Regulated Properties of the Human UGT1A1 Gene.

University Of California, San Diego, La Jolla CA

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Abstract

DESCRIPTION (provided by applicant): Human UDP-glucuronosyltransferase 1A1 is involved in the metabolism of endogenous agents such as bilirubin in addition to many clinically used therapeutics. The wide tissue distribution of UGT1A1 indicates it plays an important role in metabolism and homeostasis. This has recently been illustrated with deficiencies in the expression of UGT1A1, as observed in Gilbert's syndrome, which have been linked to a number of severe toxicological episodes. Thus, understanding the events involved in the regulation and expression of UGT1A1 is important and is the focus of this application. We will show from recent experiments conducted in our laboratory as well as others that the UGT1A1 gene can be regulated by a host of agents, all of which have been shown to regulate other important drug metabolizing genes. Agents which induce UGTIA1 such as TCDD, rifampicin, tert-butylhydroquinone, [3-napthoflavone, phenobarbital and chrysin modulate gene transcription through one of the following nuclear receptors; the aryl hydrocarbon receptor (AhR), the pregnane X receptor (PXR), the constitutive androstane receptor (CAR) as well as Nrf2 through antioxidant (ARE) dependant pathways. To our knowledge, this may represent the first example of a gene that can be regulated by most of the major classes of inducing agents. Experiments are outlined that will characterize the regulatory regions as well as cellular signaling events associated with activation of the UGT1A1 gene. These investigations will be complemented by analyzing expression of human UGT1A1 in transgenic mice that have "knocked-out" important regulators of gene expression such as Nrf2, PXR, NF-rd3 and the AhR. The development of these tools to examine UGT1A1 expression will also allow us to determine if differences exist in the inducibility and regulation of the UGT1A1 gene in promoter deficient Gilbert's syndromes. Identifying the mechanisms that underlie expression of UGT1A1 may provide us with important clues toward improving expression of this gene and avoiding potential toxicities because of inadequate gene expression.