All-trans retinoic acid enhances the transport of phase II metabolites of benzo[a]pyrene by inducing the Breast Cancer Resistance Protein expression in Caco-2 cells.
All-trans retinoic acid (atRA) is the most active metabolite of vitamin A. It is a ligand of retinoic acid receptors (RAR) as well as of retinoid X receptors (RXR) and effectively stimulates the RAR/RXR signalling pathway. In this study effects of atRA on the detoxification of the food contaminant benzo[a]pyrene (B[a]P) was elucidated by using the Caco-2 cell line as model system for the human small intestine. Caco-2 cells express a number of phase I and II xenobiotic-metabolising enzymes as well as several transport proteins of the ATP-binding cassette (ABC) superfamily. Pre-treatment of the cells with atRA resulted in enhanced apical excretion of B[a]P-3-sulfate, a phase II metabolite of B[a]P. Gene expression analysis revealed that the Breast Cancer Resistance Protein (BCRP), an ABC-transporter known to be involved in B[a]P-3-sulfate excretion, was strongly stimulated already at low concentrations of atRA. Furthermore co-incubation of the intestinal cell with RAR agonist and RXR agonist resulted in a strong additive induction of mRNA expression of BCRP. Thus, atRA was shown to induce BCRP gene expression probably via the RAR/RXR signalling pathway, resulting in effective removal of B[a]P metabolites from intestinal cells.
Hessel
Stefanie
S
Federal Institute for Risk Assessment, Department of Food Safety, Thielallee 88-92, 14195 Berlin, Germany. stefanie.hessel@bfr.bund.de
Lampen
Alfonso
A
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D001564:Benzo(a)pyrene / Q000378:metabolism*; D001565:Benzoates / Q000494:pharmacology; D018938:Caco-2 Cells; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000819:agonists; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors / Q000819:agonists; D012176:Retinoids / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D014212:Tretinoin / Q000737:chemistry / Q000494:pharmacology*
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D001565:Benzoates; C104000:CD 2608; D009363:Neoplasm Proteins; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D012176:Retinoids; D013764:Tetrahydronaphthalenes; C068073:Am 580; D001564:Benzo(a)pyrene; D014212:Tretinoin