Regulation of dioxin receptor function by procarcinogenic food-derived heterocyclic amines and indolocarbazoles

Sammanfattning: Cooking of protein-rich food generates procarcinogenic heterocyclic aromatic amines(HCA) in amounts that range in the part per billion levels. The capacity of the two most prevalent HCA, PhIP and MelQx, to induce genetic alterations in vivo was determined using a short-term liver carcinogenesis model (RH-model) in rat. Both PhIP and MeIQx were able to induce foci of initiated cells, indicating that both these compounds may be involved in initiation of carcinogenesis. HCA have been reported to induce xenobiotic metabolizing enzymes of the cyto-chrome P450 lA (CYPlA) subfamily, most notably the CYPlA2 isoform. The regulatory mechanism of the CYPlA induction by HCA is, however, unclear. Studies in vivo in rats and in primary hepatocyte cultures revealed that MeIQx induced both CYPlA1/lA2 proteins and the corresponding catalytic activities. The CYP induction pattern by HCA was reflected at the steady state mRNA levels in the hepatocytes as measured by solution hybridization technique. In contrast to previous studies, no preferential induction of CYPlA2 was observed in the present study. CYPlA1 and CYPlA2 are target genes of the intracellular dioxin receptor. This receptor interacts with xenobiotic response elements (XREs) of target promoters upon binding the environmental pollutant dioxin or related compounds. HCA exhibited capacity to activate the dioxin receptor to a form which interacts with XRE in vitro. Taken together, these results suggest that MeIQx regulates both CYPlA isozymes by the same mechanism involving the dioxin receptor. Another group of putative dioxin receptor ligands of dietary origin are the indolo-carbazoles, that may be produced in vivo under acidic conditions from precursor molecules in cruciferous plants. Indolo[3,2-b]carbazole and its dimethylated derivative potently regulated gene expression of a reporter gene driven by a minimal XRE in both mouse and human hepatoma cells. The indolocarbazole-induced human receptor appeared to form more stable complexes with XRE in vitro relative to those generated by the dioxin-activated receptor. This indicate that the indolocarbazoles and dioxin possess different mechanistic qualities with respect to activation of human dioxin receptor function. This study indicates that the HCA and the indolocarbazoles both represent distinct classes of dietary dioxin receptor agonists. The HCA are weak agonists, but are consumed in relatively high amounts, while the indolocarbazoles are high affinity ligands presumably present in considerably lower amounts in diet.