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- Title
Inhibitory Effect of TMK688 on Skin Tumor Initiation Caused by 7, 12-Dimethylbenz[a]anthracene in Relation to Inhibition of Aryl Hydrocarbon Hydroxylase Activity and Cyp1a1 mRNA Induction.
- Authors
Jiang, Hong; Yamamoto, Satoshi; Ozawa, Shogo; Shimada, Miki; Yamazoe, Yasushi; Kato, Ryuichi
- Abstract
Oral administration of TMK688 (1-{[5'-(3'-methoxy-4'-ethoxycarbonyloxyphenyl)-2',4'-pentadienoyl]aminoethyl}-4-diphenylmethoxypiperidine: 30 mg/kg) at 6 h and 30 min prior to and at 30 min after a single topical application of 7,12-dimethylbenz[a]anthracene (DMBA) to dorsal skins of mice reduced both tumor incidence and number of tumors per mouse in the DMBA-initiated and 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted two-stage mouse skin carcinogenesis. TMK688 and its active metabolite TMK777 (l-{[5'-(3'-methoxy-4'-hydroxyphenyl)-2',4'-pentadienoyl]-amino-ethyl}-4-diphenylmethoxy piperidine) inhibited 3-methylchol-anthrene (MC)-induced epidermal aryl hydrocarbon hydroxylase (AHH) activity in a concentration-dependent manner. IC50 of TMK688 and TMK777 was 0.18 and 0.01 μmol/l, respectively. Oral administration of TMK688 (30 mg/kg) almost completely suppressed Cyplal mRNA levels in mouse epidermis induced by a topical application of MC (40 mg/kg) or benzo[a]pyrene (200 nmol) to mouse skin. Oral administration of TMK688 (30 mg/kg) also almost completely inhibited induction of epidermal AHH activity caused by a topical application of MC. These results indicate that oral administration of TMK688 inhibited DMBA-caused skin tumor initiation at least in part by inhibiting Cyplal mRNA induction and epidermal AHH activity. Copyright © 1996 S. Karger AG, Basel
- Publication
Pharmacology, 1996, Vol 53, Issue 2, p123
- ISSN
0031-7012
- Publication type
Article
- DOI
10.1159/000139423