Effects of flavonoids and antioxidants on 12-O-tetradecanoyl-phorbol-13-acetate-caused epidermal ornithine decarboxylase induction and tumor promotion in relation to lipoxygenase inhibition by these compounds

The effects of flavonoids, antioxidants and related compounds on 12-O-tetradecanoylphorbol-13-acetate (TPA)-caused epidermal ornithine decarboxylase (ODC) induction, DNA synthesis and skin tumor promotion, and on epidermal lipoxygenase activity, were investigated using CD-1 mice. Morin, fisetin, kaempferol and n-propyl gallate potently inhibited epidermal lipoxygenase activity, and esculetin, butylated hydroxyanisole (BHA), α-naphthol and 2,3-dihydroxynaphthalene (2,3-DHNA) moderately inhibited it. α-Tocopherol, (+)catechin, (-)epicatechin and butylated hydroxytoluene (BHT) were inactive. Similarly, morin, fisetin, kaempferol and n-propyl gallate markedly inhibited TPA-caused ODC induction. Esculetin, BHA, α-naphthol, 2,3-DHNA and α-tocopherol inhibited it less potently, but significantly. (+)Catechin, (-)epicatechin and BRT failed to inhibit or only slightly inhibited TPA-caused ODC induction. TPA-caused DNA synthesis was not inhibited by morin, esculetin, (+)-catechin or α-tocopherol. The TPA-induced skin tumor promotion was markedly inhibited by morin and slightly suppressed by esculetin and α-tocopherol, but (+)-catechin was inactive. Thus, the inhibitory effects of flavonoids and antioxidants on the TPA-caused ODC induction and tumor promotion were roughly parallel with their activities of lipoxygenase inhibition. These results further support our hypothesis that a lipoxygenase product(s) is involved in the mechanism of TPA-caused ODC induction and tumor promotion.