A novel synthetic analogue of a constituent of Isodon excisus inhibits transcription of CYP1A1, -1A2 and -1B1 by preventing activation of the aryl hydrocarbon receptor.
We investigated the effect of a novel synthetic analogue of a constituent from the Chinese medicinal herb Isodon excisus, 3-(3-methoxy-phenyl)-N-(3, 4, 5-trimethoxy-phenyl)-acrylamide (compound 343), on the carcinogen activation pathway mediated by the aryl hydrocarbon receptor (AhR) in human hepatoma HepG2 cells. We found that compound 343 inhibited the upregulation of cytochrome P-450 (CYP) enzyme activity in cells treated with the AhR ligands and potent carcinogens, dimethylbenz[a]anthracene (DMBA) or 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD). Compound 343 also inhibited the DMBA- or TCDD-induced increase in CYP1A1, -1A2 and -1B1 mRNA levels. Carcinogen-induced transcription of CYP genes was also suppressed by compound 343, as measured by a reporter gene controlled by the xenobiotic-responsive element (XRE). This was confirmed by measuring the amount of carcinogen-induced CYP1A1 heterogeneous nuclear RNA. Compound 343 blocked the DMBA- or TCDD-induced activation of the AhR DNA-binding capacity for the XRE, as measured by a chromatin immunoprecipitation assay. Compound 343 also inhibited CYP enzyme activity in microsomes isolated from DMBA- or TCDD-treated cells, as well as the activity of recombinant CYP1A1, -1A2 and -1B1, indicating that compound 343 directly inhibits CYP enzymes. These results indicate that compound 343 is both a potent inhibitor of carcinogen-induced CYP enzyme expression, as well as a direct inhibitor of CYP enzymes.
Sienkiewicz
Pawel
P
Cellular Defense and Carcinogenesis Section, Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute at Frederick, National Institutes of Health, Frederick, MD 21702-1201, USA.
Ciolino
Henry P
HP
Leslie
Benjamin J
BJ
Hergenrother
Paul J
PJ
Singletary
Keith
K
Yeh
Grace Chao
GC
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000494:pharmacology; D000178:Acrylamides / Q000494:pharmacology; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics*; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics*; D065633:Cytochrome P-450 CYP1B1; D004790:Enzyme Induction / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D037602:Isodon / Q000737:chemistry*; D018514:Plant Structures; D010946:Plants, Medicinal; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
C520945:3-(3-methoxyphenyl)-N-(3,4,5-trimethoxyphenyl)acrylamide; D000178:Acrylamides; D016588:Anticarcinogenic Agents; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D015127:9,10-Dimethyl-1,2-benzanthracene; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D065633:Cytochrome P-450 CYP1B1