1997 Fiscal Year Final Research Report Summary
The regluretion of Glucuronosyltransferase Gene Complex
| Project/Area Number |
07458162
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Functional biochemistry
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| Research Institution | HIMEJI INSTITUTE OF TECHNOLOGY |
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Principal Investigator |
IYANAGI Takashi Himeji Institute of Technology Department of Life Science, Professor, 理学部, 教授 (50001699)
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| Co-Investigator(Kenkyū-buntansha) |
IKUSHIRO Shin-ichi Himeji Institute of Technology Department of Life Science, Assistant Professor, 理学部, 助手 (50244679)
EMI Yoshikazu Himeji Institute of Technology Department of Life Science, Assistant Professor, 理学部, 助手 (60232980)
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| Project Period (FY) |
1995 – 1997
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| Keywords | glucuronosyltransferase / isozyme / gene complex / gene expression / enzyme induction / Ah receptor / molecular biology |
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| Research Abstract |
The UDP-glucuronosyltransferases (UGTs) are a family of microsomal membrane-bound enzymes that catalyze the conjugation of endogenous substrates such as bilirubin, steroids, bile acids and xenobiotics with UDP-glucuronic acid. We have analyzed the novel UDP-glucuronosyltransferase UGT1 gene complex, which encodes a set of first exones encoding a variable amino-terminal domain and four downstream exones encoding the identical carboxy-terminal domain.
The purpose this project is to study the regulation of UGT1 gene complex. The effect of various drugs sa an inducer on the expression of each UGT1 isozyme were analyzed. The UGT1A6 and UGT1A7 isozymes were significantly induced in 3-MC-treated rats. The expression of UGT1A1 and the glucuronidation activity toward bilirubin in rat hapatic microsomes were induced two-to three fold by clofibrate and dexamethasone administration. We analyzed the 5'-flanking region of the first exone and identified a XRE (TGCGTG) in the upstream of exon 1A6. these evidences suggest that each UGT1 transcriptional unit is under the control of its own promoter, so that each leader exon 1 is differentially spliced to the conserved exons (2-5) to generate nine differtent mRNAs, thus allowing independent regulation of each isozyme at the level of transcription. We have also studied that the oligomer structure of UGTs has an important functions to the glucuronidation activity in the ER membranes.
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[Publications] Mackenzie, PI., Owen, IS., Burchell, B., Bock, K.W., Bairoch, A., Belanger, A., Fournel-Gigleux, S., Green, M., Hum, D., Iyanagi, T., Lancet, D.et al: "The UDP glycosyltransferase gene superfamily : recommended nomenclature update based on evolutionary divergence" Pharmacogenetics. 7. 255-269 (1997)
Description
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