The chemopreventive drug anethole dithiolethione decreases metabolic activation of environmental carcinogens mediated by the aryl hydrocarbon receptor signaling pathway.

B60

The organosulfur-based chemopreventive agent, anethole dithiolethione (ADT; 5-[p-methoxyphenyl]-1,2-dithiole-3-thione) has been demonstrated to protect against the development of chemical-induced liver, lung and colon cancers in animal studies, however, the mechanism of the chemopreventive action of ADT has not been fully elucidated. We hypothesize that ADT may inhibit the carcinogen activation mediated by the aryl hydrocarbon receptor (AhR) signaling pathway. We investigated our hypothesis in human hepatoma HepG2 cells and we found that ADT inhibited the up-regulation of cytochrome P-450 (CYP) enzymes activity induced by polycyclic aromatic hydrocarbons (PAH), benzo[a]pyrene (BP), dimethylbenzanthracene (DMBA) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). ADT also inhibited the activity of recombinant CYP1A1, 1A2 and 1B1, indicating that the inhibitory effect by ADT is contributed in part by direct enzyme inhibition. We further demonstrated that the inhibitory effect of ADT on CYP enzyme activities is also contributed at the transcriptional level. We found that ADT inhibited PAH-induced transcription of CYP1A1 and CYP1B1 genes, by measuring the amount of CYP mRNA as well as heterogeneous nuclear RNA levels, which is the result of blocking the TCDD-induced activation of the AhR DNA binding capacity to the xenobiotic responsive element by ADT, as measured by the chromatin immunoprecipitation assay. Furthermore, ADT significantly decreased the [³H]BP-DNA adduct formation in HepG2 cells, in a concentration dependent manner. Our results demonstrate that the inhibitory effect of ADT on PAH activation may contribute to the chemopreventive effect of ADT in animal models.