Retinoids induce cytochrome P450 3A4 through RXR/VDR-mediated pathway

Abstract

A panel of retinoids and carotenoids was screened as potential inducers of CYP3A4 through the RXR/VDR-mediated signaling pathway. Transient transfection assays revealed that 3 out of 12 retinoids screened transactivated RXRα/VDR and induced CYP3A4 reporter activity. These three retinoids are the active metabolites of retinoids, 9-cis-retinal, 9-cis-retinoic acid (9-cis-RA), and alltrans-retinoic acid (all-trans-RA). 9-cis-RA and all-trans-RA, preferentially transactivated the RXR/ VDR heterodimers and RXR homodimers. Retinoids and VDR agonist 1α, 25-dihydroxyvitamin D 3 , but not PXR or CAR activator, could induce Cyp3a11 mRNA level in hepatocytes derived from PXR/CAR double null mouse. Moreover, retinoids induced CYP3A4 enzyme activity in HepG2 human hepatoma and Caco-2 human colorectal adenocarcinoma cells. A direct role of retinoidmediated CYP3A4 induction through RXRα/VDR was proved by the results that 9-cis-retinal, 9-cis-RA, and all-trans-RA recruited RXRα and VDR to CYP3A4 regulatory region pER6 (proximal everted repeat with a 6-nucleotide spacer) and dXREM (distal xenobiotic-responsive enhancer module). Thus, using various approaches, we have unequivocally demonstrated that retinoids transactivate RXR/VDR heterodimers and RXR homodimers and induce CYP3A expression at mRNA as well as enzyme activity levels in both liver and intestinal cells. It is possible that retinoids might alter endobiotic metabolism through CYP3A4 induction in vivo.

Systematic genetic and genomic analysis of cytochrome P450 enzyme activities in human liver

“…Moreover, when the mRNA level of a key regulator is correlated to the activity of a P450, it is even more significantly correlated to the expression of the same P450. This result is not surprising given that many of these regulators are known to play regulatory roles at the transcriptional level (Waxman 1999;Cai et al 2002;GerbalChaloin et al 2002;Tirona et al 2003;Barbier et al 2004;Fan et al 2004;Gnerre et al 2004Gnerre et al , 2005Seree et al 2004;Debose-Boyd 2007;Hughes et al 2007;Plant 2007;Audet-Walsh and Anderson 2008;Gonzalez 2008;Lee et al 2008;Lim and Huang 2008;Wang et al 2008). …”

“…These regulators investigated include NR1I2 (PXR), NR1I3 (CAR), RXRA, NR1H3 (LXR), NR1H4 (FXR), HNF4A, NR3C1 (GR), PGRMC1, PPARA, VDR, and many others (Supplemental Table S4; Waxman 1999;Cai et al 2002;Gerbal-Chaloin et al 2002;Tirona et al 2003;Barbier et al 2004;Fan et al 2004;Gnerre et al 2004Gnerre et al , 2005Seree et al 2004;Debose-Boyd 2007;Hughes et al 2007;Plant 2007;AudetWalsh and Anderson 2008;Gonzalez 2008;Lee et al 2008;Lim and Huang 2008;Wang et al 2008). At an uncorrected significance threshold of P < 0.05, the expression levels of most of the known regulators are correlated with the enzyme activities of two or more P450s.…”

CYP3A5*3Polymorphism and Its Clinical Implications and Pharmacokinetic Role

“…It is found with an allele frequency of 17% in African-Americans, but is absent in Asian populations. [1,21] A single base insertion into exon 11 causes premature termination of the reading frame at the position of the 348 th amino acid in the CYP3A5*7 allele, thus producing unstable CYP3A5 proteins. Similar to CYP3A5*6, it is found only in populations of African origin (Zimbabwean, 10% and African-American, 10%), not in Caucasian and Asian populations.…”

“…Additionally, these enzymes are involved in the metabolism of cholesterol, steroid hormones and other lipids that are important in intraceullar signaling pathways. [1] The cytochrome P450 (CYP) 3A subfamily is estimated to participate in the biotransformation of 50% of the drugs known to undergo oxidative metabolism. [2] Four members of the CYP3A subfamily have been described in humans-CYP3A4, CYP3A5, CYP3A7, and CYP3A43.…”

Inhibition of Human Cytochrome P450 Metabolism by Blended Herbal Products and Vitamins

“…tBC and DD3 can modulate gene expression of CYP3A (22)(23)(24)(25); tBC can also modulate MDR1 (24). Expression of CYP3A4 can be induced through different nuclear receptors such as the pregnane X receptor (PXR), the constitutive androstane receptor (CAR) and the vitamin D receptor (VDR) (24). VDR binds to and mediates the effects of the DD3 to alter gene transcription (22).…”