Document Detail

12(R)-hydroxyeicosatrienoic acid: a vasodilator cytochrome P-450-dependent arachidonate metabolite from the bovine corneal epithelium.
MedLine Citation:
PMID:  3141417     Owner:  NLM     Status:  MEDLINE    
When corneal microsomes were incubated with arachidonic acid in the presence of an NADPH-generating system, two biologically active metabolites of arachidonic acid were formed. The structure of one of the metabolites, compound C, was previously reported to be 12(R)-hydroxy-5,8,10,14-eicosatetraenoic acid and was found to be a potent inhibitor of the Na+/K+-ATPase in the cornea. The second metabolite, compound D, was found to be a potent vasodilator as well as having the property of stimulating protein influx into the aqueous humor of the eye. Following purification of compound D by thin layer chromatography and high pressure liquid chromatography, it was found to lack a UV chromophore in contrast to the previously reported cytochrome P-450-dependent metabolite. Mass spectrometric analysis using positive and negative ionization modes was carried out on derivatized compound D that had been synthesized from a mixture of labeled [( 5,6,8,9,11,12,14,15-2H8]) and unlabeled arachidonic acid incubated with corneal microsomes. The novel arachidonate metabolite had abundant fragment ions consistent with compound D being a monooxygenated derivative of arachidonic acid with a hydroxyl substituent at carbon 12 of the eicosanoid backbone; only seven deuterium atoms from [2H8]arachidonate were retained in the structure. Oxidative ozonolysis yielded a product indicating that the double bonds in metabolite D resided between carbons at positions 8 and 9 and positions 14 and 15 of the 20-carbon chain. Compound D was therefore characterized as 12-hydroxy-5,8,14-eicosatrienoic acid. Model compounds were synthesized from dimethyl malate with the hydroxy at the 12 position with both the R and S absolute configuration and with all double bonds of the cis configuration. Only the 12(R) isomer was found to be a potent vasodilator and to increase aqueous humor protein concentration, suggesting that the biologically active compound D was 12(R)-hydroxy-5,8,14-(Z,Z,Z)-eicosatrienoic acid. As this compound possesses proinflammatory properties, it may play a role in the wound-healing processes of corneal injury.
R C Murphy; J R Falck; S Lumin; P Yadagiri; J A Zirrolli; M Balazy; J L Masferrer; N G Abraham; M L Schwartzman
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  263     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  1988 Nov 
Date Detail:
Created Date:  1988-12-14     Completed Date:  1988-12-14     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  17197-202     Citation Subset:  IM    
Department of Pharmacology, University of Colorado Health Science Center, Denver 80262.
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MeSH Terms
12-Hydroxy-5,8,10,14-eicosatetraenoic Acid
Arachidonic Acid
Arachidonic Acids / metabolism*
Cornea / cytology,  metabolism*
Cytochrome P-450 Enzyme System / metabolism*
Epithelium / metabolism
Eye / blood supply,  drug effects
Hydroxyeicosatetraenoic Acids / metabolism*,  pharmacology
Vasodilation* / drug effects
Grant Support
Reg. No./Substance:
0/Arachidonic Acids; 0/Hydroxyeicosatetraenoic Acids; 506-32-1/Arachidonic Acid; 59985-28-3/12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; 9035-51-2/Cytochrome P-450 Enzyme System

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