The UDP glucuronosyltransferase isoenzymes (UGT) are critical for the detoxification and elimination of structurally diverse lipophilic molecules including products of normal cellular metabolism, environmental pollutants, and xenobiotics including therapeutic agents. These enzymes catalyze the conjugation of their substrates with glucuronic acid, a process that acts to both inactive the potentially toxic molecule and also to increase its water solubility and subsequent excretion. Despite the importance of this pathway in protection against accumulation of endobiotics and environmental toxins and its role in metabolism of therapeutic agents, many questions regarding the function of individual UGT enzymes remain, particularly in the case of the seven members of the UG2B subfamily. One of the reasons for this is that there are enormous differences between members of the human and mouse UG2B genes. Based on sequence homology it has not been possible to define the mouse ortholog of the seven human UGT2B genes. This has prohibited the use of null mouse lines in extrapolating the role of particular human UGT2B genes in the glucuronidation of specific substrates. In this application we propose a new strategy that we believe will generate mouse lines useful for determining the function of the UGT2B genes, and in particular of UGT2B15 and UGT217. We expect that these lines will express these genes in a manner predicted by studies of human tissues and that these genes will be critical, not only in steroid metabolism, but also in protection against environmental toxins. Furthermore, we will test the hypothesis that mice carrying different UGT2B17/UGT2B15 haplotypes will differ in these responses.
Vertebrate animals have evolved a number of enzyme pathways critical for protection of the organism from the accumulation of toxins, both environmental and those that accumulate as byproducts of normal metabolism. One such pathway involves glucuronidation mediated primarily by a family of enzymes, the UDP glucuronosyltranserases, which encoded by genes of the UGT super family. These enzymes detoxify substances and also render them water soluble thus facilitating their secretion. We propose to develop mouse models to study the function of these genes. These models will allow us to determine the function of individual human UGT genes in conferring protection against pollutants and environmental or endogenous toxins.
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