Inhibition by 2(3)-tert-butyl-4-hydroxyanisole and other antioxidants of epidermal ornithine decarboxylase activity induced by 12-O-tetradecanoylphorbol-13-acetate.
The relationship between reactive oxygen and/or free radical species and tumor promotion was evaluated by investigating the inhibitory effects of 2(3)-tert-butyl-4-hydroxyanisole (BHA) and other antioxidants on the induction of ornithine decarboxylase (ODC) activity in mouse epidermis by a tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA). Mice maintained on a diet containing 0.75% BHA for 8 days showed a 50% reduction in maximal ODC induction following treatment with TPA when compared to mice fed a control diet. Topical application of BHA (55 mumol) 30 min prior to TPA treatment (17 nmol) elicited an 80% inhibition of promoter-induced ODC activity. BHA was ineffective as an inhibitor when administered either 16 hr before or 2 hr after the promoter. The inhibition by BHA was dose dependent with a dose producing a 50% inhibition of ODC induction of 6 mumol. A structure-activity study with BHA analogues (2-tert-butyl-4-hydroxyanisole, 3-tert-butyl-4-hydroxyanisole, 2-tert-butyl-1,4-dimethoxybenzene,tert-butylhydroquinone, 4-hydroxyanisole, p-hydroquinone, phenol, and 2-tert-butyl-phenol) showed that hydroxyl and tert-butyl substituents were important determinants of inhibitory activity. A spectrum of other antioxidants were also tested. Butylated hydroxytoluene was nearly equipotent to BHA; alpha-tocopherol, propyl gallate, and disulfiram were all less potent, and L-ascorbate was inactive. None of the antioxidants affected basal ODC activity in non-TPA-treated mice. Collectively, these results demonstrate an early and direct inhibition of TPA-induced ODC activity by lipophilic phenolic antioxidants and suggest a role for reactive oxygen and/or free radical species in tumor promotion.
D000287:Administration, Topical; D000818:Animals; D000840:Anisoles / Q000494:pharmacology*; D002083:Butylated Hydroxyanisole / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology*; D002262:Carboxy-Lyases / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D004817:Epidermis / Q000201:enzymology*; D005260:Female; D051379:Mice; D009955:Ornithine Decarboxylase / Q000096:biosynthesis; D065108:Ornithine Decarboxylase Inhibitors; D010704:Phorbols / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D013997:Time Factors
D000840:Anisoles; D065108:Ornithine Decarboxylase Inhibitors; D010704:Phorbols; D002083:Butylated Hydroxyanisole; D002262:Carboxy-Lyases; D009955:Ornithine Decarboxylase; D013755:Tetradecanoylphorbol Acetate