Document Detail


Inhibition of human leukocyte 5-lipoxygenase by a 4-hydroxybenzofuran, L-656,224. Evidence for enzyme reduction and inhibitor degradation.
MedLine Citation:
PMID:  2018568     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Detailed studies of the interaction of L-656,224 (2-[(4'-methoxyphenyl)methyl]-3-methyl-4-hydroxy-5-propyl-7- chlorobenzofuran) with 5-lipoxygenase were conducted using the enzymes from human and pig leukocytes. L-656,224 was a potent inhibitor of these 5-lipoxygenases although its efficiency varied with enzyme concentration. L-656,224 also stimulated the pseudoperoxidase activity of 5-lipoxygenase as measured by the consumption of 13-hydroperoxy-9,11-octadecadienoic acid (13-HPOD), indicating that this compound can reduce the enzyme. Furthermore the inhibitor was degraded rapidly by both cell-free leukocyte extracts and purified 5-lipoxygenase after incubation with 13-HPOD, ATP and calcium ions. The degradation of L-656,224 was also observed during inhibition of the lipoxygenase reaction and occurred mainly after the initial lag phase of the reaction when hydroperoxides begin to accumulate. A single major radioactive product was formed after incubation of [3H]L-656,224 with purified 5-lipoxygenase in the presence of 13-HPOD. This product was unstable and could not be isolated. During the course of the pseudoperoxidase reaction, [3H]L-656,224 covalently labelled the enzyme, suggesting that a chemically reactive species had been formed. These data are consistent with the hypothesis that L-656,224 reduces the oxidized form of the 5-lipoxygenase to an inactive form, with degradation of the inhibitor and regeneration of the active enzyme with hydroperoxides.
Authors:
C A Rouzer; D Riendeau; J P Falgueyret; C K Lau; M J Gresser
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Biochemical pharmacology     Volume:  41     ISSN:  0006-2952     ISO Abbreviation:  Biochem. Pharmacol.     Publication Date:  1991 May 
Date Detail:
Created Date:  1991-05-17     Completed Date:  1991-05-17     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0101032     Medline TA:  Biochem Pharmacol     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  1365-73     Citation Subset:  IM    
Affiliation:
Department of Pharmacology, Merck Frosst Centre for Therapeutic Research, Québec, Canada.
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MeSH Terms
Descriptor/Qualifier:
Adenosine Triphosphate
Alkylation
Arachidonate 5-Lipoxygenase / antagonists & inhibitors*,  metabolism
Benzofurans / metabolism,  pharmacology*
Calcium
Humans
Leukocytes / drug effects*,  enzymology
Linoleic Acids / metabolism
Lipid Peroxides*
Oxidation-Reduction
Peroxidases / metabolism
Chemical
Reg. No./Substance:
0/Benzofurans; 0/Linoleic Acids; 0/Lipid Peroxides; 102612-16-8/L 656224; 23017-93-8/13-hydroperoxy-9,11-octadecadienoic acid; 56-65-5/Adenosine Triphosphate; 7440-70-2/Calcium; EC 1.11.1.-/Peroxidases; EC 1.13.11.34/Arachidonate 5-Lipoxygenase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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