| The specificity of inhibition of debrisoquine 4-hydroxylase activity by quinidine and quinine in the rat is the inverse of that in man. | |
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MedLine Citation:
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PMID: 2775304 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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 (IC50: 3.6 microM). However, its stereoisomer, quinine, is some 60 times less potent (IC50:223 microM). Both compounds are able to inhibit greater than 95% of 4-hydroxylase activity. In rat liver microsomes quinine is approximately 50 times more potent an inhibitor (IC50:2.4 microM) than quinidine (IC50:137 microM). Again, 4-hydroxylase activity is inhibited by greater than 95%. Inhibition of debrisoquine 4-hydroxylase activity by both quinine and quinidine in human and rat liver is competitive. Values of Ki for quinidine in human and rat were 0.6 microM and 50 microM, whereas with quinidine the Ki values were 13 microM and 1.7 microM, respectively. The data in this paper are consistent with 4-hydroxylation of debrisoquine in both rat and human liver catalysed by a specific form of cytochrome P-450. Although both quinidine and quinine are competitive inhibitors of debrisoquine 4-hydroxylase activity in rat and man, their potency is reversed. This suggests that the nature of the active site of cytochrome P-450dbl differs between the two species, and indicates that data on the specificity of this isoenzyme in the rat should be extrapolated to man with extreme caution. |
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Authors:
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S Kobayashi; S Murray; D Watson; D Sesardic; D S Davies; A R Boobis |
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Publication Detail:
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Type: Comparative Study; In Vitro; Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Biochemical pharmacology Volume: 38 ISSN: 0006-2952 ISO Abbreviation: Biochem. Pharmacol. Publication Date: 1989 Sep |
Date Detail:
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Created Date: 1989-09-27 Completed Date: 1989-09-27 Revised Date: 2009-09-29 |
Medline Journal Info:
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Nlm Unique ID: 0101032 Medline TA: Biochem Pharmacol Country: ENGLAND |
Other Details:
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Languages: eng Pagination: 2795-9 Citation Subset: IM |
Affiliation:
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Department of Clinical Pharmacology, Royal Postgraduate Medical School, London, U.K. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cytochrome P-450 CYP2D6 Cytochrome P-450 Enzyme System / antagonists & inhibitors* Debrisoquin / metabolism Humans Liver / drug effects*, enzymology Male Mixed Function Oxygenases / antagonists & inhibitors* Quinidine / pharmacology* Quinine / pharmacology* Rats Rats, Inbred Strains Species Specificity |
| Grant Support | |
ID/Acronym/Agency:
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//Wellcome Trust |
| Chemical | |
Reg. No./Substance:
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1131-64-2/Debrisoquin; 130-95-0/Quinine; 56-54-2/Quinidine; 9035-51-2/Cytochrome P-450 Enzyme System; EC 1.-/Mixed Function Oxygenases; EC 1.14.14.1/Cytochrome P-450 CYP2D6 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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