Retinoids induce cytochrome P450 3A4 through RXR/VDR-mediated pathway.
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 RXRalpha/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 all-trans-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 1alpha, 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 retinoid-mediated CYP3A4 induction through RXRalpha/VDR was proved by the results that 9-cis-retinal, 9-cis-RA, and all-trans-RA recruited RXRalpha 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.
Wang
Kun
K
Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, 2146 W 39th Avenue, Kansas City, KS 66160, United States.
Chen
Shiyong
S
Xie
Wen
W
Wan
Yu-Jui Yvonne
YJ
D000077556:Alitretinoin; D000818:Animals; D045744:Cell Line, Tumor; D002762:Cholecalciferol / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis* / Q000235:genetics; D004790:Enzyme Induction / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism*; D047490:Retinoid X Receptor alpha / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D012176:Retinoids / Q000494:pharmacology*; D014212:Tretinoin / Q000494:pharmacology
D018167:Receptors, Calcitriol; D047490:Retinoid X Receptor alpha; D012176:Retinoids; D002762:Cholecalciferol; D000077556:Alitretinoin; D014212:Tretinoin; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human