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.

Full Text

     

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.

Full Text