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.
Consumption of soy diets 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 reduced AhR expression have been studied. The SPI-effect on AhR was not observed after 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 after 24 h exposure to SPI-serum without any changes in the overall expression of chaperone proteins--HSP90 and XAP2. SPI-serum-stimulated AhR degradation was inhibited by 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-serum-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 which differs from those established for known AhR antagonists.
Singhal
Rohit
R
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Badger
Thomas M
TM
Ronis
Martin J
MJ
D000818:Animals; D015153:Blotting, Western; D002364:Caseins / Q000494:pharmacology; D002843:Chromatin / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis*; D004247:DNA / Q000378:metabolism; D004032:Diet; D004790:Enzyme Induction / Q000187:drug effects; D004968:Estrogens, Non-Steroidal / Q000494:pharmacology; D005260:Female; D019833:Genistein / Q000494:pharmacology; D047468:Immunoprecipitation; D007529:Isoflavones / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008856:Microscopy, Fluorescence; D011084:Polycyclic Aromatic Hydrocarbons / Q000494:pharmacology*; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects*; D030262:Soybean Proteins / Q000737:chemistry / Q000494:pharmacology*
D002364:Caseins; D002843:Chromatin; D004968:Estrogens, Non-Steroidal; D007529:Isoflavones; D011084:Polycyclic Aromatic Hydrocarbons; D018336:Receptors, Aryl Hydrocarbon; D030262:Soybean Proteins; C004742:daidzein; D012313:RNA; D004247:DNA; D019833:Genistein; D019363:Cytochrome P-450 CYP1A1