Journal of Endocrinology and Reproduction

Amit K. Dash ¹, Ashutosh S. Yende ¹, Sudhir Kumar ¹, Shashi Kala Singh ¹, Deepak Kotiya ¹, Manjul Rana ¹, Rakesh K. Tyagi ¹

Affiliations
1 Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi-110067, IN

Abstract

Constitutive Androstane Receptor (CAR, NR1I3), a member of the nuclear receptor superfamily of transcription factors, has emerged as one of the key regulators of the drug and xenobiotic metabolism. The unique feature that separates CAR from other members of the superfamily is that it remains active in the absence of ligand and is further regulated by activators. From its first isolation in 1994, a number of studies related to its distribution, characteristics, functions, and relation to other members of the superfamily have been conducted that place it centrally, governing many key events of the body. Human CAR is expressed relatively higher in liver and epithelial cells of the small intestine villi and less in heart, muscle, kidney, brain and lung. Though there are some controversies regarding its subcellular localization in different cell lines, in general, the subcellular localization of CAR is reported to be predominantly cytoplasmic, in complex with co-chaperone partners HSP90 and CCRP (cytoplasmic CAR retention protein). To execute transcription functions, nuclear translocation is a prerequisite event for a NR, including CAR. In this context, existence of two pathways is suggested, i) direct mechanism of action; and ii) indirect mechanism of action that is governed via nuclear translocation of CAR. Additionally, existence of species-specific differences in its modulation with ligands acting either as an agonist, antagonist or inverse agonist is also apparent. Like the other xenobiotic receptor PXR, CAR also functions as an alternative 'xenosensor' to defend the body against persistent chemical insults. It responds to diverse array of chemically distinct compounds, including endobiotics and xenobiotics, to regulate the clearance of noxious chemicals and toxic metabolites in liver and intestine via induction of genes involved in their metabolism. The usefulness of targeting CAR in metabolic diseases including bilirubinemia, obesity, type 2 diabetes mellitus, atherosclerosis, preeclampsia, hypertension, cholestasis and also in liver cancer is being extensively studied in animal models. However, to determine the human relevance it requires further investigation. Though a large number of natural and synthetic compounds act as modulators of CAR, designing new derivatives with defined therapeutic benefit need to be investigated. The purpose of this review is to highlight the general aspects of nuclear receptor CAR, its mechanism of action and importance in human health and disease.

Keywords

Nuclear Receptors, Transcription Factors, Constitutive Androstane Receptor, Xenosensor, Drug Metabolism, Metabolic Diseases, Sub-Cellular Localization, Cancer.

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Seema Negi ¹, Mohammad A. Akbarsha ², Rakesh K. Tyagi ¹

Affiliations
1 Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi – 110067, IN
2 Department of Animal Science, School of Life Sciences, Bharathidasan University Tiruchirappalli - 620 024, IN

Abstract

Pregnane and Xenobiotic Receptor (PXR), a vital xenosensor, acts as master regulator of phase-I (cytochrome P450) and phase-II enzymes (glutathione S-transferases, sulfotransferases, and uridine 5'-diphosphate glucuronosyltransferases) as well as several drug transporters (multi-drug resistance protein, and multidrug resistance-associated protein). PXR can bind to a variety of chemically distinct endobiotics (steroids, bile acids and their derivatives, vitamins, etc.) and xenobiotics (prescription drugs, herbal medicines, endocrine disruptors, etc.). Activation of PXR by various compounds leads to trans-activation of PXR-target genes involved in detoxification system (phase-I and phase-II enzymes, and efflux proteins). Herbal medicines are readily used without prescription under the belief that anything natural is safe. These medicines contain active chemical constituents which execute distinctly different or similar pharmacological response(s). But, like prescription drugs, herbal drugs also have both therapeutic and, sometimes, adverse effects. Some of the herbal drugs induce drug metabolizing enzymes (especially CYP3A4) and drug efflux proteins via activation of PXR. Phase-I enzyme CYP3A4 is involved in the metabolism of 50-60% of clinical drugs as well as the chemical ingredients in herbal medicines. In addition to this, 25-30% of these compounds are metabolized by the CYP2B isoenzymes. The combined metabolic effects of phase-I and phase-II enzymes and drug transporters, following induction by therapeutic molecules, constitute the molecular basis for many drug-herbal interactions. For example, if one drug activates PXR, it can encourage the elimination of a co-administered drug that is also metabolized and eliminated by PXR-target gene products, thereby affecting the therapeutic efficacy of the drug in the context of combination therapy. The present review highlights some of the recent clinical correlates in drug-herbal interactions mediated primarily via PXR and cytochrome P450.

Keywords

Drug-Herbal Interactions, Pregnane and Xenobiotic Receptor (PXR), Cytochrome P450 (CYP450), Drug Transporters.

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Subodh Kumar ¹, Rakesh K. Tyagi ¹

Affiliations
1 Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi – 110067, IN

Abstract

The Pregnane & Xenobiotic Receptor (PXR), a member of the nuclear receptor family of ligand-activated transcription factors, is an integral component of the body's defense mechanism against toxic xenobiotics and endobiotic metabolites. Due to highly promiscuous nature and broad ligand specificity, this 'xenosensor' has emerged as a master-regulator of xenobiotic metabolism and regulator of all phases of drug metabolism and clearance. It has also been implicated to play an important role in induction of drug-drug interactions. During the past few years, research has unveiled some novel and mostly unanticipated roles for PXR in inflammation, lipid homeostasis, bone homeostasis, vitamin D metabolism, energy homeostasis, endocrine-related functions and cancer. Recent evidences have revealed existence of PXR cross-talk with several other cellular signaling pathways that profoundly expand the horizon of this promiscuous xenosensor. These cross-talks between PXR and other signaling pathways may elucidate molecular mechanisms to explain the involvement of PXR in several hitherto unanticipated physiological functions. The present article summarizes some of the important cross-talks of PXR with other nuclear receptors and different signaling pathways to describe how these cross-talks integrate into novel biological functions. It is anticipated that better understanding towards the mechanisms of PXR cross-talk might divulge novel therapeutic approaches to combat various diseases.

Keywords

Cross-Talk, Drug Metabolism, Nuclear Receptor, PXR, Xenobiotics.

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Amit K. Dash ¹, Rakesh K. Tyagi ¹

Affiliations
1 Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi – 110067, IN

Abstract

The ‘Nuclear Receptor Super-family’ is a group of ligand-modulated transcription factors with 48 members identified in human genome. Members of this family of receptors are now established to be involved in regulation of a plethora of physiological processes in the paradigms of development, reproduction, metabolism and homeostasis. Also, in the myriads of patho-physiological processes, these receptors have consistently exhibited enormous potential as targets for the treatment of diseases such as cancers, osteoporosis, diabetes, obesity, coronary heart disease, asthma, hypertension, thyroid conditions and multiple other metabolic disorders. In recent times, it is estimated that about 15% of the clinical drugs, used in treatments of different ailments, target nuclear receptors. These receptors include steroid/thyroid hormone receptors and orphan/adopted receptors that function as intra-cellular transcription factors to regulate expression of several hundreds of genes in response to their cognate ligands. Interestingly, nuclear receptors are also being assigned a novel role in serving as ‘epigenetic marks’ for the retention and transmission of cellular ‘transcriptional memory’. These receptors function primarily either as homodimers or heterodimers with Retinoid X Receptor (RXR) or sometimes as monomers. Being ‘drug responsive’ these receptors offer attractive targets for drug discovery since their activities can be favorably modulated by interacting ligands. However, many of the newly discovered members of this family of receptors remain incompletely understood, both in terms of physiological roles and activating ligands. In brief, nuclear receptors represent enormous potential for drug discovery and are continuously being examined to unravel the mysteries underlying their mechanisms of action. It has been well-over three decades since the cloning of steroid/nuclear receptors in the 1980s. Therefore, it’s only appropriate to prepare a comprehensive review that provides a compendium of facts and events from receptor cloning and characterization to establishment of receptor domain structures, physiological functioning and consequences of receptor malfunctioning. This review is expected to serve as a refreshing compendium of nuclear receptors for both, the beginners, as well as experts working in the areas of nuclear receptor biology.

Keywords

Classification, Diseases, Diversity, Drug Targets, Epigenetics, Nuclear Receptors, Transcription Factors, Structure.

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Shashi Kala Singh ¹, Rakesh K. Tyagi ¹

Affiliations
1 Special Centre for Molecular Medicine, Jawaharlal Nehru University New Delhi – 110067, IN

Abstract

The human body has developed a defence system to prevent the accumulation of endogenous (bile acids, steroids, cholesterol metabolites, neurotransmitters, etc.) as well as exogenous (xenobiotics, clinical drugs, etc.) small molecules at toxic levels. This task is accomplished by ‘drug metabolism and disposition (DMD) machinery’ which entails phase I and phase II enzymes, and phase III transporter proteins. The components of this machinery act in a coordinated manner to biotransform and facilitate the elimination of small toxic molecules from the cellular milieu. Constitutive androstane receptor (CAR), a member of the nuclear receptor superfamily, acts as one of the major transcriptional regulators of the DMD machinery. Prescription of combination therapy is a common regimen during the treatment of diverse metabolic disorders and infectious diseases. In such combination therapies one drug may modulate the expression of genes of DMD, influencing the metabolism of another co-administered drug. This leads to decreased bioavailability or increased toxicity of the latter. Evaluation of drug-drug interactions (DDIs) has now become a major safety concern during drug discovery and development processes. Pre-assessment of the small molecules for modulatory effects on CAR and induction of the components of DMD can resolve the safety concerns, treatment failures and drug withdrawals due to the harmful DDIs. In the present study, we have followed a ‘reverse approach’ to assess CAR activation by drugs previously withdrawn from clinical practices. We selected three redundant members of thiazolidinedione family of anti-diabetic drugs and examined their potential in regulation of CAR and its target gene CYP2B6. These drugs showed differential transcriptional activation of CAR. Two of the TZD i.e., rosiglitazone and pioglitazone enhanced CAR activity by behaving as receptor ligands while the other (troglitazone) did not influence the receptor function and was justly withdrawn since it inflicted cytotoxicity.

Keywords

Anti-Diabetic Drugs, Constitutive Androstane Receptor, Drug Metabolism and Disposition Machinery, Nuclear Receptor, Nuclear Translocation.

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Jyoti Kashyap ¹, Ayushi Chhabra ¹, Sheeba Rizvi ¹, Rakesh K. Tyagi ¹

Affiliations
1 Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi - 110067, IN

Abstract

Vitamin D Receptor (VDR) is a key regulator of bone metabolism and calcium homeostasis. Various investigations suggest its association with many life-threatening diseases including bone-related disorders, cancers, diabetes, cardiovascular diseases, infectious diseases and metabolic disorders. VDR forms a heterodimeric complex with Retinoid X Receptor (RXR) when activated with 1α,25-dihydroxyvitamin D3 and binds to vitamin D response elements (VDREs) in the DNA sequences located upstream of target genes. Ligand binding and heterodimerization play critical roles in receptor activation and gene regulation. Many studies have shown that any change in VDR function influences target gene functions. Numerous VDR polymorphisms have been reported in various populations around the world. Additionally, a number of case-control studies have established a link between the VDR polymorphism(s) and human diseases. However, some contradictory studies have also been reported. Recent investigations have identified several critical VDR polymorphism(s) that may influence or alter the receptor’s function and contribute to the genesis/etiology of disease states. In this review, we have highlighted and analyzed the relevance of VDR and its polymorphism(s) vis-a-vis risk to some disease conditions. The current review highlights the importance of VDR-SNPs in decoding the importance of a receptor as a transcription factor as well as a molecular marker for diagnosis of diverse health conditions.

Keywords

Nuclear Receptors, Polymorphism, Retinoid X Receptor, Transcription Factors, Vitamin D Receptor.

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