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Biochemical, Molecular, and Genetic Mechanisms

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 Receptor¹

² Department of Pharmacology and Toxicology and ³ Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR 72205 and ⁴ Arkansas Children's Nutrition Center, Little Rock, AR 72202

^* To whom correspondence should be addressed. E-mail: ronismartinj{at}uams.edu.

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.

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