The effects of therapy with rifampicin and isoniazid on basic investigations for Cushing’s syndrome

Zawawi, Tarif H.; Al-Hadramy, M. S.; Abdelwahab, Shaimaa M.

doi:10.1007/bf02943098

Cited by 7 publications

(3 citation statements)

References 16 publications

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“…Interestingly, the current best SXR activator, rifampicin, is also known to be involved in numerous drug-drug interactions as a consequence of drastically altering their metabolism by inducing CYP3A4. Thus, long-term rifampicin therapy for tuberculosis also increases steroid clearance, in some cases leading to a misdiagnosis of Cushing's syndrome (Kyriazopoulou and Vagenakis 1992;Terzolo et al 1995;Zawawi et al 1996). In patients with Addison's disease, who are on steroid replacement therapy, or women taking oral contraceptives, rifampicin treatment leads to rapid depletion of administered steroids, confirming that induction of CYP3A4 causes increased steroid catabolism as predicted by the model (Edwards et al 1974;Kyriazopoulou et al 1984).…”

Section: Sxr-a Steroid and Xenobiotic Sensormentioning

confidence: 68%

Orphan nuclear receptors—new ligands and new possibilities: Figure 1.

Blumberg¹,

Evans²

1998

Genes Dev.

299

167

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Nuclear hormone receptors comprise a large superfamily of ligand-modulated transcription factors that, in part, mediate response to steroids, retinoids and thyroid hormones and play key roles in development and body physiology (for review, see Beato et al. 1995;Enmark and Gustaffson 1996;Willy and Mangelsdorf 1998). Ten years ago the first orphan nuclear receptors were isolated, raising the first portents toward a new era in physiology (Giguere et al. 1988). Although structurally related to the known receptors, no physiological ligands or activators were known for these orphan receptors which are more numerous (19 families) than receptors with known ligands (10 families). Orphan receptors represent a diverse and ancient component of the nuclear receptor superfamily, being found in nearly all animal species examined. Orphan nuclear receptors provide a unique and, until recently, largely untapped resource to uncover regulatory systems that impact on both health and human disease. Shortly after their isolation, strategies were devised to identify orphan ligands using the receptor as a screening target. This process, referred to as 'reverse endocrinology,' has led previously to the identification of ligands for RXRs [9-cis retinoic acid receptors (RARs), a.k.a. retinoid X receptors], PPARs (peroxisome proliferator-activated receptors), FXRs (farnesoid X receptors), and LXRs (liver X receptors).In a review eight years ago, Bert O'Malley predicted that the field of orphan receptors would provide much excitement for the future (O'Malley 1990). The promise of orphan receptors is that they provide an opportunity to identify not only novel ligands but perhaps unsuspected classes of ligands and potentially new principles of physiology. Because all known receptors are important in the treatment of human disease, their signaling pathways have direct implications for drug discovery. The purpose of this review is to highlight advances made on four new orphan receptor-mediated signaling pathways [BXR (benzoate X receptor), CAR␤ (constitutive androstane receptor), PXR (pregnane X receptor), and SXR (steroid and Xenobiotic receptor)] with brief updates on recent progress for FXR, PPAR␥, and LXR␣. To restrict the scope of the review, we will focus only on orphans forming heterodimers with RXR and studies that have been reported in the last year. We will emphasize what has been learned about the nature of the ligands, new modes of regulation, insights into physiology, and potential new drug targets. RXR heterodimers and ligand dependenceAlthough inherently promising, not all orphans (and perhaps only a few) can be expected to represent unidentified endocrine systems. Therefore, a central and critical problem is identifying which of the many orphan receptors are good candidates to be ligand responsive. An interesting feature of the known, nonsteroidal ligand-activated nuclear receptors is that they all require heterodimerization with RXR, for high-affinity DNA binding. We and others speculated that RXR heterodimerization might be a ...

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Section: Sxr-a Steroid and Xenobiotic Sensormentioning

confidence: 68%

Orphan nuclear receptors—new ligands and new possibilities: Figure 1.

Blumberg¹,

Evans²

1998

Genes Dev.

299

167

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“…Interestingly, the PXR transgenic mice exhibited normal ACTH secretion in pituitary, and intact suppression of dexamethasone by corticosterone, indicating a functionalhypothalamus-pituitary-adrenal axis in spite of severely disrupted adrenal steroidhomeostasis. Consistent with these observations, several clinical studies reported that rifampicin increased steroid secretion in urine and may have resulted in misdiagnosis of Cushing’s syndrome [118, 119]. Therefore, PXR has a potential to disrupt endocrine homeostasis, and it may be broadly implicated in drug-hormone interactions.…”

Section: Pxr In Endobiotic Metabolismmentioning

confidence: 73%

Nuclear receptor PXR, transcriptional circuits and metabolic relevance

Ihunnah

Jiang

Xie

2011

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

191

124

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The pregnane X receptor (PXR, NR1I2) is a ligand activated transcription factor that belongs to the nuclear hormone receptor (NR) superfamily. PXR is highly expressed in the liver and intestine, but low levels of expression have also been found in many other tissues. PXR plays an integral role in xenobiotic and endobiotic metabolism by regulating the expression of drug metabolizing enzymes and transporters, as well as genes implicated in the metabolism of endobiotics. PXR exerts its transcriptional regulation by binding to its DNA response elements as a heterodimer with the retinoid X receptor (RXR) and recruitment of a host of coactivators. The biological and physiological implications of PXR activation are broad, ranging from drug metabolism and drug-drug interactions to the homeostasis of numerous endobiotics, such as glucose, lipids, steroids, bile acids, bilirubin, retinoic acid, and bone minerals. The purpose of this article is to provide an overview on the transcriptional circuits and metabolic relevance controlled by PXR.

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“…When synthetic steroids, such as prednisolone (McAllister et al 1983;Lee et al 1993) or 17␣-ethynylestradiol (Guengerich 1990) are administered together with rifampicin, plasma levels are rapidly decreased due to enhanced urinary clearance. In some patients undergoing rifampicin therapy for tuberculosis, the increase in urinary steroid levels has led to misdiagnosis of Cushing's syndrome (Kyriazopoulou and Vagenakis 1992;Terzolo et al 1995;Zawawi et al 1996). Steroid production and clearance normalized when rifampicin was withdrawn.…”

Section: Discussionmentioning

confidence: 99%

SXR, a novel steroid and xenobioticsensing nuclear receptor

Blumberg

Sabbagh²,

Juguilon³

et al. 1998

Genes Dev.

856

765

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An important requirement for physiologic homeostasis is the detoxification and removal of endogenous hormones and xenobiotic compounds with biological activity. Much of the detoxification is performed by cytochrome P-450 enzymes, many of which have broad substrate specificity and are inducible by hundreds of different compounds, including steroids. The ingestion of dietary steroids and lipids induces the same enzymes; therefore, they would appear to be integrated into a coordinated metabolic pathway. Instead of possessing hundreds of receptors, one for each inducing compound, we propose the existence of a few broad specificity, low-affinity sensing receptors that would monitor aggregate levels of inducers to trigger production of metabolizing enzymes. In support of this model, we have isolated a novel nuclear receptor, termed the steroid and xenobiotic receptor (SXR), which activates transcription in response to a diversity of natural and synthetic compounds. SXR forms a heterodimer with RXR that can bind to and induce transcription from response elements present in steroid-inducible cytochrome P-450 genes and is expressed in tissues in which these catabolic enzymes are expressed. These results strongly support the steroid sensor hypothesis and suggest that broad specificity sensing receptors may represent a novel branch of the nuclear receptor superfamily.[Key Words: Steroid; xenobiotic receptor; nuclear receptor; transcriptional activity] Received July 24, 1998; revised version accepted August 26, 1998. Lipophilic hormones, such as steroids, retinoic acid, thyroid hormone, and vitamin D3, control broad aspects of animal growth, development, and adult organ physiology. The effects of these hormones are mediated by a large superfamily of intracellular receptors that function as ligand-dependent and sequence-specific transcription factors. The nonsteroidal nuclear receptors for thyroid hormone (TR), vitamin D3 (VDR), all-trans retinoic acid (RAR), and fatty acids and eicosanoids (PPAR) form heterodimers with the 9-cis retinoic acid receptor (RXR) that bind bipartite hormone-response elements (HREs) composed of directly repeated half sites related to the sequence AGGTCA (Mangelsdorf and Evans 1995). In contrast, the steroid receptors function as homodimers and bind to palindromic target sequences spaced by three nucleotides . In addition to the known receptors, a large group of structurally related 'orphan' nuclear receptors has been described; that these receptors possess obvious DNA and ligand-binding domains but lack identified ligands . Each has the potential to regulate a distinct endocrine signaling pathway.It is widely viewed that the hormone response is a consequence of the release from an endocrine gland of a ligand that circulates through the blood, and coordinately regulates responses in target tissues by acting through specific nuclear receptors. Hormone responsiveness is dependent on the ability to rapidly clear ligand from the blood and the body so that, in absence of a stimulus, target tissues re...

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The effects of therapy with rifampicin and isoniazid on basic investigations for Cushing’s syndrome

Cited by 7 publications

References 16 publications

Orphan nuclear receptors—new ligands and new possibilities: Figure 1.

Orphan nuclear receptors—new ligands and new possibilities: Figure 1.

Nuclear receptor PXR, transcriptional circuits and metabolic relevance

SXR, a novel steroid and xenobioticsensing nuclear receptor

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