| Project/Area Number |
15390043
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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 |
Medical pharmacy
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| Research Institution | Tohoku University |
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Principal Investigator |
YAMAZOE Yasushi Tohoku University, Graduate School of Pharmaceutical Sciences, Professor, 大学院・薬学研究科, 教授 (00112699)
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| Co-Investigator(Kenkyū-buntansha) |
NAGATA Kiyoshi Tohoku University, Grad.Sch.Pharm.Sci., Associate Professor, 大学院・薬学研究科, 助教授 (80189133)
MIYATA Masaaki Tohoku University, Grad.Sch.Pharm.Sci., Research Instructor, 大学院・薬学研究科, 助手 (90239418)
FURUKAWA Masayuki Otsuka Pharma Co., Drug Metabolism Research Section, Research Scientist, 研究員
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥15,300,000 (Direct Cost: ¥15,300,000)
Fiscal Year 2004: ¥5,000,000 (Direct Cost: ¥5,000,000)
Fiscal Year 2003: ¥10,300,000 (Direct Cost: ¥10,300,000)
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| Keywords | hepatotoxicity / nuclear receptor / induction / Bile acid / Liver toxicity / FXR / PXR / Lithocholic acid |
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| Research Abstract |
Supplement of 1% lithocholic acid (LCA) in the diet for 5-9 days resulted in elevated levels of the marker for liver damage aspartate aminotransferase (AST) and alkaline phosphatase (ALP) activities in both FXR-null and wild-type female mice. The levels were clearly higher in wild-type mice than in FXR-null mice. Consistent with liver toxicity marker activities, serum and liver levels of bile acids, particularly LCA and tauroLCA, were clearly higher in wild-type mice than in FXR-null mice after 1% LCA supplement. Marked increases in hepatic sulfating activity for LCA (5.5-fold) and hydroxysteroid sulfotransferase St2a (5.8-fold) were detected in liver of FXR-null mice. A 7.4-fold higher 3a-sulfated bile acid concentration was observed in gallbladder bile of FXR-null mice fed a LCA diet compared to that of wild-type mice. These results indicate that LCA sulfation catalyzed by hydroxysteroid sulfotransferase is at least one pathway for protection against LCA-induced liver damage. Further
… More
more, northern blot analysis using FXR-null, PXR-null and FXR-PXR double-null mice suggests a repressive role of these nuclear receptors on basal St2a expression.
FXR-null mice are highly sensitive to cholic acid (CA)-induced liver toxicity. AST activity was elevated 15.7-fold after feeding a 0.25% CA diet, whereas only slight increases in serum AST (1.7-fold and 2.5-fold) were observed in wild-type mice fed 0.25% and 1% CA diet, respectively. The bile acid output rate was 2.0-fold and 3.7-fold higher after feeding of 0.25 and 1.0% CA diet in wild-type mice, respectively. On the other hand, no significant increase in bile acid output rate was observed in FXR-null mice fed 0.25% CA diet in contrast to a significant decrease observed in mice fed a 1.0% CA diet in spite of the markedly higher levels of hepatic tauro-conjugated bile acids. These results suggest that the CA-induced enhancement of canalicular bile acid output rate is involved in adaptive responses for prevention of CA-induced toxicity. Less
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