Comparative kinetics and tumor promoting activity of the antimicrobial agent triclosan in humanized UGT1 mouse models expressing either the UGT1A1*1 or the UGT1A1*28 allele
Final Report Abstract
Part1: Using intestinal epithelial cell specific NCoR1 deficient mice we could demonstrate that intrinsic intestinal NCoR1 plays an important role in regulating IEC proliferation and enterocyte maturation during neonatal development. Furthermore, we could demonstrate that NCoR1 is an important key factor in the maintenance of intestinal homeostasis. When we explored NCoR1 function in the context of the gastrointestinal disease ulcerative colitis (UC), we discovered that deletion of intestinal NCoR1 led to an increased disease severity. A closer look at early stages of the disease indicated that intestinal NCoR1 protects crypt cells through regulating the function of colonic secretory cells. UC is a chronic disease that strongly impairs the life quality of the patients and additionally increases the risk for other diseases such as colorectal cancer. Our discovery of the important role NCoR1 plays for protecting the intestine and in parts the biochemical and molecular events behind it will lead to a better understanding of the disease and thus will help in finding therapy strategies for reducing the development of UC. Part2: Variations of the expression of drug metabolizing enzymes such as the UDP-glucuronosyltransferases (UGTs) as well as activation or inhibition of these enzymes can have severe adverse effects on drugs or hormone balance. Therefore, it is of high importance to have a deep understanding on how these enzymes are regulated. We could demonstrate that additionally to UGT1A3, UGT1A1 and UGT1A4 are positively regulated target genes of the liver X receptor (LXR), a member of the nuclear receptor family that consists of the two isoforms LXRa and LXRb. With the development of humanized UGT1 mice that alternatively express either only one of the two isoforms or neither of them, we evidenced the differential manner in which the two LXR isoforms mediate the T0901317-dependent induction of UGT1 gene expression and activity. These findings contribute to a better understanding of molecular events during xeno- and endobiotic metabolism.
Publications
- Crypt Organoid Culture as an in Vitro Model in Drug Metabolism and Cytotoxicity Studies. Drug Metab. Dispos., 2017, 45, 748-754
W. Lu, E. Rettenmeier, M. Paszek, M. F. Yueh, R. H. Tukey, J. Trottier, O. Barbier, S. Chen
(See online at https://doi.org/10.1124/dmd.117.075945) - Intestinal NCoR1, a regulator of epithelial cell maturation, controls neonatal hyperbilirubinemia. Proc. Natl. Acad. Sci. USA, 2017, 114, E1432-E1440
S. Chen, W. Lu, M. F. Yueh, E. Rettenmeier, M. Liu, J. Auwerx, R. T. Yu, R. M. Evans, K. Wang, M. Karin, R. H. Tukey
(See online at https://dx.doi.org/10.1073%2Fpnas.1705671114)
