| Project/Area Number |
04454602
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| Research Category |
Grant-in-Aid for General Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
代謝生物化学
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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) |
IKYUSHIRO Shinichi Himeji Institute of Technology Department of Life Science Assistant, 理学部, 助手 (50244679)
EMI Yoshikazu Himeji Institute of Technology Department of Life Science Assistant, 理学部, 助手 (60232980)
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| Project Period (FY) |
1992 – 1994
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| Project Status |
Completed (Fiscal Year 1994)
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| Budget Amount *help |
¥6,200,000 (Direct Cost: ¥6,200,000)
Fiscal Year 1994: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1993: ¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 1992: ¥3,500,000 (Direct Cost: ¥3,500,000)
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| Keywords | UDP-glucuronosyltransferase / Gene Complex / drug-metabolizing enzume / enzyme induction / glucuronidation / bilirubin / Gunn rat / molecular biology / 発現制御 / 遺伝子構造 |
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| Research Abstract |
The UDP-glucuronosyltransferses (UGTs) are a superfamily of catabolic enzymes involved in the glucuronidation of endogenou compounds such as steroid hormones, bilirubin, and bile acids as well as thousand of exogenous compounds that include drugs and xenobiotics. The UGT can be divided into two families termed UGT1 and UGT2.
The purpose of this project is to study the gene organization and regulation of UGT1 isoenzymes. We isolated and determined the structure of an 120-Kb locus of rat family 1 (UGT1) . The data suggest that the RNAs are transcribed from a single gene complex, which encodes at least nine UGTs. Flanking exons 2-5 in a linear array are nine unique exon 1 sequences, which are individually spliced to exons 2-5 to produced the different RNA transcripts. Each exon 1 encodes the substrate-binding domain of the different isoenzymes, and exons 2-5 encode the identical carboxyl terminus corresponding to UDP-glucuronic acid binding domain. The nine first exon can be divided into phenol (A1-4) and bilirubin (B1-5) clusters. In the Gunn rats, a single base deletion was found in the exon 4. These results indicate that a mutation in the exons encoding the conserved carboxyl-terminal domain result in the syntheses of mutated family 1 enzyme. The expressin of each mRNAs and proteins was studied by using isoenzyme specific DNA probes and antibodies. The A1 and A2 were selectively induced by 3-methylcholanthrene (3-MC) . The B1 was a major form for bilirubin activity, and was induced by drugs, dexamethasone and clofibrate. The cis-acting DNA element "GCGTG" was identified in the A1 isoenzumes. The phenol-A1 isoenzyme decreases after birth, but bilirubin-B1 develops after birth. The mechanism for this different expression is studied.
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