Rats fed soy protein isolate (SPI) have impaired hepatic CYP1A1 induction by polycyclic aromatic hydrocarbons as a result of interference with aryl hydrocarbon receptor signaling

Authors: SINGHAL, ROHIT - ACNC/UAMS; BADGER, THOMAS - ACNC/UAMS; RONIS, MARTIN - ACNC/UAMS

Submitted to: Journal of Toxicology and Applied Pharmacology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/12/2007
Publication Date: 3/1/2008
Citation: Singhal, R., Badger, T.M., Ronis, M.J. 2008. Rats fed soy protein isolate (SPI) have impaired hepatic CYP1A1 induction by polycyclic aromatic hydrocarbons as a result of interference with aryl hydrocarbon receptor signaling. Journal of Toxicology and Applied Pharmacology. 227(2):275-283.

Interpretive Summary: Consumption of soy has been linked with reduced cancer incidence in epidemiological and laboratory studies. There could be a number of mechanisms by which consumption of soy-based diets protect against cancer generation. One of the potential sources of cancer is the exposure to environmental contaminants that come from automobile exhaust, smoke, oil sites, etc. and include polycyclic aromatic hydrocarbons. These chemical compounds are known to bind aryl hydrocarbon receptor (AhR) in the cytoplasm of the cells and, thus, mediate carcinogenesis. In our previous studies we demonstrated that consumption of soy results in reduction in AhR levels. The present study was conducted to elucidate the mechanism behind this phenomenon. We observed that treatment of cells with the serum obtained from rats fed with soy-containing diets results in AhR degradation by stimulating protein cleavage machinery called as proteasome. The AhR moves to nucleus and does not bind to the gene before it gets degraded. We also observed that soy-mediated AhR degradation is not observed with soy-associated phytochemicals--genistein and daidzein. The significance of this study is that it provides a novel mechanism for AhR degradation that is different from those studied earlier by other people. Moreover, it provides an insight into one of the mechanisms of chemoprevention by the consumption of soy-based diets.

Technical Abstract: Consumption of soy diet has been found to reduce cancer incidence in animals and is associated with reduced cancer risk in humans. Previously, we have demonstrated that female Sprague-Dawley rats fed purified AIN-93G diets with soy protein isolate (SPI) as the sole protein source had reduced CYP1A1 induction and basal aryl hydrocarbon receptor (AhR) levels relative to those fed the same diet containing casein (CAS). In the present study, the molecular mechanisms underlying SPI-associated AhR reduction have been studied. The SPI-effect on AhR was not observed on feeding diets containing the purified soy isoflavones genistein or daidzein. Rat hepatoma FGC-4 cells were treated with the serum obtained from rats fed CAS or SPI-containing diets. Reduced AhR levels (P<0.05) were observed upon 24-h exposure to SPI-serum without any changes in the overall expression of chaperone proteins - HSP90 and XAP2. The AhR degradation was inhibited upon treating the cells with the proteasome inhibitor MG132, and was observed to be preceded by ubiquitination of the receptor. A reduced association of XAP2 with the immunoprecipitated AhR complex was observed. SPI-mediated AhR degradation was preceded by nuclear translocation of the receptor. However, the translocated receptor was found to be unable to heterodimerize with ARNT or to bind to XRE elements on the CYP1A1 enhancer. These data suggest that feeding SPI-containing diets antagonizes AhR signaling by a novel mechanism that differs from those established for known AhR antagonists.