rifampin and Intestinal-Neoplasms

The pregnane X receptor (PXR) is the key regulator of our defense mechanism against foreign substances such as drugs, dietary nutrients, or environmental pollutants. Because of increased health consciousness, the use of dietary supplements has gradually increased, and most of them can activate PXR. Therefore, an analysis of the interaction between drugs and nutrients is important because altered levels of drug-metabolizing enzymes or transporters can remarkably affect the efficiency of a co-administered drug. In the present study, we analyzed the effect of vitamin K-mediated PXR activation on drug metabolism-related gene expression in intestine-derived LS180 cells via gene expression studies and western blotting analyses. We demonstrated that menaquinone 4 (MK-4), along with other vitamin Ks, including vitamin K

Topics: ATP Binding Cassette Transporter, Subfamily B; Carcinoma; Cell Line, Tumor; Cytochrome P-450 CYP3A; Gene Expression; Humans; Intestinal Neoplasms; Nutritional Physiological Phenomena; Pregnane X Receptor; Rifampin; Vitamin K; Vitamin K 1; Vitamin K 2

To study the effect of the toxic secondary bile acid lithocholic acid (LCA) on the expression of fibroblast growth factor 19 (FGF19) in intestinal cells and to characterize the pregnane-X-receptor (PXR) response of the FGF19 promoter region.. The intestinal cell line LS174T was stimulated with various concentrations of chenodeoxy-cholic acid and lithocholic acid for several time points. FGF19 mRNA levels were determined with quantitative realtime RT-PCR. FGF19 deletion promoter constructs were generated and the LCA response was analzyed in reporter assays. Co-transfections with PXR and RXR were carried out to study FGF19 regulation by these factors.. LCA and CDCA strongly up-regulate FGF19 mRNA expression in LS174T cells in a time and dose dependent manner. Using reporter gene assays with several deletion constructs we found that the LCA responsive element in the human FGF19 promoter maps to the proximal regulatory region containing two potential binding sites for PXR. Overexpression of PXR and its dimerization partner retinoid X receptor (RXR) and stimulation with LCA or the potent PXR ligand rifampicin leads to a significant induction of FGF19 promoter activity in intestinal cells.. LCA induced feedback inhibition of bile acid synthesis in the liver is likely to be regulated by PXR inducing intestinal FGF19 expression.

Topics: Adenocarcinoma; Base Sequence; Cell Line, Tumor; Detergents; Enzyme Inhibitors; Feedback, Physiological; Fibroblast Growth Factors; Gene Expression Regulation, Neoplastic; Humans; Intestinal Neoplasms; Lithocholic Acid; Molecular Sequence Data; Pregnane X Receptor; Promoter Regions, Genetic; Receptors, Steroid; Rifampin; RNA, Messenger; Signal Transduction; Up-Regulation