The Phytoestrogen Coumestrol Is a Naturally Occurring Antagonist of the Human Pregnane X Receptor

Wang, Hongwei; Li, Hao; Moore, Linda B.; Johnson, Michael D. L.; Maglich, Jodi M.; Goodwin, Bryan; Ittoop, Olivia; Wisely, Bruce; Creech, Katrina L.; Parks, Derek J.; Collins, Jon L.; Willson, Timothy M.; Kalpana, Ganjam V.; Venkatesh, Madhukumar; Xie, Wen; Cho, Sool Y.; Roboz, John; Redinbo, Matthew R.; Moore, John T.; Mani, Sridhar

doi:10.1210/me.2007-0218

Cited by 106 publications

(112 citation statements)

References 58 publications

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“…8) Coumestrol can also bind to the surface of the pregnane X receptor (PXR) and antagonize PXR activities in primary hepatocytes. 9) In addition, coumestrol shows anti-aging effects on skin and inhibits UVB-induced matrix metallopeptidase (MMP)-1 expression by suppressing the kinase activity of fms-related tyrosine kinase 3 (FLT3). 10) However, no studies have investigated the effects of coumestrol on melanogenesis or skin hyperpigmentation.…”

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confidence: 99%

Coumestrol Down-Regulates Melanin Production in Melan-a Murine Melanocytes through Degradation of Tyrosinase

Hwang

Park

et al. 2017

Biological & Pharmaceutical Bulletin

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Pigmentation reflects skin darkening caused by melanin production, but excessive melanin synthesis may cause problems, such as melasma, solar lentigo, dark spots, and freckles. Considerable effort has been devoted to alleviating these undesired symptoms through the development of safe and effective depigmenting agents. Coumestrol, a plant-derived natural isoflavone with an estrogen-like structure and actions, is known to have anti-aging ability, but its potential depigmenting efficacy has not been evaluated. In the present study, we investigated the effects of coumestrol on melanin synthesis in normal melan-a murine melanocytes. Coumestrol significantly reduced melanin synthesis in a concentration-dependent manner up to a concentration of 25 µM without causing cytotoxicity. It also brightened tissue in an artificial skin model (MelanoDerm) that incorporates both human keratinocytes and melanocytes. Interestingly, although coumestrol did not inhibit tyrosinase activity or transcript level in melan-a cells, it clearly decreased the expression level of tyrosinase protein at a concentration of 25 µM. This coumestrol-induced reduction in tyrosinase protein levels was prevented by pretreatment with the proteasome inhibitor MG-132 or the lysosomal proteolysis inhibitor chloroquine. Collectively, our findings indicate that coumestrol exerts an inhibitory effect on melanin synthesis in melan-a cells, at least in part, through degradation of tyrosinase. These findings suggest that coumestrol is a good candidate for use in depigmentary reagents from a cosmetic and clinical perspective.

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mentioning

confidence: 99%

Coumestrol Down-Regulates Melanin Production in Melan-a Murine Melanocytes through Degradation of Tyrosinase

Hwang

Park

et al. 2017

Biological & Pharmaceutical Bulletin

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“…For example, coumestrol is an isoflavonoid-like phytooestrogen with oestrogen structure and actions. In vivo assays using hPXR mice revealed a significant inhibition of coumestrol on human PXR and no activity towards rodent PXR; these results were supported by additional in vitro binding analysis (Wang et al, 2008). Coumestrol could bind PXR at a site other than the ligandbinding pocket of the receptor protein and this binding disrupts the association of PXR with the steroid receptor coactivator-1.…”

Section: Screening Of Hpxr Agonist and Antagonistmentioning

confidence: 78%

Pregnane X receptor‐ and CYP3A4‐humanized mouse models and their applications

Cheng

Gonzalez

2011

British J Pharmacology

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Pregnane X receptor (PXR) is a pivotal nuclear receptor modulating xenobiotic metabolism primarily through its regulation of CYP3A4, the most important enzyme involved in drug metabolism in humans. Due to the marked species differences in ligand recognition by PXR, PXR-humanized (hPXR) mice, and mice expressing human PXR and CYP3A4 (Tg3A4/hPXR) were established. hPXR and Tg3A4/hPXR mice are valuable models for investigating the role of PXR in xenobiotic metabolism and toxicity, in lipid, bile acid and steroid hormone homeostasis, and in the control of inflammation. AbbreviationAlb, albumin promoter; AUC, area under the curve; CAR, constitutive androstane receptor; CYP3A4, cytochrome P450-3A4; CYP3A4-A, mice with albumin promoter-targeted liver-specific expression of CYP3A4; CYP3A4-humanized mice, CYP3A4-humanized mice lacking of mouse Cyp3a; CYP3A4-V, mice with villin promoter-targeted intestinespecific expression of CYP3A4; Cyp3a-null, Cyp3a knockout mice; DBD, DNA-binding domain; FABP, fatty acid-binding protein; FXR, farnesoid X receptor; hPXR mice, PXR-humanized mice; IBD, inflammatory bowel disease; LBD, ligandbinding domain; LCA, lithocholic acid; LXR, liver X receptor; PPAR, peroxisome proliferator-activated receptor; PXR, pregnane X receptor; Pxr-null, Pxr knockout mice; RXR, retinoid X receptor; Tg3A4, transgenic CYP3A4 (CYP3A7) mice with the mouse Cyp3a background; Tg3A4/hPXR, CYP3A4 and human PXR double transgenic mice lacking of mouse PXR Human pregnane X receptor (PXR), encoded by the nuclear receptor subfamily 1, group I, member 2 (NR1I2) gene, is located on chromosome 3q12-q13.3 and consists of nine exons; exons 2 to 9 contain the coding region for a 434 amino acid protein (Ekins et al., 2009). Similar to other nuclear receptors, PXR possesses the common modulator structure of a conserved N-terminal DNA-binding domain (DBD) and C-terminal ligand-binding domain (LBD). It functions as a heterodimer with the 9-cis retinoic acid receptor, also known as retinoid X receptor (RXR) to control gene transcription (Ngan et al., 2009). However, unlike most other nuclear receptors, PXR has a markedly flexible pocket which can bind structurally diverse ligands (Kliewer et al., 2002), including prescription drugs, natural products, dietary supplements, environmental pollutants, endogenous hormones and bile acids (Ma et al., 2008b). Human and mouse PXR share nearly 80% amino acid identity across the LBD, 96% amino acid identity in the DBD, and display similar tissue-specific expression patterns. However, the differences between the LBD sequence result in species-specific responses to ligand activation by human and mouse PXR (Lehmann et al., 1998). For example, rifampicin has virtually no activity on the mouse PXR at typical pharmacological doses, but is a very potent activator of human PXR. Conversely, pregnenolone-16a-carbonitrile (PCN) only weakly activates human PXR but is an efficacious activator of mouse PXR (Lehmann et al., 1998). Site-directed mutagenesis studies have revealed that four-polar amino acids c...

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“…It has been shown that KTZ disrupts the interaction of PXR with coactivator SRC1 (32). Furthermore, coumestrol inhibits PXR and SRC1 interactions regardless of the ligand presented (33). Therefore, it is of particular interest to determine 1) whether RES exerts its suppressive effects through the competition of binding to LBD with ligands, 2) whether RES inhibits ligand-induced dissociation from co-repressor and recruitment of co-activator proteins to PXR, and 3) whether RES interferes with the binding of PXR: RXRa heterodimer to CYP3A4 promoter.…”

Section: Discussionmentioning

confidence: 99%

Resveratrol Suppresses the Inducible Expression of CYP3A4 Through the Pregnane X Receptor

Deng

Chen

et al. 2014

J Pharmacol Sci

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Abstract. The pregnane X receptor (PXR, NR1I2), a member of the nuclear receptor superfamily, is activated by a number of clinically prescribed drugs and herbal extracts. The inducible expression of several important cytochrome P450 (CYP450) enzymes has been shown to be regulated by the activation of PXR in the liver. In the current study, reporter gene-transfected cells were used to identify potential antagonists of PXR. Here, we showed that resveratrol (RES), a natural polyphenolic compound could significantly suppress the rifampicin-induced PXR transactivation of the CYP3A4 promoter. Treatment of hPXR-over-expressed cells with RES reduced the rifampicin-inducible expression of CYP3A4 in a concentration-dependent manner. Moreover, the induction of mRNA and protein expression of CYP3A11 by pregnenolone 16a-carbonitrile was also significantly reduced when RES was applied in primary cultures of mouse hepatocytes. Taking together, these findings suggest that RES can attenuate the PXR-mediated induction of CYP3A enzyme. Therefore, it would be possible for RES to antagonize the elevation in CYP3A-mediated drug metabolism by identified PXR activators.

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The Phytoestrogen Coumestrol Is a Naturally Occurring Antagonist of the Human Pregnane X Receptor

Cited by 106 publications

References 58 publications

Coumestrol Down-Regulates Melanin Production in Melan-a Murine Melanocytes through Degradation of Tyrosinase

Coumestrol Down-Regulates Melanin Production in Melan-a Murine Melanocytes through Degradation of Tyrosinase

Pregnane X receptor‐ and CYP3A4‐humanized mouse models and their applications

Resveratrol Suppresses the Inducible Expression of CYP3A4 Through the Pregnane X Receptor

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