Ocular effects of a novel cytochrome P-450-dependent arachidonic acid metabolite.
Compound D is a novel arachidonic acid metabolite formed by a cytochrome P-450-dependent mono-oxygenase in bovine corneal epithelium. The structure of compound D was recently identified as 12-hydroxy-5,8,14-eicosatrienoic acid. In the current study, we described the biological properties and the ocular effects of this compound. Compound D is a potent vasodilator, and caused a dose-dependent relaxation of the rat tail artery preconstricted with phenylephrine with an EC50 of 1.5 microM, 4-5-fold more potent than acetylcholine. Topical application of as little as 10 ng of compound D onto the rabbit cornea produced a vasodilation of the conjunctival blood vessels. Intracameral injection of compound D (1-10 ng) caused a dose-dependent increase of up to 30-fold of the aqueous humor protein, indicating a breakdown of the blood-aqueous barrier. Compound D was also found to be a potent angiogenic factor, ie, it induced the appearance of new vessels in the cornea. The effects of 12-(R)-hydroxyeicosatrienoic acid (compound D) on the rabbit eye mimics the response of the eye to an inflammatory stimulus. We hypothesize, therefore, that ocular inflammation that occurs following injury to the cornea is mediated, at least in part, by the production of compound D by the corneal epithelium.
Masferrer
J L
JL
Department of Pharmacology, New York Medical College, Valhalla 10595.
Murphy
R C
RC
Pagano
P J
PJ
Dunn
M W
MW
Laniado-Schwartzman
M
M
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D000818:Animals; D001082:Aqueous Humor / Q000378:metabolism; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism*; D001158:Arteries; D002417:Cattle; D055598:Chemical Phenomena; D002621:Chemistry; D003228:Conjunctiva / Q000098:blood supply; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D005123:Eye / Q000187:drug effects*; D005136:Eye Proteins / Q000378:metabolism; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology* / Q000502:physiology; D008297:Male; D009389:Neovascularization, Pathologic / Q000503:physiopathology; D051381:Rats; D011919:Rats, Inbred Strains; D013623:Tail / Q000098:blood supply; D014655:Vascular Resistance / Q000187:drug effects
D001095:Arachidonic Acids; D005136:Eye Proteins; D006893:Hydroxyeicosatetraenoic Acids; D016718:Arachidonic Acid; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D003577:Cytochrome P-450 Enzyme System