1998 Fiscal Year Final Research Report Summary
STUDY OF BILE ACID BIOSYNTHESIS OF FETAL BILE ACIDS AND CONGENITAL DISORDERS
| Project/Area Number |
09672197
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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 |
Physical pharmacy
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| Research Institution | HEALTH SCIENCES UNIVERSITY OF HOKKAIDO |
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Principal Investigator |
KUROSAWA Takao HEALTH SCI.UNIV.HOKKAIDO,FAC.PHARM.SCI,PROF., 薬学部, 教授 (50103198)
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| Co-Investigator(Kenkyū-buntansha) |
YOSHIMURA Teruki HEALTH SCI.UNIV.HOKKAIDO,FAC.PHARM.SCI,AST.PROF., 薬学部, 講師 (60220737)
TOHMA Masahiko HEALTH SCI.UNIV.HOKKAIDO,FAC.PHARM.SCI,PROF., 薬学部, 教授 (30001043)
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| Project Period (FY) |
1997 – 1998
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| Keywords | fetal bile acid / bile acid biosynthesis disorder / C27-bile acid / biosynthesis intermediates / HPLC / GC / MS / enzymatic specificitiy / stereospecificity |
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| Research Abstract |
Biosynthetic pathway of bile acids in the neonatal petiod is of interest in connection with the development of neonatal liver function. However, the above pathway has not been clearly established.Recently, the fetal bile acids have been found and their expected intermediateshave also been identified in the biological fluids of patients with congenital bile acid disorder. From the above point of view, the following subjects have been studied in this project.
1)Synthesis of bile acid intermediates in neonatal period. 2)Establishment of quantitative analysis for bile acid intermediates. 3)Olarification of the role and function of enzymes in bile acid biosynthesis andquantitative analysis of bile acid component in congenital disorder.
The biosynthetic intermediates (1beta and Gci-hydroxylated cholestan-26-oic acids) and their analogues with deifrent hydroxyl group numbers and side chain structures were synthesized by the modification of previously reported method as the authentic specimens for establishment of analysis and as substrates for enzymatic study. Usingthe above compounds, the quantitative analytical methods were establised by the use of HPLC, GO and GO/MS.The above methods were then applied for the determination of metabolites of enzymatic reaction (hydratase/dehydrogenase, thiolase in side chain degradation step). The results indicated that the enzymatic reaction (hydratase/dehydrogenase) proceed substrate and stereospecifically to give 24-hydroxylated cholestanoic acid with 24R,25R-stereochemistry. It was also indicated that steroid carieer protein 2 shows the thiolase actvities. The analysis of bile acids in urine and serum of patients with liver disease showed the significant accumulation of abnormal bile acids (3-oxo-DELTA4-bile acids) indicating enzymatic disorder (probably disorder of 3-oxo-DELTA4-steroid reductase) of bile acid biosynthesis of the above patients, .
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