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

Hong Jiang, Satoshi Yamamoto, Shogo Ozawa, Miki Shimada, Yasushi Yamazoe, Ryuichi Kato

    Research output: Contribution to journalArticle

    4 Citations (Scopus)

    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 (1-{[5'-(3'-methoxy-4'-hydroxyphenyl)-2',4'-pentadienoyl]-aminoethyl}-4 -diphenylmethoxy piperidine) inhibited 3-methylcholanthrene (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 Cyp1a1 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 Cyp1a1 mRNA induction and epidermal AHH activity.

    Original languageEnglish
    Pages (from-to)123-132
    Number of pages10
    JournalPharmacology
    Volume53
    Issue number2
    Publication statusPublished - 1996 Aug

    Keywords

    • 3-methylcholanthrene
    • 7,12-dimethylbenz[a]anthracene
    • Aryl hydrocarbon hydroxylase
    • Benzo[a]pyrene
    • Cyp1a1
    • Polycyclic aromatic hydrocarbons
    • Skin tumor initiation
    • TMK688
    • TMK777

    ASJC Scopus subject areas

    • Pharmacology

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