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.