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1.
J Nutr ; 139(5): 898-904, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19297428

RESUMO

Pregnane X receptor (PXR) is an important component of the body's adaptive defense system responsible for the elimination of various toxic xenobiotics. PXR activation by endogenous and exogenous chemicals, including steroids, antibiotics, bile acids, and herbal compounds, results in induction of drug metabolism. We investigated the ability of the isoflavones genistein, daidzein, and the daidzein metabolite equol to activate human and mouse PXR in vitro using cell-based transient transfection studies and primary hepatocytes and in vivo in a mouse model. In transient transfection assays, the isoflavones genistein and daidzein activate full-length, wild-type mouse PXR, but not a mutant form, with genistein being the most potent. In contrast, equol was a more potent activator of human PXR than genistein or daidzein. In a mammalian 2-hybrid assay, isoflavones induced recruitment of the coactivator steroid receptor coactivator 1 to PXR. When tested against the native human Cytochrome P450 3A4 (CYP3A4) promoter, equol was the more potent activator and treatment of human hepatocytes with equol increased CYP3A4 mRNA and immunoreactive protein expression. Treatment of wild-type, but not PXR(-/-), mouse hepatocytes showed that genistein and daidzein induced the expression of Cytochrome P450 3A11 (Cyp3A11) mRNA, whereas equol had no effect. Cyp3A11 mRNA was also induced in vivo in mice fed a soy protein-containing diet. The results presented herein demonstrate that there is a species-specific difference in the activation of PXR by isoflavones and equol.


Assuntos
Citocromo P-450 CYP3A/genética , Genisteína/farmacologia , Isoflavonas/farmacologia , Proteínas de Membrana/genética , Receptores de Esteroides/efeitos dos fármacos , Receptores de Esteroides/fisiologia , Animais , Carcinoma Hepatocelular , Linhagem Celular Tumoral , Chlorocebus aethiops , Citocromo P-450 CYP3A/análise , Equol , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Rim , Neoplasias Hepáticas , Masculino , Proteínas de Membrana/análise , Camundongos , Camundongos Knockout , Reação em Cadeia da Polimerase , Receptor de Pregnano X , Regiões Promotoras Genéticas/genética , RNA Mensageiro/análise , Receptores de Esteroides/deficiência , Especificidade da Espécie , Transfecção
2.
Physiol Genomics ; 26(1): 8-14, 2006 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-16507786

RESUMO

Intake of soy protein has been associated with improvements in lipid metabolism, with much attention being focused on the serum cholesterol-lowering property of soy. The component or components of soy that are responsible for improvements in lipid metabolism have been investigated and their specific actions debated. One component, the isoflavones, has been shown to have weak estrogenic activity, and recently, several research groups have suggested that isoflavones are activating peroxisome proliferator-activated receptors (PPARs). The three different isoforms of PPARs (alpha, gamma, and delta) have overlapping tissue distributions and functions associated with lipid metabolism. The goal of the present study was to investigate the hypothesis that the effect of isoflavones is mediated through the PPARalpha receptor. Male and female 129/Sv mice were obtained, including both wild-type and genetically altered PPARalpha knockout mice. Groups of mice were fed high-fat atherogenic diets containing soy protein +/- isoflavones and PPARalpha agonist fenofibrate for 6 wk. At the end of 6 wk, serum and tissue lipid levels were measured along with hepatic gene expression. Most notably, serum triglycerides were reduced by isoflavone consumption. Compared with intake of a low-isoflavone basal diet, isoflavone intake reduced serum triglyceride levels by 36 and 52% in female and male wild-type mice, respectively, compared with 55 and 52% in fenofibrate-treated mice. Isoflavones also improved serum triglyceride levels in knockout mice, whereas fenofibrate did not, suggesting that two different regulatory mechanisms may be affected by isoflavone intake. Isoflavone intake resembled action of fenofibrate on PPARalpha-regulated gene expression, although less robustly compared with fenofibrate. We suggest that, at the levels consumed in this study, isoflavone intake is altering lipid metabolism in a manner consistent with activation of PPARalpha and also via a PPARalpha-independent mechanism as well.


Assuntos
Suplementos Nutricionais , Hipolipemiantes/farmacologia , Isoflavonas/farmacologia , Metabolismo dos Lipídeos , Fígado/efeitos dos fármacos , PPAR alfa/agonistas , Animais , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Colesterol/sangue , Dieta , Dieta Aterogênica , Feminino , Fenofibrato/administração & dosagem , Fenofibrato/farmacologia , Regulação Enzimológica da Expressão Gênica , Hipolipemiantes/administração & dosagem , Isoflavonas/administração & dosagem , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Knockout , PPAR alfa/genética , PPAR alfa/metabolismo , RNA Mensageiro/metabolismo , Fatores Sexuais , Triglicerídeos/sangue
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