Role of Retinoids, Rexinoids and Thyroid Hormone in the Expression of Cytochrome P450 Enzymes

Brtko, Július; Dvořák, Zdeněk

doi:10.2174/138920011795016881

Cited by 47 publications

(41 citation statements)

References 327 publications

(325 reference statements)

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“…In addition, ATRA is inactivated in vivo by inducible and constitutively expressed cytochrome P450 enzymes. 7,8 While 9CRA may also have a cellular role as a ligand to activate transcription factors, a natural physiological function for 13CRA as a transcription-factor ligand is less certain. 5 We have previously described two light-stable synthetic retinoid analogues, EC23 and EC19 (Figure 1, left), 9 differing from each other only in the position of the carboxylic acid group on the terminal substituted ring.…”

Section: Introductionmentioning

confidence: 99%

The molecular basis of the interactions between synthetic retinoic acid analogues and the retinoic acid receptors

et al. 2017

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. (2017) 'The molecular basis of the interactions between synthetic retinoic acid analogues and the retinoic acid receptors. ', MedChemComm., 8 (3). pp. 578-592. Further information on publisher's website:https://doi.org/10.1039/C6MD00680APublisher's copyright statement:Additional information: Use policyThe full-text may be used and/or reproduced, and given to third parties in any format or medium, without prior permission or charge, for personal research or study, educational, or not-for-pro t purposes provided that:• a full bibliographic reference is made to the original source • a link is made to the metadata record in DRO • the full-text is not changed in any way The full-text must not be sold in any format or medium without the formal permission of the copyright holders.Please consult the full DRO policy for further details. All-trans-retinoic acid (ATRA) and its synthetic analogues EC23 and EC19 direct cellular differentiation by interacting as ligands for the retinoic acid receptor (RARα, β and γ) family of nuclear receptor proteins. To date, a number of crystal structures of natural and synthetic ligands complexed to their target proteins have been solved, providing molecular level snap-shots of ligand binding. However, a deeper understanding of receptor and ligand flexibility and conformational freedom is required to develop stable and effective ATRA analogues for clinical use. Therefore, we have used molecular modelling techniques to define RAR interactions with ATRA and two synthetic analogues, EC19 and EC23, and compared their predicted biochemical activities to experimental measurements of relative ligand affinity and recruitment of coactivator proteins. A comprehensive molecular docking approach that explored the conformational space of the ligands indicated that ATRA is able to bind the three RAR proteins in a number of conformations with one extended structure being favoured. In contrast the biologically-distinct isomer, 9-cis-retinoic acid (9CRA), showed significantly less conformational flexibility in the RAR binding pockets. These findings were used to inform docking studies of the synthetic retinoids EC23 and EC19, and their respective methyl esters. EC23 was found to be an excellent mimic for ATRA, and occupied similar binding modes to ATRA in all three target RAR proteins. In comparison, EC19 exhibited an alternative binding mode which reduces the strength of key polar interactions in RARα/γ but is well-suited to the larger RARβ binding pocket. In contrast, docking of the corresponding esters revealed the loss of key polar interactions which may explain the much reduced biological activity. Our computational results were complemented using an in vitro binding assay based on FRET measurements, which showed that EC23 was a strongly binding, pan-agonist of the RARs, while EC19 exhibited specificity for RARβ, as predicted by the docking studies. These findings can account for the distinct behaviour of EC23 and EC19 in cellular differentiation assays, and additionally, the methods described ...

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Section: Introductionmentioning

confidence: 99%

The molecular basis of the interactions between synthetic retinoic acid analogues and the retinoic acid receptors

et al. 2017

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“…In spite of that rapid progress novel synthetic retinoids and rexinoids with greater retinoid receptor selectivity, reduced teratogenic and other side effects are still highly required 3,5 . In coming time, sophisticated molecular biology approaches will open new possibilities for retinoids/rexinoids and its synthetic analogues exploitation in novel directed therapies for renal cell carcinomas.…”

Section: Resultsmentioning

confidence: 99%

“…All these compounds act through interactions with two basic types of nuclear receptors: retinoic acid receptors (RAR α, β and γ) and retinoid X receptors (RXR α, β and γ) as ligand-activated, DNAbinding, trans-acting, transcription-modulating proteins involved in a general molecular mechanism responsible for transcriptional responses in target genes. In higher organisms, retinoids affect a broad spectrum of biochemical and molecular biological reactions 5 . However, they have both beneficial and as well as detrimental effects.…”

Section: Introductionmentioning

confidence: 99%

The relationship between renal cell carcinoma and nuclear retinoid/rexinoid receptors

Lenko¹,

Bialešová²,

Macejova³

et al. 2013

BIOMED PAP

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Background. Renal cell carcinoma (RCC) is a urologic malignancy with a steady rise in incidence and high mortality rate. Between 60 to 70% of patients with renal cell carcinoma can only be cured with surgery but despite advances in early diagnostis, in around 20-30% of cases there is metastasis. For these patients, chemotherapy and radiotherapy are ineffective and hence the prognosis is poor. Retinoids are biologically active compounds of either natural or synthetic origin that are involved in complex physiological and developmental processes in many tissues including cell proliferation and activation of tumour suppression genes. This article reviews the role of retinoids and their cognate nuclear retinoid/rexinoid receptors in relation to renal cell carcinoma. Methods. A literature search using ScienceDirect and Medline with a focus on the relationship between renal cell carcinoma and nuclear retinoid/rexinoid receptors. Results. Use of retinoids/rexinoids in the treatment of locally advanced and metastatic RCC significantly prolongs median time of tumour progression and overall survival of patients. Combination therapy with other preparations has greater efficacy than treatment with retinoids alone. Patient survival can be predicted on the basis of the expression of different all-trans retinoic acid receptor (RAR) and 9-cis retinoic acid receptor (RXR) subtypes. Conclusions. Since nuclear retinoid receptors play a crucial role as ligand-activated, DNA binding, trans-acting, transcription-modulating proteins involved in a general molecular mechanism responsible for transcriptional responses in target genes, retinoids might be an alternative approach for the treatment of renal cell carcinoma.

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“…investigated P450s) may also be partly due to the reduced concentration of thyroid hormone (T 3 ), which negatively regulates these enzymes (Yamazoe et al, 1989). The signaling pathways of AhR and the thyroid hormone receptor share several coactivators and transcription factors (e.g., retinoid X receptor), a phenomenon that may lead to a transcriptional cross-talk between these pathways and alterations in CYP1A gene expression (Brtko and Dvorak, 2011). The present results confirm our earlier observations that the transcription of the CYP1A1 gene in the rat is more responsive to hormonal modulation than is that of the CYP1A2 gene (Sadakierska-Chudy et al, 2013).…”

Section: Tablementioning

confidence: 99%

Damage to the Brain Serotonergic System Increases the Expression of Liver Cytochrome P450

et al. 2015

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Genes coding for cytochrome P450 are regulated by endogenous hormones such as the growth hormone, corticosteroids, thyroid, and sex hormones. Secretion of these hormones is regulated by the respective hypothalamus-pituitary-secretory organ axes. Since the brain sends its serotonergic projections from the raphe nuclei to the hypothalamus, we have assumed that damage to these nuclei may affect the neuroendocrine regulation of cytochrome P450 expression in the liver. Thereby, 5,7-dihydroxytryptamine (5,7-DHT), a serotonergic neurotoxin, was injected into the dorsal and median raphe nuclei of male Wistar rats. Ten days after the neurotoxin injections, the brain concentrations of neurotransmitters, serum hormone, and cytokine levels, as well as the expression of cytochrome P450 in the liver were measured. Injection of 5,7-DHT decreased serotonin concentration in the brain followed by a significant rise in the levels of the growth hormone, corticosterone, and testosterone, and a drop in triiodothyronine concentration in the serum. No changes in interleukin (IL) levels (IL-2 and IL-6) were observed. Simultaneously, the activity and protein level of liver CYP1A, CYP3A1, and CYP2C11 rose (the activity of CYP2A/2B/2C6/2D was not significantly changed). Similarly, the mRNA levels of CYP1A1, CYP1A2, CYP2C11, and CYP3A1 were elevated. This is the first report demonstrating the effect of intracerebral administration of serotonergic neurotoxin on liver cytochrome P450. The obtained results indicate involvement of the brain serotonergic system in the neuroendocrine regulation of liver cytochrome P450 expression. The physiologic and pharmacological significance of the findings is discussed.

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Role of Retinoids, Rexinoids and Thyroid Hormone in the Expression of Cytochrome P450 Enzymes

Cited by 47 publications

References 327 publications

The molecular basis of the interactions between synthetic retinoic acid analogues and the retinoic acid receptors

The molecular basis of the interactions between synthetic retinoic acid analogues and the retinoic acid receptors

The relationship between renal cell carcinoma and nuclear retinoid/rexinoid receptors

Damage to the Brain Serotonergic System Increases the Expression of Liver Cytochrome P450

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