| Project/Area Number |
08672624
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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 |
応用薬理学・医療系薬学
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| Research Institution | Showa University |
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Principal Investigator |
YASUHARA Hajime Showa University, School of Medicine, Professor, 医学部, 教授 (70053999)
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| Co-Investigator(Kenkyū-buntansha) |
KURATA Norimitu Showa University, Shcool of Medicine, lecturer, 医学部, 講師 (80231299)
UCHIDA Eiji Showa University, Shcool of Medicine, Assistant Professor, 医学部, 助教授 (80175223)
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| Project Period (FY) |
1996 – 1997
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| Project Status |
Completed (Fiscal Year 1997)
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| Budget Amount *help |
¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 1997: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1996: ¥1,400,000 (Direct Cost: ¥1,400,000)
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| Keywords | Omeprazole / CYP2C19 / Phenotype / Genotype / Polymorphism / Trimethadione / CYP2E1 / Pharmacogenetics / Human Liver / Cytochrome P450 / Chlorzoxazone / Ethics |
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| Research Abstract |
In this project, we have specified the cytochrome P450 isozyme that responsible to trimethadione metabolism which widely employed for the estimation of hepatic drug-metabolizing capacity in human in vivo. And also to establish the simple and reliable procedure for the evaluate the enzyme deficiency by genotyping procedure, relationship between phenotype determined by employing the probe drug and genotype were compared.
Trimethadione metabolism had been determined by employing the human liver microsomal fraction and human lymphoblastoid cell expressed cytochrome P450 enzymes. By these experiments, it had been defined that trimethadione is predominantly metabolyzed by CYP2E1 enzyme in human.
On the other hand, relationship between CYP2C19 phenotype and genotype of the couple of mutations, CYP2C19m1 in exon 5 and CYP2C19m2 in exon 4 were determined by using the 28 of phenotyped recruted healthy volunteers. Six out of 28 subjects were homozygous for the wild-type (wt/wt) allele in both exon 4 and exon 5,11 heterozygous for the CYP2C19m1 (wt/m1) ; 5 heterozygous for the CYP2C19m2 (wt/m2) ; 5 homozygous for the CYP2C19m1 (m1/m1) ; 1 heterozygous for both defects (m1/m2). The homozygous genotype was compatible with the phenotype of the extensive metabolizer (EMs : wt/wt) and PMs (m1/m1). The heterozygous genotype, however, was not clearly compatible with the phenotype : one out of 11 with wt/m1 genotype was judged as PM.Five subjects with wt/m2 were EMs. The phenotype of one subject with m1/m2 could not be identified since extremely low serum concentration of omeprazole and 5-OH omeprazole. From these results, genotype and phenotype of CYP2C19 were well correlated among the subjects. Further detail study will be needed to clarify the relationship between the CYP2C19 genotype and phenotype in subjects with a heterozygous genotype.
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