Genetic Multiplicity of the Human UDP-Glucuronosyltransferases and Regulation in the Gastrointestinal Tract

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Abstract
The metabolism of ingested foods and orally administered drugs occurs in the hepato-gastrointestinal tract. This process is facilitated by several supergene families that catalyze oxidative metabolism as well as conjugation of the small molecular weight substances that enter the systemic circulation through resorption in the gastrointestinal tract. The catalytic action carried out by one of several conjugation reactions leads to the eventual elimination of the resultant metabolites from the cell. As early as 1959 (R. T. Williams,Detoxification Mechanisms) it was suggested that the detoxification of most agents is efficiently performed by the phase II conjugation reactions, because the addition of bulky, water-soluble groups to the target substrates facilitates the partitioning of these metabolites from the lipid into the aqueous compartments of the cell. The combined efforts of the phase II reactions provides remarkable redundancy in a biological system that seems to be designed to assure that many endogenously generated catabolic products as well as exogenous agents introduced through the surface tissues of the digestive tracts are efficiently removed through excretion to the bile or urine. In this review, we focus on recent findings that highlight the genetic multiplicity and regulatory patterns of the phase II superfamily UDP-glucuronosyltransferases (UGTs). Although much is known regarding the number of UGTs that make up the UGT1 andUGT2 gene families, as demonstrated after the characterization of expressed cDNAs, examples are also presented in which information obtained from the human genome project will aid in the final characterization of the genetic multiplicity. In addition, tools have now been developed and examples presented to identify the expression patterns of the UGTs in human tissues, paying particular attention to expression patterns of these genes in the hepato-gastrointestinal tract.