Effects of two novel inhibitors of 5-lipoxygenase, L-651,392 and L-651,896, in a guinea-pig model of epidermal hyperproliferation.
The effects of two novel and structurally different 5-lipoxygenase inhibitors, L-651,392 (4-bromo-2,7-dimethoxy-3H-phenothiazin-3-one) and L-651,896 (2,3-dihydro-6-(3-(2-hydroxymethyl)phenyl-2-propenyl)-5-benzo furanol), on epidermal proliferation were examined in the guinea-pig ear stimulated with the calcium ionophore A23187. Topical application of A23187 on the guinea-pig ear induced epidermal hyperproliferation which could be quantitated by tritiated-thymidine incorporation into DNA in the heat-separated epidermis. The ionophore-induced response was inhibited dose dependently by either L-651,392 or L-651,896 when the guinea-pigs were pretreated topically with these compounds. In separate experiments, it was demonstrated that A23187 induced a significant increase in the levels of immunoreactive-LTB4 in the guinea-pig ear which could be blocked by either inhibitors. It was suggested that L-651,392 and L-651,896 inhibited the ionophore-induced epidermal proliferation via their inhibitory action on the 5-lipoxygenase pathway of arachidonic acid metabolism.
Chan
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CC
Department of Pharmacology, Merck Frosst Canada, Pointe Claire-Dorval, Quebec.
Dubois
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L
Young
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D000818:Animals; D001091:Arachidonate Lipoxygenases / Q000037:antagonists & inhibitors*; D001572:Benzofurans / Q000494:pharmacology*; D000001:Calcimycin / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects*; D004247:DNA / Q000096:biosynthesis; D015232:Dinoprostone; D000078404:Epidermal Cells; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007975:Leukotriene B4 / Q000378:metabolism; D016859:Lipoxygenase Inhibitors; D008297:Male; D010640:Phenothiazines / Q000494:pharmacology*; D011458:Prostaglandins E / Q000378:metabolism
D001572:Benzofurans; D016859:Lipoxygenase Inhibitors; D010640:Phenothiazines; D011458:Prostaglandins E; D007975:Leukotriene B4; D000001:Calcimycin; D004247:DNA; C053726:4-bromo-2,7-dimethoxy-3H-phenothiazin-3-one; C053727:L 651896; D001091:Arachidonate Lipoxygenases; D015232:Dinoprostone