Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/15/2006
Publication Date: 1/15/2007
Citation: Singhal, R., Badger, T.M., Ronis, M.J. 2007. Reduction in 7,12-dimethylbenz[a]anthracene-induced hepatic cytochrome-P450 1A1 expression following soy consumption in female rats is mediated by degradation of the aryl hydrocarbon receptor. Journal of Nutrition. 137(1):19-24.
Interpretive Summary: Consumption of a soy diet has been found to reduce cancer incidence in animals and is associated with reduced cancer risk in humans. In the present study we evaluated one of the mechanisms that could reduce cancer incidence. The aryl hydrocarbon receptor (AhR) is responsible for activating of many genes, including CYP1A1, which is directly responsible for DNA adducts, which cause cancer. In our studies, rats fed soy-containing diets had lower AhR protein levels and fewer cancers. To investigate the mechanisms in more detail, a cell model was developed whereby serum from rats fed with soy was used to treat the cells. Our findings suggest that the cancer preventive effect of soy-based diets is mediated in part by reduction in AhR protein level.
Technical Abstract: Consumption of a soy diet has been found to reduce cancer incidence in animals and is associated with reduced cancer risk in humans. In this study, the effect of consuming soy protein isolate (SPI) on the aryl hydrocarbon receptor (AhR)-mediated signaling pathway was investigated. Female Sprague-Dawley rats were fed AIN-93G diets with (+) or without (-) SPI-bound phytochemicals or casein (CAS) protein and gavaged orally with 7,12-dimethylbenz[a]anthracene (DMBA) or sesame oil. We found reduced (P < 0.05) DMBA-induced hepatic cytochrome-P450 1A1 (CYP1A1) activity, apoprotein, and mRNA expression, along with the reduced binding of AhR-AhR nuclear translocator complex to CYP1A1 gene promoter in SPI(+)-fed rats compared with CAS- or SPI(-)-fed rats. Basal AhR protein expression was lower (P < 0.05) in SPI(+)-fed rats compared with CAS- or SPI(-)-fed groups. AhR levels were reduced (P < 0.05) after rats were fed SPI(+) for >20 d. Experiments in which SPI(+)-fed rats were weaned to CAS diets demonstrated that AhR reduction by SPI(+) is not imprinted metabolically. To determine the molecular mechanisms of SPI(+)-mediated AhR reduction, an ex vivo model was developed using FGC-4 cells treated with serum from CAS- or SPI(+)-fed rats. SPI(+) serum treatment of FGC-4 cells reduced AhR expression and DMBA-induced CYP1A1 expression (P < 0.05). The reduction in AhR expression was in part due to the shorter half-life of AhR protein. Our findings suggest that the cancer preventive effect of soy-based diets is mediated in part by reduction in AhR protein level posttranslationally, which reduces procarcinogen-induced CYP1A1 induction and metabolic activation.