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

Abstract

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.