Polymorphism of Hepatic Dung Metabolizing Enzymes and Extrapolation of its Data from Animal to Human
| Project/Area Number |
01570114
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
General pharmacology
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| Research Institution | Showa University |
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Principal Investigator |
YASUHARA Hajime Showa Univ. , School of Med. , Professor, 医学部, 教授 (70053999)
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| Co-Investigator(Kenkyū-buntansha) |
UEDA Takako Showa Univ. , School of Med. , Instructor, 医学部, 助手 (00175499)
KOBAYASHI Shinichi SHOWA Univ. , School of Med. Associate professor, 医学部, 助教授 (20129836)
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| Project Period (FY) |
1989 – 1990
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| Project Status |
Completed (Fiscal Year 1990)
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| Budget Amount *help |
¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1990: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1989: ¥1,300,000 (Direct Cost: ¥1,300,000)
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| Keywords | drug metabolizing enzymes / polymorphism / model substrates / antipyrine / trimethadione / debrisoquine / extrapolation / エノキサシン / チトクロ-ムPー450 / ラット |
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| Research Abstract |
The 4-hydroxylation of debrisoquine is polymorphic in man. The kinetics of inhibition of debrisoquine 4-hydroxylase activity by quinidine and quinine in rat and human liver microsomes have been compared. Quinidine is a potent inhibitor of debrisoquine 4-hydroxylase activity of human liver. However, its stereoisomer, quinine is some 60 times less potent. In the rat liver microsomes quinine is approximately 50 times more potent an inhibitor than quinidine. Both compounds are able to inhibit >95% of 4-hydroxylase activity in both rat and human. Both quinidine and quinine are competitive inhibitor of debrisouine 4-hydroxylase activity in rat and man, their potency is reversed. This suggests that the nature of the active site of cytochrome P-450dbl differ between the two species. The effects of dilitiazem on hepatic mixed function-monoxygenase system was investigated in rat. Trimethadione metabolism and urinary excretion of 4-hydroxyantipyrine were increased but debrisoquine 4-hydroxylation
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was inhibited by diltiazem. In human study, antipyrine clearance was decreased, especially formation clearance of 4-hydroxyantipyrine was decreased. Debrisoquine 4-hydroxylation was inhibited and trimethadione metabolism was not changed by diltiazem. From this results, the effects of diltiazem on 4-hydroxylation of antipyrine was reversed in rat and human, however, inhibitory effect of 4-hydroxylation of debrisoquine was shown in both rat and human. The effects of enoxacin on hepatic microsomal drug metabolizing enzymes were studied in rat and man, because enoxacin decresed plasma clearance of theophyllin in man. Formation clearance of 3-hydroxymethylantipyrine was decreased, while that of norantipyrine was increased by multiple dose of enoxacin in rat. Enoxacin had no effect on trimethadione metabolism in rat. In man, clearances of 3-hydroxymethylantipyrine, norantipyrine and 4-hydroxyantipyrine were all significantly decreased after treatment of enoxacin. Trimethadione metabolism was enhanced by enoxacin. This results suggest that enoxacin affects several P-450 isozymes in different manner such as inhibition and induction and that characteristics of P-450 isozymes involved in antipyrine and trimethadione are possibly different between rat and man. From these studies, it may indicate that the data on hepatic drug metabolizing enzyme capacity in rat should be extrapolated to man with extreme caution and with using many model substrates. Less
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Report
(3 results)
Research Products
(14 results)
