Inhibition by lipoxygenase inhibitors of 7-bromomethylbenz[a]anthracene-caused epidermal ornithine decarboxylase induction and skin tumor promotion in mice.
7-Bromomethylbenz[a]anthracene (BrMBA) has been shown to have a tumor-promoting action in mouse skin without an initial direct interaction with protein kinase C, which is believed to be a receptor for phorbol ester tumor promoters such as 12-O-tetradecanoylphorbol-13-acetate (TPA). An application of BrMBA to mouse dorsal skin caused epidermal ornithine decarboxylase (ODC) induction in a dose-dependent manner with a peak of activity at 12 h after the application. A single topical application of BrMBA failed to induce mouse ear edema formation, i.e. inflammation. However, repeated applications of BrMBA, i.e. twice a week for 3-4 times, caused a significant edema. Unlike TPA, BrMBA failed to stimulate the superoxide anion generation of rabbit peritoneal polmorphonuclear leukocytes. Lipoxygenase inhibitors such as 3,4,2',4'-tetrahydroxychalcone, nordihydroguaiaretic acid, quercetin and 2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone (AA861) effectively inhibited BrMBA-caused epidermal ODC induction and ear edema formation. In addition, BrMBA-caused skin tumor promotion was also potently inhibited by 3,4,2'4'-tetrahydroxychalcone and quercetin. These results indicate that a mechanism susceptible to lipoxygenase inhibitors plays a role not only in the TPA-caused but also in the BrMBA-caused epidermal ODC induction, skin inflammation and tumor promotion. It seems unlikely that superoxide anion generation is involved in the mechanism of BrMBA-caused skin tumor promotion.
Nakadate
T
T
Department of Pharmacology, School of Medicine, Keio University, Tokyo, Japan.
Yamamoto
S
S
Aizu
E
E
Kato
R
R
D000818:Animals; D001551:Benz(a)Anthracenes; D002273:Carcinogens; D003043:Cocarcinogenesis; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D004817:Epidermis / Q000201:enzymology; D016859:Lipoxygenase Inhibitors; D051379:Mice; D009955:Ornithine Decarboxylase / Q000096:biosynthesis*; D011794:Quercetin / Q000494:pharmacology; D012878:Skin Neoplasms / Q000139:chemically induced*; D013481:Superoxides / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D001551:Benz(a)Anthracenes; D002273:Carcinogens; D016859:Lipoxygenase Inhibitors; D013481:Superoxides; C001903:7-bromomethylbenzanthracene; D011794:Quercetin; D009955:Ornithine Decarboxylase; D013755:Tetradecanoylphorbol Acetate