Human CYP3A4 and Murine Cyp3A11 Are Regulated by Equol and Genistein via the Pregnane X Receptor in a Species-Specific Manner

Abstract

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.

The effect of dietary calcium on 1,25(OH)2D3 synthesis and sparing of serum 25(OH)D3 levels

“…Interestingly, in separate experiments, while CYP3A4 has been shown to stimulate the 25-hydroxylation of vitamin D [11,12], CYP3A4 has also been shown to be stimulated by treatment with 1,25D and was able to generate three major metabolites of 1,25D catabolism [13], suggesting that CYP3A4 in humans may be a target enzyme responsible for 25D catabolism as well. While rats do not possess CYP3A4, several other isoforms of CYP3A are expressed in liver tissue with reported similar actions to CYP3A4 [14][15][16]. In the current study, however, none of these CYP3A isoforms appear to be regulated in such a way as to explain the differences in serum 25D levels observed.…”

Effect of Natural Polyphenols on CYP Metabolism: Implications for Diseases

“…Moreover, isoflavones promoted the interaction of PXR with the steroid receptor coactivator 1. 153 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 29 to evaluate the ability of major bioactive compounds of traditional Chinese medicines to activate PXR signaling pathway. Out of the thirty four tested molecules, eight were found to transactivate PXR and induce CYP3A4 reporter gene.…”

Molecular Biology of Atherosclerosis

“…LOX-1 ligation also results in powerful proapoptotic and inflammatory responses due to inactivation of PI3K and PKB (1040,1082). A major mechanism for these effects appears to be formation of a complex on the receptor cytoplasmic tail which includes ARHGEF1 and ROCK2.…”