1999 Fiscal Year Final Research Report Summary
Gene polymorphism of CYP2C subfamily and inter-individual differences in drug metabolism
| Project/Area Number |
10672145
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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 | Chiba University |
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Principal Investigator |
CHIBA Kan Chiba University, Faculty of Pharmaceutical Sciences, Professor, 薬学部, 教授 (40159033)
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| Co-Investigator(Kenkyū-buntansha) |
KUBOTA Takahiro Research Testing Department, SRL, Inc., 研究員
KOBAYASHI Kaoru Chiba University, Faculty of Pharmaceutical Sciences, Research Associate, 薬学部, 助手 (30255864)
HOSOKAWA Masakiyo Chiba University, Faculty of Pharmaceutical Sciences, Lecturer, 薬学部, 講師 (70181500)
ISHIZAKI Takashi Graduate School of Kumamoto University, Faculty of Pharmaceutical Sciences, Professor, 大学院, 教授 (50158747)
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| Project Period (FY) |
1998 – 1999
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| Keywords | CYP2C9 / CYP2C18 / CYP2C19 / Polymorphism / inter-individual differences / linkage |
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| Research Abstract |
The coincidence of mutant alleles of CYP2C18 and CYP2C19 was studied in 154 Japanese subjects. The mutant alleles of CYP2C18 were CYP2C18m1(T204A) and CYP2C18mFR(A-460T) and those of CYP2C19 were CYP2C19m1(G689A) and CYP2C19m2(G636A). The results indicated that genotypes of CYP2C18m1 and CYP2C18mFR are completely coincident with those of CYP2C19m2 and CYP2C19m1, respectively. The finding suggests that the mutations of CYP2C18 and CYP2C19 examined in the present study are very closely linked with each other at least in a Japanese population. We also studied the kinetics of seven metabolic reactions using wild-type (CYP2C9-Ile359) and mutant (CYP2C9-Leu359) of CYP2C9 expressed in yeast cells. For the metabolism of all the substrates studied, The Leu variant exhibited smaller Vmax/Km values than wild-type. The differences in Vmax/Km between wild-type and Leu variant varied from 3.4-fold to 26.9-fold. The result suggests that Ile359Leu changes decreases the catalytic activity of CYP2C9-mediated reactions although the extent of decrease in the activity varies between substrates.
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