Homology modelling of the nuclear receptors: human oestrogen receptorβ (hERβ), the human pregnane-X-receptor (PXR), the Ah receptor (AhR) and the constitutive androstane receptor (CAR) ligand binding domains from the human oestrogen receptor α (hERα) crystal structure, and the human peroxisome proliferator activated receptor α (PPARα) ligand binding domain from the human PPARγ crystal structure

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Abstract

We have generated by homology the three-dimensional structures of the ligand binding domain (LBD) of several interrelated human steroid hormone receptors (SHRs).

These are the oestrogen receptor β (hERβ), the pregnane-X-receptor (PXR), the Ah receptor (AhR) and the constitutive androstane receptor (CAR). They were produced by homology modelling from the human oestrogen receptor α (hERα) crystallographic coordinates [Nature 389 (1997) 753] as a template together with the amino acid sequences for hERβ [FEBS Lett. 392 (1996) 49], PXR [J. Clin. Invest. 102 (1998) 1016], AhR [Proc. Natl. Acad. Sci. U.S.A. 89 (1992) 815] and CAR [Nature 395 (1998) 612; Mol. Cell. Biol. 14 (1994) 1544], respectively. The selective endogenous ligand, in each case, was docked interactively within the putative ligand binding site using the position of oestradiol in hERα as a guide, and the total energy was calculated. In each receptor model a number of different ligands known to fit closely within the ligand binding site were interactively docked and binding interactions noted. Specific binding interactions included combinations of hydrogen bonding and hydrophobic contacts with key amino acid sidechains, which varied depending on the nature of the ligand and receptor concerned. We also produced the human peroxisome proliferator activated receptor α (PPARα) by homology modelling using the human PPARγ (hPPARγ) LBD crystallographic coordinates summarised in [Toxicol. In Vitro 12 (1998) 619] as a template together with the amino acid sequence for hPPARα [Toxicol. In Vitro 12 (1998) 619; Nature 395 (1998) 137].

The models will provide a useful tool in unravelling the complexity in the physiologic response to xenobiotics by examining the ligand binding interactions and differences between the steroid hormone receptors activation or inactivation by their ligands.

Introduction

Nuclear steroid hormone receptors are a large protein superfamily that are involved in a wide range of physiological functions including development, reproduction, differentiation and homeostasis. They are regulated by hormones and chemicals that can mimic hormones [9]. After a hormone is produced, circulating and intracellular binding proteins regulate the hormones bioavailability. Then the hormone triggers action by binding to a specific cellular receptor by docking into a ligand binding domain (LBD) which is a hydrophobic pocket, and binding with specific amino acids [10].

An important requirement for homeostasis is the detoxication and removal of endogenous hormones and xenobiotic compounds with biological activity. This crucial metabolic role is conducted by the cytochrome P450 (CYP) enzyme superfamily. The induction of specific CYPs via the adaptive increase of CYP gene expression commonly utilises the nuclear receptor pathway where exposure to xenobiotics and drugs activates specific members of the nuclear receptor superfamily which in turn bind to their cognate DNA elements and stimulate the CYP target gene transcription [11], [12], [13], [14]. Knowledge of nuclear hormone–receptor activation and action upon the regulation of gene expression can aid the understanding of the progression of certain diseases, and facilitate the design of drugs with improved efficacy and fewer side effects. The super family is broadly divisible into three subclasses: the type I receptors for steroid hormones, including progestins (PR), estrogens (ER), androgens (AR), glucocrticoids (GR) and mineralocorticoids (MR); the type II receptors for thyroid hormone (TR), Vitamin D (VDR), 9-cis retinoic acid (RXRs), all-trans retinoic acid (RARs) PPAR and the orphan class, for which cognate ligands have not yet been characterised, such as the PXR, CAR, COUP-TFs, HNF4, Rev Erb [15], [16], [17], [18], [19].

The currently accepted theory of steroid hormone-binding suggests that in the absence of the hormone, each receptor is associated with certain ‘chaperone’ proteins [10]. Binding of the steroid hormone with the receptor protein causes a conformational change. This molecular switch results in the removal of the heat shock complex and allows the receptors to dimerise. Then binding to a hormone response element (HRE) on DNA occurs, to produce a complex that can trigger or suppress the transcription of a selected set of genes [10], [20], see Fig. 1.

So far 48 nuclear receptors have been identified in the human genome [16], but most of these are ‘orphan receptors’, in that they are awaiting the recognition of specific ligands and functions, and it is likely that more receptors will be discovered in the future. Each type of receptor has the potential to regulate a distinct endocrine signalling pathway, of which we only have a rudimentary knowledge. Members of this receptor family are related to each other in terms of their amino acid sequence and their function within cells. They therefore have structural features in common. These include a central highly conserved DNA binding domain (DBD) that targets the receptor to specific DNA sequences, termed hormone response elements (HREs). This domain contains eight cysteines, which form a pair of tetra coordinate binding sites for zinc atoms. When the zinc atoms allow folding of the protein, an α-helix is placed into the major groove of the DNA double helix. The amino acids on this α-helix enable the receptor to recognise the DNA in a sequence specific fashion. A terminal portion of this receptor (COOH) includes the ligand binding domain (LBD) which interacts directly with the hormone. This part of the receptor is larger and more complex than the DNA-binding domain. It is composed of three layers of α-helices forming a pocket. Embedded within this pocket is a hormone dependent transcriptional activation domain, and this is where ligands are transported prior to binding [10].

In essence the LBD acts as a molecular switch that recruits co-activator proteins and activates the transcription of target genes when flipped into the active conformation by hormone-binding (Fig. 1). From a refinement of the characterisation of the role of the 3′ untranslated region (3′UTR) of hERα mRNA, the existence of another level in the control of the expression of the ligand-activated transcription factor hER in addition to transcriptional regulation has been determined [21]. Due to the general similarities in the structure and function of members of the steroid hormone family, it is likely that elements that influence the stability of mRNAs of other steroid hormones receptors should also be found in their 3′UTR [21]. The members of this family also have dimerisation receptor partners in common, particularly with the ubiquitous 9-cis-retinoic acid receptor (RXR) [12].

The ligand activated nuclear receptors CAR, PXR, and PPAR bind to their cognate DNA elements as heterodimers with RXR and thus activate the transcription of their CYP2B, CYP3A, and CYP4A genes (Fig. 2). This process of gene activation then leads to enhanced metabolism of the compound of exposure [12], [14], [16].

However, there are further complications as there may be competition between the receptors for RXR, as well as reduced RXR availability and activation in response to stress-signaling, triggered from a variety of environmental stimuli [22]. This suggests that stress-signaling will also indirectly affect all the receptors that dimerise with RXR, disabling gene activation even though ligand binding has occurred. Several receptors may be affected by the lack of availability of the dimerisation partner, including the ERs, PXR, CAR, the PPARs and other receptors. This will affect their ability to trigger or suppress gene transcription.

SHRs are subject to cross-talk interactions with other nuclear receptors, nuclear proteins, drug metabolizing enzymes (such as UGTs [23], and the transporter P-glycoprotein (Pgp) [24]) and with a broad range of other intracellular signaling pathways [12]. There may even be a cascade effect, where metabolites produced through the activities of one receptor are specific signaling molecules (and ligands) to modulate the next receptor, along the chain of a nuclear receptor intercommunication web.

Dependency upon interactions with other nuclear proteins or cofactors that are important tissue/cell specific mediators of nuclear receptor function introduces further regulation of the members of the SHR family. These may differ between receptors, or receptors may hold certain proteins or receptors in common with each other, such that part of the mechanism of action may be ascribable to competition between the receptor signalling pathways from the co activators or co repressors. This has been reported for the ER and AhR for example [25].

Fig. 3 provides a generalized schematic diagram of tissue distribution of steroid hormone receptors reported in the literature, representing potential sites of receptor action and the distribution of the selected steroid hormone receptors in humans, as reviewed in [26], and Table 1 summarises a number of activation compounds for these receptors, as reported in the literature.

The oestrogen receptors are known to exist as two subtypes, each one encoded by a separate gene. These are ERα [1], and the recently discovered ERβ [2] and its isoforms, of which a spliced isoform, ERβ/2 appears to be equally expressed in animal model tissue density studies [27]. The classical ERα subtype and ERβ receptors and isoforms apparently evolutionarily diverged over 450 million years ago, suggesting that although they have evolved in parallel, this ancient duplication was to facilitate unique roles in vertebrate physiology and reproduction [28]. The ERs differ in tissue distribution and relative ligand binding affinities for both endogenous and exogenous ligands (Table 2) [29], [30], which may help explain the selective action of oestrogens and androgens in different tissues (Fig. 3) [31], [32].

The Pregnane-X Receptor (PXR), recently isolated and published by Lehmann [3] and Kliewer et al. [33], and later Blumberg et al. [34] is involved in activating the expression of several P450 detoxifying enzymes, including CYP3A4 in the adult and CYP3A7 in the foetus in response to xenobiotics and steroids [35]. CYP3A4 is the major human hepatic P450, and is involved in the metabolism of over 60% of drugs in clinical use [36].

PXR is highly divergent between species, with great differences in PXR activation profiles due to differences in the LBD [37].

The major site of PXR expression is in the liver hepatocytes and the gastrointestinal tissues, but they are also present in both normal and neoplastic breast tissue. Indeed a statistically inverse relationship between the level of PXR mRNA expression and ER status has been observed by ligand binding analysis [38]. PXR can be activated by a variety of chemically distinct ligands (Table 1), in a species dependent manner [37], [39], [40], including endogenous hormones such as pregnenolone, and progesterone and their synthetic derivatives such as pregnenolone 16α-carbonitrile (PCN), trans-nonachlor, rifampicin, dexamethasone, corticosterone, spironolactone, phenobarbital, and hyperforin (the active constituent of St. John’s wort) [39].

It appears that there is a specific regulatory pathway where the accumulation of steroidal PXR ligands, including xenobiotics such as organochlorine pesticides, results in increased CYP3A transcription and steroid catabolism, possibly providing the route for excess steroids to be eliminated from the body. So not only is PXR a xenobiotic sensor, it is also a key player in the regulation of steroid homeostasis, steroid metabolism (by involvement in the expression of steroid hydroxylases [12]) and detoxication.

The constitutive androstane receptor (CAR) is a member of the same nuclear receptor subfamily as PXR, sharing around 40% amino acid identity in their LBDs, with 70% similarity between hCAR and rodent CAR LBD regions [40]. In a pattern similar to that of the ERs, based upon phylogenetic analyses, it has been suggested that PXR and CAR are closely related to each other [40]. CAR is also present largely in the liver (and also the intestine, kidneys, lungs, heart, and muscle) [6] (Fig. 3), but it interacts with and is inhibited by two endogenous testosterone metabolites, androstanol and androstenol, via a mechanism that involves a widely expressed nuclear receptor coactivator, SRC-1 [5]. The hierarchy of ligand activation differs between the receptors as well as for receptors isolated from different species, and in many instances, as identified in CAR, molecules that were previously regarded as metabolic intermediates are in fact “intracrine” signalling molecules within tightly coupled metabolic pathways for altering gene expression.

Unlike most nuclear receptors, including PXR and ER, the steroidal ligand for CAR inhibits receptor-dependent gene transcription by way of a ligand-independent recruitment of transcriptional co-activators [5]. CAR functions in a manner opposite to that of the conventional nuclear receptor pathways and can be considered a ‘repressed’ nuclear receptor in the presence of androstane metabolites [41]. In cell based reporter gene assays, exogenously expressed CAR enters the nucleus and regulates the expression of target genes [5], [6], it is not present in the nucleus but is sequestered in the cytoplasm, unlike the other receptors modelled and discussed here. There are significant sex differences in plasma androstane levels and it has been recently implicated as a transcriptional regulator of the gene governing the steroid hydroxylase CYP2B after binding with its cognate DNA response elements as a heterodimer with RXR [5]. There appear to be additional mechanisms for the regulation of CAR activity, including phosphorylation by phenobarbital (PB). The effects of PB on CYP2B expression are blocked by the phosphatase inhibitor okadaic acid [42] suggesting that dephosphorylation of CAR, rather than direct ligand binding, is involved in its translocation into the nucleus. This receptor suggests a new area of androgen physiology whose significance is unknown as yet [43]. A model of CAR can aid in the design of synthetic ligands that can help investigate the relevance of CAR to human metabolism and health.

The Ah receptor is a member of the Per-Arnt-Sim family of nuclear regulatory basic helix loop–helix proteins [4], [44] that has been detected in nearly all vertebrate groups examined [45]. The Ah receptor binds to 2,3,7,8 TCDD and other structurally similar PAHs to activate the cognate xenobiotic response element of the CYP 1A and 1B1 genes [11], [44], [45].

However, the AhR is the only member of that regulatory family known to bind to a ligand prior to heterodimerisation and bind to DNA in upstream regulatory regions of target genes. Predominantly found in hepatocytes, but also in breast cancer cells [25], the AhR regulates the expression of a number of genes, including cytochrome P450 1A1, 1A2, 1B1, glutathione S transferase M (GSTM), DT-diaphorase, UGT and aldehyde dehydrogenase in a ligand dependent manner [46]. AhR is also up regulated during cell division and is expressed in a specific spatial and temporal pattern in the developing foetus in vivo [47]. The best-characterised high affinity AhR ligands include a variety of ubiquitous lipophilic environmental contaminants in the polyhalogenated aromatic hydrocarbon family including dioxins, furans, coplanar biphenyls and polycyclic aromatic hydrocarbons [10]. Other lower affinity ligands can be found endogenously (e.g. biliverdin [48], [49]) and in the diet [50], [51]. Synthetic retinoids and pesticides have also been reported to activate the AhR pathway [52], [53]. Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most potent AhR ligand known, results in a wide variety of species- and tissue-specific toxic and biological responses [54]. They are associated with the disruption of almost every hormone system that has been examined and responses to activation include developmental and reproductive toxicity. Animals treated with 2,3,7,8 TCDD have developed abnormalities in several organs including the thyroid, thymus, lung and liver, immune and endocrine function. Wasting, lethality and induction of gene expression have also been shown to be AhR dependent [47], [55], [56], [57], [58].

Within the cytosol of the cell the AhR is associated with a heterodimeric transporter protein partner, termed the aryl hydrocarbon receptor nuclear transporter protein (ARNT). The unliganded AhR may also act through other mechanisms by being phosphorylated to key regulatory proteins such as HSP90, p37, AIP, XAP2, src, rel, and Rb [59].

The peroxisome proliferator-activated receptors are a family of orphan receptors with fundamental roles in regulating energy balance [14], [41], [60], [61], [62], [63], [64], [65], [66]. A number of prevalent metabolic disorders such as obesity, atherosclerosis and type 2 diabetes are associated with a shift in this balance. The peroxisome proliferator activated receptors are activated by xenobiotics, which elicit increases in the number and size of peroxisomes when administered to rodents [12], and also induce hepatocellular carcinoma development by a non-genotoxic mechanism [63].

There are three known closely related receptors: PPARα β/δ and γ, found in the liver, kidney, heart, haematopoietic and adipose tissue, but having different expression patterns. PPARα is found in liver, kidney, heart and muscle, PPARδ is expressed in nearly all tissues and PPARγ is expressed in fat cells, the large intestine, and monocyte lineage cells [60]. They each play key roles in lipid metabolism and homeostasis; PPARα is responsible for CYP4A induction; peroxisomal enzyme induction and hepatic peroxisome proliferation. PPARα has a central role in hepatogenesis, and PPARγ, a central regulatory role in adipogenesis [17], [63], [64], [66].

PPARα regulates key steps in lipid and fibrate metabolism. It is the molecular target for naturally occurring plant fatty acids (pristinic acid and phytanic acid) present at physiological concentrations [67], long chain polyunsaturated fatty acids (LCPUFA), eicosanoids [61], [64], and peroxisome proliferators, which include drugs such as the fibrates, (used widely to lower high triglyceride levels, a risk factor in coronary heart disease), and synthetic chemicals such as the phthalate ester plasticisers, and pesticides [63]. PPARγ ligands include fatty acids, prostaglandins and the antidiabetic thiazolidinedione (TZD) drugs [17], [66]. Pristinic acid and phytanic acid are branch chained fatty acids obtained through the diet from the chlorophyll in plants. Present at micromolar concentrations in healthy individuals, they can accumulate in a variety of inherited disorders. Potent binding of pristinic acid and phytanic acid in PPARα [67] indicates a primary mechanism for metabolising these dietary fatty acids.

The LBD consists of 13 α-helices and a small 4-stranded β sheet forming a hydrophobic ligand binding pocket with a volume at least twice that of other receptors [68]. The PPARs have a far larger ligand binding pocket than the receptors so far discussed (Table 3) [69], and there are differences in the shape of each PPAR ligand binding pocket [68], [70] giving broad ligand specificity on a structural basis. Rosiglitazone occupied a fraction of the available LBD space in PPARα, and less than that in PPARγ, particularly the rosiglitazone TZD head group, and thus comparatively reduced selectivity was observed. This has been observed for different ligands in the PPAR family, and is a clear descriptor for PPAR selectivity.

There may be expression of a dominant-negative inhibitory human PPARα variant (found in some individuals) [71] and human polymorphisms. It is possible that PPARγ and PPARδ (highly expressed in multiple human tissues) may be transactivated and consequently perturbed by a subset of peroxisome proliferating compounds, affecting the PPAR metabolic pathways, to elicit a pathophysiological response.

Another factor to be considered is modulation through cross-talk between PPAR and other nuclear receptors/signalling molecules. For example thyroid hormone suppresses hepatic peroxisome proliferation responses and exhibits inhibitory cross-talk with PPARα, due in part to competition between the thyroid receptor and PPAR for their common heterodimerization partner RXR [72]. (See Fig. 1). Indeed, all the receptors discussed here are interlinked not least by their requirement for RXR as the heterodimerisation partner (except AhR) (see Fig. 2).

In order to understand the role of ligand in receptor activation molecular models of the ERβ, hPXR, AhR and hCAR LBDs have been generated from a ligand bound hERα crystal structure [1]. Similarly, for the investigation of the role of ligand in hPPARα activation, a molecular model of the hPPARα ligand-bound hormone-binding domain (HBD) has been generated from a ligand bound hPPARγ crystal structure [7], [8]. Using natural and synthetic ligands as chemical tools, the nature of receptor activation can be examined by assessing the structural mechanisms computationally, indicating highly probable modes and mechanisms of binding, together with the key amino acids involved. This can aid in the discovery of new hormone signalling pathways and cross-talk, and provide receptor specific insight into various disease scenarios, which in the case of hPPARα for example, would include the regulation and perturbation of lipid and TZD drug metabolism.

Section snippets

Materials and methods

The steroid hormone receptor super family shares a conserved primary sequence and it is likely that there three-dimensional structures are similar, so it is possible to model one member of the family from another.

The alignment was determined based upon previous alignments in the literature [1]. Domains of human ERα, retinoic acid receptor (RARα) and retinoid X receptor (RXRα), show conserved residues, these were used as the basis for modelling the HBD of hERβ, hPXR, AhR and CAR. The respective

Results and discussion

Table 4 shows the results of the modelling of the receptors, including the energy before and after ligand binding, and indicates the main amino acid contacts between the ligands and receptors.

Conclusion

The nuclear receptors modelled display a spectrum of ligand specificities, ranging from the highly specific, as seen in CAR which binds 5α-androstan-3α-ol (androstanol) but not 5α-androstan-3β-ol [40] and seen in PPAR selectivity, to the highly non-specific, such as hPXR which is very flexible, and can bind with a large number of wide ranging molecules, from rifampicin to steroidal structures.

They also display a spectrum of binding modes within the LBD, from hydrogen bonding with variable key

Acknowledgements

Miriam Jacobs is supported by a BBSRC and GSK case studentship. David Lewis is supported by GSK, Merck Sharp & Dohme and the University of Surrey.

References (83)

  • I. Tzameli et al.

    Role reversal: new insights from new ligands for the xenobiotic receptor CAR

    Trends Endocrinol. Metab.

    (2001)
  • M.E. Hahn

    The aryl hydrocarbon receptor: a comparative perspective

    Comp. Biochem. Physiol. (C)

    (1998)
  • B.D. Abbott et al.

    Adverse reproductive outcomes in the transgenic Ah receptor-deficient mouse

    Toxicol. Appl. Pharmacol.

    (1999)
  • D. Phelan et al.

    Activation of the Ah receptor signal transduction pathway by bilirubin and biliverdin

    Arch. Biochem. Biophys.

    (1998)
  • T.E. Johnson et al.

    Structural requirements and cell type specifity for ligand activation of peroxisome proliferator activated receptors

    J. Steroid Biochem. Mol. Biol.

    (1997)
  • J. Bar-Tana

    Peroxisome proliferator-activated receptor gamma (PPARγ) activation and its consequences in humans

    Toxicol. Letts.

    (2001)
  • D.J. Waxman

    P450 Gene induction by structurally diverse xenochemicals: central role of nuclear receptors CAR, PXR, and PPAR

    Arch. Biochem. Biophys.

    (1999)
  • H.E. Xu et al.

    Molecular recognition of fatty acids by peroxisome proliferator activated receptors

    Mol. Cell

    (1999)
  • A.W.M. Zomer et al.

    Pristanic acid and phytanic acid: naturally occurring ligands for the nuclear receptor peroxisome proliferator activated receptorα

    J. Lipid Res.

    (2000)
  • T. Miyamoto et al.

    Inhibition of peroxisome proliferator signaling pathways by thyroid hormone receptor—competitive binding to the response element

    J. Biol. Chem.

    (1997)
  • T. Sueyoshi et al.

    Phenobarbital-responsive enhancer module (PBREM) of human CYP2B6 gene and inducible transactivation by nuclear receptor CAR

    J. Biol. Chem.

    (1999)
  • J.-M. Pascussi et al.

    Interleukin-6 negatively regulates the expression of pregnane X receptor and constitutively activated receptor in primary human hepatocytes

    Biochem. Biophys. Res. Commun.

    (2000)
  • A.M. Brzozowski et al.

    Molecular basis of agonism and antagonism in the oestrogen receptor

    Nature

    (1997)
  • J.M. Lehmann et al.

    The human orphan nucler receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions

    J. Clin. Invest.

    (1998)
  • K.M. Burbach et al.

    Cloning of the Ah-receptor cDNA reveals a distinctive ligand-activated transcription factor

    Proc. Natl. Acad. Sci. U.S.A.

    (1992)
  • B.M. Forman et al.

    Androstane metabolites bind to and deactivate the nuclear receptor CAR-β

    Nature

    (1998)
  • M. Baes et al.

    A new orphan member of the nuclear hormone receptor superfamily that interacts with a subset of retinoic acid response elements

    Mol. Cell. Biol.

    (1994)
  • R.T. Nolte et al.

    Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma

    Nature

    (1998)
  • P. Honkakoski et al.

    Regulation of cytochrome P450 (CYP) genes by nuclear receptors

    Biochem. J.

    (2000)
  • N. Weigel

    Steroid hormone receptors and their regulation by phosphorylation

    Biochem. J.

    (1996)
  • M.S. Dennison et al.

    Xenobiotic-inducible transcription of cytochrome P450 genes

    J. Biol. Chem.

    (1995)
  • S.A. Kliewer et al.

    Orphan nuclear receptors: shifting endocrinology into reverse

    Science

    (1999)
  • M. Negishi et al.

    Induction of drug metabolism by nuclear receptor CAR: molecular mechanisms and implications for drug research

    Eur. J. Pharm. Sci.

    (2000)
  • Nuclear Receptors Nomenclature Committee, A unified nomenclature system for the nuclear receptor superfamily, Cell 97...
  • T.M. Willson et al.

    The Science of orphan nuclear receptors, Core findings, a gene-to-function approach to drug discovery

    Odyssey

    (2000)
  • T.M. Willson et al.

    The PPARs: from orphan receptors to drug discovery

    J. Med. Chem.

    (2000)
  • E. Cottone et al.

    Role of coactivators and corepressors in steroid and nuclear recptor signalling: potential markers of tomor growth and drug sensitivity

    Int. J. Bio. Markers

    (2001)
  • B. Alberts, D. Bray, A. Johnson, J. Lewis, M. Raff, K. Roberts, P. Walter, Essential Cell Biology, Garland publishing,...
  • M.-R. Kenealy et al.

    The 3′untranslated region of the human estrogen receptor α gene mediates rapid messenger ribonucleic acid turnover

    Endocrinology

    (2000)
  • T.W. Synold et al.

    The orphan nuclear receptor SXR co-ordinately regulates drug metabolism and efflux

    Nat. Med.

    (2001)
  • M.N. Jacobs et al.

    Steroid hormone receptors and dietary ligands: a selected review

    Proc. Nutr. Soc.

    (2002)
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