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 twomost prevalent HCA, PhIP and MelQx, to induce genetic alterations in vivo wasdetermined using a short-term liver carcinogenesis model (RH-model) in rat. BothPhIP and MeIQx were able to induce foci of initiated cells, indicating that both thesecompounds 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. Theregulatory mechanism of the CYPlA induction by HCA is, however, unclear. Studiesin vivo in rats and in primary hepatocyte cultures revealed that MeIQx induced bothCYPlA1/lA2 proteins and the corresponding catalytic activities. The CYP inductionpattern by HCA was reflected at the steady state mRNA levels in the hepatocytes asmeasured by solution hybridization technique. In contrast to previous studies, nopreferential induction of CYPlA2 was observed in the present study. CYPlA1 andCYPlA2 are target genes of the intracellular dioxin receptor. This receptor interactswith xenobiotic response elements (XREs) of target promoters upon binding theenvironmental pollutant dioxin or related compounds. HCA exhibited capacity toactivate the dioxin receptor to a form which interacts with XRE in vitro. Taken to-gether, these results suggest that MeIQx regulates both CYPlA isozymes by the samemechanism involving the dioxin receptor.Another group of putative dioxin receptor ligands of dietary orgin are the indolo-carbazoles, that may be produced in vivo under acidic conditions from precursormolecules in cruciferous plants. Indolo[3,2-b]carbazole and its dimethylated derivativepotently regulated gene expression of a reporter gene driven by a minimal XRE inboth mouse and human hepatoma cells. The indolocarbazole-induced human receptorappeared to form more stable complexes with XRE in vitro relative to those generatedby the dioxin-activated receptor. This indicate that the indolocarbazoles and dioxinpossess different mechanistic qualities with respect to activation of human dioxinreceptor function.This study indicates that the HCA and the indolocarbazoles both represent distinctclasses of dietary dioxin receptor agonists. The HCA are weak agonists, but areconsumed in relatively high amounts, while the indolocarbazoles are high affinityligands presumably present in considerably lower amounts in diet.Keywords: heterocyclic aromatic amine, indolocarbazole, dioxin receptor, CYPlAISBN 91-628-2116-4