Inhibition of Aryl Hydrocarbon-Induced Cytochrome P-450 1A1 Enzyme Activity and CYP1A1 Expression by Resveratrol

• Published in: Molecular pharmacology 1999-10, Vol.56 (4), p.760-767
• Main Authors: Ciolino, Henry P., Yeh, Grace Chao
• Format: Article
• Language: English
• Subjects: 9,10-Dimethyl-1,2-benzanthracene - pharmacology; Anticarcinogenic Agents - pharmacology; Benzo(a)pyrene - metabolism; Carcinogens - pharmacology; Cytochrome P-450 CYP1A1 - antagonists & inhibitors; Cytochrome P-450 CYP1A1 - biosynthesis; Cytochrome P-450 CYP1A1 - genetics; Cytochrome P-450 CYP1A1 - metabolism; Enzyme Activation; Enzyme Inhibitors - pharmacology; Gene Expression - drug effects; Humans; Receptors, Aryl Hydrocarbon - metabolism; Stilbenes - pharmacology; Tumor Cells, Cultured
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1016/S0026-895X(24)12538-2

We investigated the effect of resveratrol, a constituent of the human diet that has been shown to inhibit aryl hydrocarbon-induced carcinogenesis in animals, on the carcinogen activation pathway regulated by the aryl hydrocarbon receptor. Resveratrol inhibited the metabolism of the environmental aryl hydrocarbon benzo[a]pyrene (B[a]P) catalyzed by microsomes isolated from B[a]P-treated human hepatoma HepG2 cells. Resveratrol competitively inhibited, in a concentration-dependent manner, the activity of the carcinogen activating enzymes cytochrome P-450 (CYP)1A1/CYP1A2 in microsomes and intact HepG2 cells. Resveratrol inhibited the B[a]P-induced expression of the CYP1A1gene, as measured at the mRNA and transcriptional levels. Resveratrol abolished the binding of B[a]P-activated nuclear aryl hydrocarbon receptor to the xenobiotic-responsive element of theCYP1A1 promoter but did not itself bind to the receptor. Resveratrol was also effective in inhibiting CYP1A1transcription induced by the aryl hydrocarbon dimethylbenz[a]anthracene in human mammary carcinoma MCF-7 cells. These data demonstrate that resveratrol inhibits aryl hydrocarbon-induced CYP1A activity in vitro by directly inhibiting CYP1A1/1A2 enzyme activity and by inhibiting the signal transduction pathway that up-regulates the expression of carcinogen activating enzymes. These activities may be an important part of the chemopreventive activity of resveratrol in vivo.