolizing enzyme induction is not fully understood.
- The Retinoid X Receptor (RXR) and Vitamin D Receptor (VDR) are nuclear receptors involved in gene regulation.
Purpose of the Study:
- To investigate whether retinoids can induce CYP3A4 expression via the RXR/VDR signaling pathway.
- To identify specific retinoids that activate RXR/VDR and influence CYP3A4.
- To determine the functional consequences of retinoid-mediated CYP3A4 induction in liver and intestinal cells.
Main Methods:
- Screening of retinoids and carotenoids for CYP3A4 induction potential.
- Transient transfection assays to assess transactivation of RXRalpha/VDR and CYP3A4 reporter activity.
- Quantitative analysis of Cyp3a11 mRNA levels in hepatocytes from PXR/CAR-double null mice.
- Measurement of CYP3A4 enzyme activity in human hepatoma (HepG2) and colorectal adenocarcinoma (Caco-2) cells.
- Chromatin immunoprecipitation assays to confirm receptor recruitment to CYP3A4 regulatory regions.
Main Results:
- Three retinoids—9-cis-retinal, 9-cis-retinoic acid (9-cis-RA), and all-trans-retinoic acid (all-trans-RA)—induced CYP3A4 reporter activity.
- 9-cis-RA and all-trans-RA preferentially transactivated RXR/VDR heterodimers and RXR homodimers.
- Retinoids induced Cyp3a11 mRNA in mouse hepatocytes and CYP3A4 enzyme activity in human HepG2 and Caco-2 cells, independent of PXR/CAR.
- Retinoids recruited RXRalpha and VDR to specific CYP3A4 regulatory elements (pER6 and dXREM).
Conclusions:
- Retinoids unequivocally induce CYP3A expression at both mRNA and enzyme activity levels through RXR/VDR activation.
- This induction occurs in both liver and intestinal cell models.
- Retinoids may modulate endobiotic metabolism in vivo via CYP3A4 induction.
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