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.
Oral administration of TMK688 (1-([5'-(3"-methoxy-4"-ethoxycarbonyloxyphenyl)-2',4'-pentadien oyl] 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-diphenylmethox y 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 mumol/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.
Jiang
H
H
Department of Pharmacology, School of Medicine, Keio University, Tokyo, Japan.
Yamamoto
S
S
Ozawa
S
S
Shimada
M
M
Yamazoe
Y
Y
Kato
R
R
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000008:administration & dosage / Q000633:toxicity; D000284:Administration, Oral; D000287:Administration, Topical; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001483:Base Sequence; D001564:Benzo(a)pyrene / Q000008:administration & dosage / Q000633:toxicity; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D004817:Epidermis / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D016859:Lipoxygenase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D012878:Skin Neoplasms / Q000188:drug therapy*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002273:Carcinogens; D016859:Lipoxygenase Inhibitors; D010880:Piperidines; D012333:RNA, Messenger; C061008:TMK 777; C087493:TMK 688; D001564:Benzo(a)pyrene; D015127:9,10-Dimethyl-1,2-benzanthracene; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1