Organization /regulation /expression of Udp transferase

Child Health And Human Development

Investigators

Abstract

We study the regulation of UDP glucuronosyltransferase (transferase) genes at the molecular level using the human system. (1). We have completed the description of the UGT1 complex locus identifying 13 exons 1 with individual promoters and arranged in conjunction with 4 common exons so as to account for 13 genes that span 218 kb. Nine genes are transcribable into viable mRNAs. (2). Our studies show that UGT1A1 and UGT1A7 through UGT1A10 are expressed in the gastrointestinal tract (GI) and that their primary function is to glucuronidate (detoxify) aromatic-type chemicals that are dietary associated. Although the hepatic version of UGT1A1 is responsible for bilirubin clearance, our recent studies show that with the distribution of this isozyme to the GI tract it has the capability of metabolizing numerous ingested chemicals. Flavonoids, anthraquinones, hydrocarbons, certain plant phenolic condiments/phytoestrogens, and therapeutic agents are among those converted to excretable products. UGT1A7 and UGT1A1 have the potential for metabolizing the greatest variation in chemical structures and under different optimal conditions of pH and concentrations. The UGT1A10 isoform metabolizes nonsteroidal antiinflammatory drugs, different types of phytoestrogens, 2 benzaldehyde derivatives (vanillin and o-vanillin), and all categories of estrogens. Simple phenolic acids found in plants were either metabolized by UGT1A10 or UGT1A3. (3). UGT1A8 is the most avid metabolizer of nitrogen-containing chemicals among which are many consumed for therapeutic reasons. Nitrogen-containing chemicals, many of which have serious side-effects, create complex biotransformation issues. (4). Overall the UGT1A1, UGT1A7 through UGT1A10 isozymes are differentially and segmentally distributed to the mucosal epithelia of the gastrointestinal tract, have broad and overlapping substrate specificity, have broad and differential pH optima, and show alternative isoform usage to sustain metabolism over high substrate concentrations. (5). Finally, we have shown for the first time that all UGT isozymes require phosphorylation by the PKC signaling pathway. Structure-function studies of predicted phosphorylation sites in UGTs demonstrate that phospho- serine/threonine plays an important role(s) in controlling the pH optima and substrate selection for catalysis. Publications: 1. Gong Q-H, Cho JW, Huang T, Potter C, Gholami N, Basu NK, Kubota S, Carvalho S, Pennington MW, Owens I S. Thirteen UDPglucuronosyltransferase genes are encoded at the human UGT1 gene complex locus. Pharmacogenetics 11, 357-368 (2001). 2.Sugatani, J., Kojima, H., Ueda, A., Kakizaki, S., Yoshinari, K., Gong, Q-H., Owens, I.S., Negishi, M., and Sueyoshi, T. The phenobarbital response enhancer module in the human bilirubin UDP-glucuronosyltransferase UGT1A1 gene and regulation by the nuclear receptor CAR. Hepatology 33, 1232-1238. Other personnel in the lab: Basu, Nikhil K. PhD (HGB), Kole, Labanyamoy, PhD (HGB), Kubota, Shigeki, Gong, Qi-Hui, PhD (HGB) and Partha Mitra, PhD (HGB).