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. The hepatic version of UGT1A1 is responsible for bilirubin clearance. Flavonoids, anthraquinones, hydrocarbons, and certain plant phenolic condiments/phytoestrogens are converted to excretable products. The UGT1A10 isoform metabolizes nonsteroidal antiinflammatory drugs, different types of phytoestrogens, and all categories of estrogens, 2 benzaldehyde derivatives (vanillin and o-vanillin). 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 uncovered and described a new and novel pathway that involves the UGT enzyme system.Publication: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, In press.
