| Project/Area Number |
09672313
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Human genetics
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| Research Institution | Kumamoto University |
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Principal Investigator |
ENDO Fumio Kumamoto University School of Medicine Department of Pediatrics, Professor, 医学部, 教授 (00176801)
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| Project Period (FY) |
1997 – 1998
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| Project Status |
Completed (Fiscal Year 1998)
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| Budget Amount *help |
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 1998: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1997: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | apoptosis / liver failure / tyrosinemia / mitochondria / cytochrome c / gene transfer / hepatocellular carcinomas / 化学発がん |
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| Research Abstract |
Hereditary tyrosinemia 1(HT1) is due to mutations in the fumarylacetoacetate hydrolase gene FAH, encoding the last enzyme in the tyrosine catabolic pathway. HT1 patients have severe liver damage and hepatocellular carcinomas, hence liver transplantation has to be done for such children. We developed double mutant mice in which the phenotype of the primary homozygous defect (FAH-/-) is completely concealed by another homozygous mutant allele (HPD-/-). In this model, the inherent defect can be reconstituted by in vivo gene transfer or by a metabolic procedure. These approaches facilitated investigations on the early process of hepatocyte injury, and it became clear that the hepatocyte death was due to apoptosis. Apoptosis of hepatocytes was induced and an acute onset of liver failure occurred following administration of homogentisic acid (HGA), the intermediate metabolite between HPD and FAH.Cytochrome c was released from mitochondria prior to liver failure in the Fah^<-/-> Hpd^<-/-> double mutant mice following the administration of HGA.We also found that caspase inhibitors were highly effective in preventing the liver failure induced by HGA in the double mutant mice. It is highly likely that fumarylacetoacetate apparently induces the release of cytochrome c which in turn triggers activation of the caspase cascade in hepatocytes of subjects with hereditary tyrosinemia type 1.
These knowledge on the hepatic injury in HT1 will facilitate understanding of carcinogenesis in FAH deficiency.
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