Vitamin A5/X, a New Food to Lipid Hormone Concept for a Nutritional Ligand to Control RXR-Mediated Signaling.

Vitamin A is a family of derivatives synthesized from carotenoids acquired from the diet and can be converted in animals to bioactive forms essential for life. Vitamin A1 (all-trans-retinol/ATROL) and provitamin A1 (all-trans-ß,ß-carotene/ATBC) are precursors of all-trans-retinoic acid acting as a ligand for the retinoic acid receptors. The contribution of ATROL and ATBC to formation of 9-cis-13,14-dihydroretinoic acid (9CDHRA), the only endogenous retinoid acting as retinoid X receptor (RXR) ligand, remains unknown. To address this point novel and already known retinoids and carotenoids were stereoselectively synthesized and administered in vitro to oligodendrocyte cell culture and supplemented in vivo (orally) to mice with a following high-performance liquid chromatography-mass spectrometry (HPLC-MS)/UV-Vis based metabolic profiling. In this study, we show that ATROL and ATBC are at best only weak and non-selective precursors of 9CDHRA. Instead, we identify 9-cis-13,14-dihydroretinol (9CDHROL) and 9-cis-13,14-dihydro-ß,ß-carotene (9CDHBC) as novel direct nutritional precursors of 9CDHRA, which are present endogenously in humans and the human food chain matrix. Furthermore, 9CDHROL displayed RXR-dependent promnemonic activity in working memory test similar to that reported for 9CDHRA. We also propose that the endogenous carotenoid 9-cis-ß,ß-carotene (9CBC) can act as weak, indirect precursor of 9CDHRA via hydrogenation to 9CDHBC and further metabolism to 9CDHROL and/or 9CDHRA. In summary, since classical vitamin A1 is not an efficient 9CDHRA precursor, we conclude that this group of molecules constitutes a new class of vitamin or a new independent member of the vitamin A family, named "Vitamin A5/X".

Bexarotene normalizes chemotherapy-induced myelin decompaction and reverses cognitive and sensorimotor deficits in mice.

Frequently reported neurotoxic sequelae of cancer treatment include cognitive deficits and sensorimotor abnormalities that have long-lasting negative effects on the quality of life of an increasing number of cancer survivors. The underlying mechanisms are not fully understood and there is no effective treatment. We show here that cisplatin treatment of mice not only caused cognitive dysfunction but also impaired sensorimotor function. These functional deficits are associated with reduced myelin density and complexity in the cingulate and sensorimotor cortex. At the ultrastructural level, myelin abnormalities were characterized by decompaction. We used this model to examine the effect of bexarotene, an agonist of the RXR-family of nuclear receptors. Administration of only five daily doses of bexarotene after completion of cisplatin treatment was sufficient to normalize myelin density and fiber coherency and to restore myelin compaction in cingulate and sensorimotor cortex. Functionally, bexarotene normalized performance of cisplatin-treated mice in tests for cognitive and sensorimotor function. RNAseq analysis identified the TR/RXR pathway as one of the top canonical pathways activated by administration of bexarotene to cisplatin-treated mice. Bexarotene also activated neuregulin and netrin pathways that are implicated in myelin formation/maintenance, synaptic function and axonal guidance. In conclusion, short term treatment with bexarotene is sufficient to reverse the adverse effects of cisplatin on white matter structure, cognitive function, and sensorimotor performance. These encouraging findings warrant further studies into potential clinical translation and the underlying mechanisms of bexarotene for chemobrain.

Therapeutic modulation of retinoid X receptors - SAR and therapeutic potential of RXR ligands and recent patents.

Introduction: Retinoid X receptor (RXR) agonists have a limited role in cancer therapy with bexarotene and alitretinoin as approved drugs but their use is limited by adverse effects. Several evidence from in vitro, in vivo, and small clinical studies points to various further potential applications of RXR ligands in neurodegenerative and inflammatory diseases. Areas covered: The authors review known RXR ligand classes with their key structure-activity relationships and recent reports on pharmacological effects of RXR modulation. Based on these aspects, the authors evaluate recent patents claiming novel RXR ligands or their use. Expert opinion: While the use of RXR modulators has been claimed in several novel and promising indications, little progress has been made in the development of innovative rexinoids with improved (subtype-)selectivity. Next-generation RXR modulators that selectively target the RXR subtypes for individual indications may be required to exhaustively exploit the therapeutic potential of RXRs.

Multispecies study: low-dose tributyltin impairs ovarian theca cell cholesterol homeostasis through the RXR pathway in five mammalian species including humans.

Tributyltin (TBT), an organotin chemical used as a catalyst and biocide, can stimulate cholesterol efflux in non-steroidogenic cells. Since cholesterol is the first limiting step for sex hormone production, we hypothesized that TBT disrupts intracellular cholesterol transport and impairs steroidogenesis in ovarian theca cells. We investigated TBT's effect on cholesterol trafficking, luteinization, and steroidogenesis in theca cells of five species (human, sheep, cow, pig, and mice). Primary theca cells were exposed to an environmentally relevant dose of TBT (1 or 10 ng/ml) and/or retinoid X receptor (RXR) antagonist. The expression of RXRα in sheep theca cells was knocked down using shRNA. Steroidogenic enzymes, cholesterol transport factors, and nuclear receptors were measured by RT-qPCR and Western blotting, and intracellular cholesterol, progesterone, and testosterone secretion by ELISA. TBT upregulated StAR and ABCA1 in ovine cells, and SREBF1 mRNA in theca cells. TBT also reduced intracellular cholesterol and upregulated ABCA1 protein expression but did not alter testosterone or progesterone production. RXR antagonist and RXRα knockdown demonstrates that TBT's effect is partially through RXR. TBT's effect on ABCA1 and StAR expression was recapitulated in all five species. TBT, at an environmentally relevant dose, stimulates theca cell cholesterol extracellular efflux via the RXR pathway, triggers a compensatory upregulation of StAR that regulates cholesterol transfer into the mitochondria and SREBF1 for de novo cholesterol synthesis. Similar results were obtained in all five species evaluated (human, sheep, cow, pig, and mice) and are supportive of TBT's conserved mechanism of action across mammalian species.

Efflux inhibition by H2S confers sensitivity to doxorubicin-induced cell death in liver cancer cells.

AIMS: Hydrogen sulfide (H2S), an important gasotransmitter, is involved in a variety of cellular functions and pathophysiologic processes. Drug resistance due to alterations in drug trafficking and metabolism severely limits the effectiveness of cancer therapy. This study examined the role of H2S in drug resistance in liver cancer cells. MATERIALS AND METHODS: Human primary hepatocellular carcinoma cell line (HepG2) and doxorubicin (Dox)-resistant cells were used in this study. Cell survival was analyzed by MTT, Annexin V-FITC/propidium iodide staining and clonogenic assay. Western blotting was used for analysis of protein expression, and immunoprecipitation was used to determine interactions of LXR/RXR. KEY FINDINGS: The expression of H2S-generating enzyme cystathionine gamma-lyase (CSE) was inhibited by doxorubicin treatment in HepG2 cells, and H2S sensitized Dox-inhibited cell survival and colony formation. In addition, H2S promoted cellular retention of Dox by suppressing the expressions of ABCA1 and ABCG8. H2S significantly blocked Dox-induced heterodimer formation between LXRα and RXRß and attenuated the binding of LXRα/RXRß to the promoters of ABCA1 and ABCG8 genes. RXRß but not LXRα was S-sulfhydrated by H2S, and blockage of RXRß S-sulfhydration abolished the inhibitory role of H2S on LXRα/RXRß heterodimer formation. CSE expression was reduced in Dox-resistant cells in comparison with their parental cells, while H2S could reverse drug resistance in Dox-resistant cells. SIGNIFICANCE: Our study provides a novel solution for reversing drug resistance in cancer cells by targeting H2S signalling.

Nuclear receptors as potential drug targets in osteoarthritis.

Osteoarthritis is amongst the major causes of disability worldwide, but no medications that can slow or stop progression of this disorder have been identified. Recent evidence suggests roles for a variety of members of the nuclear receptor family of ligand-activated transcription factors in various forms of osteoarthritis. Since nuclear receptors are amongst the major classes of drug targets, these studies suggest that modulators of nuclear receptor activity might provide novel strategies to treat osteoarthritis. This review focuses on recent advances in our understanding of the role of nuclear receptors in osteoarthritis onset and progression, as well as their therapeutic implications. Future studies should continue to examine the possible roles of additional nuclear receptors in the pathophysiology of different types of osteoarthritis.

Retinoid X Receptor Activation Alters the Chromatin Landscape To Commit Mesenchymal Stem Cells to the Adipose Lineage.

Developmental exposure to environmental factors has been linked to obesity risk later in life. Nuclear receptors are molecular sensors that play critical roles during development and, as such, are prime candidates to explain the developmental programming of disease risk by environmental chemicals. We have previously characterized the obesogen tributyltin (TBT), which activates the nuclear receptors peroxisome proliferator-activated receptor γ (PPARγ) and retinoid X receptor (RXR) to increase adiposity in mice exposed in utero. Mesenchymal stem cells (MSCs) from these mice are biased toward the adipose lineage at the expense of the osteoblast lineage, and MSCs exposed to TBT in vitro are shunted toward the adipose fate in a PPARγ-dependent fashion. To address where in the adipogenic cascade TBT acts, we developed an in vitro commitment assay that permitted us to distinguish early commitment to the adipose lineage from subsequent differentiation. TBT and RXR activators (rexinoids) had potent effects in committing MSCs to the adipose lineage, whereas the strong PPARγ activator rosiglitazone was inactive. We show that activation of RXR is sufficient for adipogenic commitment and that rexinoids act through RXR to alter the transcriptome in a manner favoring adipogenic commitment. RXR activation alters expression of enhancer of zeste homolog 2 (EZH2) and modifies genome-wide histone 3 lysine 27 trimethylation (H3K27me3) in promoting adipose commitment and programming subsequent differentiation. These data offer insights into the roles of RXR and EZH2 in MSC lineage specification and shed light on how endocrine-disrupting chemicals such as TBT can reprogram stem cell fate.

Sn- and Ge- triorganometallics exert different cytotoxicity and modulation of migration in triple-negative breast cancer cell line MDA-MB-231.

Among a variety of metal containing organic compounds, tin derivatives are enjoying an increasing interest and appear to be very promising as potential drug candidates. We studied eight organometallic derivatives, nuclear retinoid X receptor (RXR) ligands and two germanium containing derivates that do not serve as RXR ligands. Tributylgermanium chloride (TBGe) and triphenylgermanium chloride (TPGe) did not inhibit growth of human triple negative MDA-MB-231 breast cancer cells. On the other hand, the tributyltin derivatives were highly, the triphenyltin derivatives less cytotoxic, both groups with IC50 values of nanomolar range. All trialkyltin derivatives (tributyltin chloride, tributyltin bromide, tributyltin iodide, tributyltin hydride) and three triaryltin derivatives (triphenyltin chloride, triphenyltin hydride and triphenyltin hydroxide) caused caspase-3/7 dependent apoptosis. Those derivatives that showed no or weak cytotoxicity, TBGe, TPGe, and triphenyltin acetate, we found to reduce migration of tested triple negative breast cancer cells.

Retinoid X Receptor Ligands with Anti-Type 2 Diabetic Activity.

Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-dependent transcription factor that plays an important role in regulating glucose metabolism. Agonists of PPARγ, such as thiazolidinediones, have anti-hyperglycemic activity, and are therefore used to treat type 2 diabetes. However, the functional activity of PPARγ is manifested by heterodimers of PPARγ with retinoid X receptors (RXRs). Since RXR/PPARγ heterodimers can be activated not only by PPARγ agonists, but also by RXR agonists, RXR agonists are also attractive candidates for treatment of type 2 diabetes. However, RXR full agonists have side effects, such as triglyceride elevation and hypothyroidism. Therefore, RXR partial agonists have been developed as new anti-type 2 diabetes agent candidates with reduced side effects. In addition, RXR antagonists also show therapeutic potency in type 2 diabetes patients. Here, we review RXR full agonists, RXR antagonists, and RXR modulators (partial agonists) with reported anti-diabetic effects, and we discuss their potential suitability as anti-diabetic agents.

Radioligand binding assay for accurate determination of nuclear retinoid X receptors: A case of triorganotin endocrine disrupting ligands.

Nuclear 9-cis retinoic acid receptors (retinoid X receptors, RXR) are promiscuous dimerization partners for a number of nuclear receptors. In the present study, we established a novel in vitro method for quantitative determination of the nuclear retinoid X receptors in rat liver. One type of high affinity and limited capacity RXR specific binding sites with the Ka value ranging from 1.011 to 1.727×10(9)l/mol and the Bmax value ranging from 0.346 to 0.567pmol/mg, was demonstrated. Maximal 9-cis retinoic acid (9cRA) specific binding to nuclear retinoid X receptors was achieved at 20°C, and the optimal incubation time for the 9cRA-RXR complex formation was 120min. From a number of endocrine disruptors, tributyltins and triphenyltins are known as RXR ligands. Our data confirmed the property of tributyltin chloride or triphenyltin chloride to bind to a high affinity and limited capacity RXR binding sites. Described optimal conditions for ligand binding to RXR molecules enabled us to calculate maximal binding capacity (Bmax) and affinity (Ka) values. This study provides an original RXR radioligand binding assay that can be employed for investigation of novel RXR ligands that comprise both drugs and endocrine disruptors.

Pharmacological evaluation of the mechanisms involved in increased adiposity in zebrafish triggered by the environmental contaminant tributyltin.

One proposed contributing factor to the rise in overweight and obesity is exposure to endocrine disrupting chemicals. Tributyltin chloride (TBT), an organotin, induces adipogenesis in cell culture models and may increases adipose mass in vivo in vertebrate model organisms. It has been hypothesized that TBT acts via the peroxisome proliferator activated receptor (PPAR)γ-dependent pathway. However, the mechanisms involved in the effects of TBT exposure on in vivo adipose tissue metabolism remain unexplored. Semitransparent zebrafish larvae, with their well-developed white adipose tissue, offer a unique opportunity for studying the effects of toxicant chemicals and pharmaceuticals on adipocyte biology and whole-organism adiposity in a vertebrate model. Within hours, zebrafish larvae, treated at environmentally-relevant nanomolar concentrations of TBT, exhibited a remarkable increase in adiposity linked to adipocyte hypertrophy. Under the experimental conditions used, we also demonstrated that zebrafish larvae adipose tissue proved to be highly responsive to selected human nuclear receptor agonists and antagonists. Retinoid X receptor (RXR) homodimers and RXR/liver X receptor heterodimers were suggested to be in vivo effectors of the obesogenic effect of TBT on zebrafish white adipose tissue. RXR/PPARγ heterodimers may be recruited to modulate adiposity in zebrafish but were not a necessary requirement for the short term in vivo TBT obesogenic effect. Together, the present results suggest that TBT may induce the promotion of triacylglycerol storage in adipocytes via RXR-dependent pathways without necessary using PPAR isoforms.

Synergistic activation of human pregnane X receptor by binary cocktails of pharmaceutical and environmental compounds.

Humans are chronically exposed to multiple exogenous substances, including environmental pollutants, drugs and dietary components. Many of these compounds are suspected to impact human health, and their combination in complex mixtures could exacerbate their harmful effects. Here we demonstrate that a pharmaceutical oestrogen and a persistent organochlorine pesticide, both exhibiting low efficacy when studied separately, cooperatively bind to the pregnane X receptor, leading to synergistic activation. Biophysical analysis shows that each ligand enhances the binding affinity of the other, so the binary mixture induces a substantial biological response at doses at which each chemical individually is inactive. High-resolution crystal structures reveal the structural basis for the observed cooperativity. Our results suggest that the formation of 'supramolecular ligands' within the ligand-binding pocket of nuclear receptors contributes to the synergistic toxic effect of chemical mixtures, which may have broad implications for the fields of endocrine disruption, toxicology and chemical risk assessment.

Mechanism of retinoid X receptor partial agonistic action of 1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1H-benzotriazole-5-carboxylic acid and structural development to increase potency.

We have reported that retinoid X receptor (RXR) partial agonist 1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1H-benzotriazole-5-carboxylic acid (CBt-PMN, 4a) shows a significant antidiabetes effect in the KK-A(y) type 2 diabetes model mice, with reduced side effects compared to RXR full agonists. To elucidate the mechanism of the RXR partial agonist activity of 4a, we synthesized derivatives of 4a, evaluated their RXR agonist activity, and performed structure-activity relationship analysis. Reporter gene assay revealed that though 6b, which possesses an amino group at the 2-position of 5-carboxybenzimidazole, showed RXR full-agonist activity, compounds 6d and 6e, which possess an oxygen atom and a sulfur atom at the corresponding position, respectively, showed weak RXR agonist activity. On the other hand, 6c, which has a trifluoromethyl group at the corresponding position, acts as an RXR partial agonist, having similar Emax (67 ± 2%) and lower EC50 (15 ± 0 nM) compared to those of 4a (Emax = 75 ± 4%, EC50 = 143 ± 2 nM). A fluorescence polarization assay of cofactor recruitment confirmed that fluorescein-labeled D22 coactivator peptide was less efficiently recruited to RXR by 4a and 6c than by LGD1069 (1), a known RXR full agonist. Electrostatic potential field calculations and computational docking studies suggested that full agonists show an electrostatic attraction, which stabilizes the holo structure and favors coactivator recruitment, between the side chain at the benzimidazole 2-position and the α-carbonyl oxygen of asparagine-306 in helix 4 (H4) of the RXR receptor. However, RXR partial agonists 4a and 6c lack this interaction. Like 4a, 6c showed a significant antidiabetes effect in KK-A(y) type 2 diabetes model mice with reduced levels of the side effects associated with RXR full agonists. These findings should aid the design of new RXR partial agonists as antitype 2 diabetes drug candidates.

Relaxant effect of all-trans-retinoic acid via NO-sGC-cGMP pathway and calcium-activated potassium channels in rat mesenteric artery.

Intraperitoneal injection of all-trans-retinoic acid (ATRA) results in a reduction of blood pressure in spontaneously hypertensive rats. However, the mechanisms involved in this effect are not clear. We hypothesized that ATRA may relax resistance arteries. In this study, we found that ATRA relaxed phenylephrine-preconstricted mesenteric arterial rings, which were abrogated by the removal of the endothelium. Pretreatment of endothelium-intact arterial rings with an inhibitor of endothelial nitric oxide (NO) synthase, N(G)-nitro-l-arginine methyl ester (l-NAME), or soluble guanylyl cyclase, 1H-[1,2,4]-oxadiazole-[4,3-α]-quinoxaline-1-one, reduced the vasorelaxant effect of ATRA. Incubation of mesenteric arterial rings with ATRA increased the production of NO and cGMP, which were blocked by N(G)-nitro-l-arginine methyl ester. The vasorelaxant effect of ATRA was markedly attenuated in the presence of an inhibitor of big conductance calcium-activated potassium channels (charybdotoxin), but not with an inhibitor of voltage-dependent potassium channel (4-aminopyridine) or ATP-sensitive potassium channel (glibenclamide). Activation of retinoic acid receptors (RARs) with CH55 or retinoic X receptors (RXRs) with LGD1069 induced the vasorelaxation of phenylephrine-preconstricted mesenteric arterial rings. The RAR (BMS493) and RXR (UVI3003) antagonists blocked the ATRA-induced vasorelaxation. The vasorelaxant effect ATRA is physiologically relevant because the intravenous infusion of ATRA decreased blood pressure in normotensive rats. We conclude that ATRA relaxes resistance vessels via both RARs and RXRs receptors that are mediated by the endothelium-dependent NO-cGMP pathway, which may participate in the control of blood pressure.

Retinoic acid mediates the expression of glutamate transporter-1 in rat astrocytes through genomic RXR action and non-genomic protein kinase C signaling pathway.

Astrocytic glutamate transporter-1 (GLT-1) is responsible for 90% of forebrain glutamate uptake in the adult CNS. Retinoic acid (RA) is a potent regulator of neural cell differentiation and neuronal maturation in the developing CNS through activation of RA receptors/retinoic X receptors (RXRs) or non-genomic mechanisms. Although rat GLT-1 contains several RXR binding regions, RA-triggered RXR mechanisms regulating GLT-1 expression remain unknown. RA applied at submicromolar concentrations for 24 h significantly reduced GLT-1 mRNA and membrane levels in astrocytes and dibutyryl cAMP (dbcAMP)-primed astrocytes. An RXR agonist reduced astrocytic GLT-1 mRNA expression, whereas an RXR antagonist blocked the effects of RA on the reduction of astrocytic GLT-1 mRNA expression. Electrophoresis motility shift assay indicated that RA-treatment increased astrocytic RXR-DNA binding activity. RA-induced reduction in GLT-1 mRNA expression was also observed in dbcAMP-primed astrocytes. Through lentivirus-mediated astrocytic over-expression of rat GLT-1, levels of GLT-1 in the processes of dbcAMP-treated astrocytes were attenuated by exposure to RA. The protein kinase C inhibitor, Bis I, restored GLT-1 distribution in the processes of RA-treated dbcAMP-primed astrocytes. These results suggest that RA reduces astrocytic GLT-1 levels through both RXR-mediated inhibition at the transcriptional level and triggering activation of protein kinase C which reduces cell surface GLT-1 levels.

Cocaine decreases expression of neurogranin via alterations in thyroid receptor/retinoid X receptor signaling.

Mounting evidence suggests a potential link between cocaine abuse, disruptions in hypothalamic-pituitary-thyroid axis signaling, and neuroplasticity, but molecular mechanisms remain unknown. Neurogranin (Ng) is a gene containing a thyroid hormone-responsive element within its first intron that is involved in synaptic plasticity. Transcriptional activation requires heterodimerization of thyroid hormone receptor (TR) and retinoid X receptor (RXR) bound by their respective ligands, tri-iodothryonine and 9-cis-retinoic acid (9-cis-RA), and subsequent binding of this complex to the thyroid hormone-responsive element of the Ng gene. In this study, the effects of chronic cocaine abuse on Ng expression in euthyroid and hypothyroid mice were assessed. In cocaine-treated mice, decreased Ng expression was observed in the absence of changes in levels of thyroid hormones or other hypothalamic-pituitary-thyroid signaling factors. Therefore, we hypothesized that cocaine decreases Ng expression via alterations in 9-cis-RA availability and TR/RXR signaling. In support of this hypothesis, RXR-γ was significantly decreased in brains of cocaine-treated mice while CYP26A1, the main enzyme responsible for neuronal RA degradation, was significantly increased. Results from this study provide the first evidence for a direct effect of cocaine abuse on TR/RXR signaling, RA metabolism, and transcriptional regulation of Ng, a gene essential for adult neuroplasticity.

Diphenylamine-based retinoid antagonists: regulation of RAR and RXR function depending on the N-substituent.

Based upon the structure-activity relationships of diphenylamine derivatives with retinoid synergistic activity (RXR agonists), novel diphenylamine derivatives with a long alkyl chain (9a and 9b) or a benzyl group (10a-f) as the N-substituent were designed and synthesized. All the synthesized compounds dose-dependently inhibited HL-60 cell differentiation induced by 3.3×10(-10)M Am80. Among them, compound 10f showed the most potent inhibitory activity, and the mechanism was shown, by means of transactivation assay for RARs and RXRs, to involve antagonism against RARs. The N-substituent of the diphenylamine skeleton plays an important role in determining the receptor selectivity for RARs or RXRs, as well as the agonist or antagonist nature of the activity.

Chemoprevention of hepatocellular carcinoma by acyclic retinoid.

The prognosis for patients with hepatocellular carcinoma (HCC) is poor and effective prevention strategies are urgently required. Here, we review abnormalities in the expression and function of retinoids and their receptors, and how they play a critical role in the development of HCC. In particular, a malfunction of RXRalpha due to phosphorylation by Ras-MAPK signaling pathway is profoundly associated with liver carcinogenesis and thus may be a promising target for HCC chemoprevention. Acyclic retinoid (ACR), a synthetic retinoid, inhibits Ras-MAPK activation and RXRalpha phosphorylation, thereby suppressing growth in HCC-derived cells. In clinical trials, ACR has been shown to improve patient survival by preventing viral HCC development, a possible manifestation of the concept of "clonal deletion" therapy. "Combination chemoprevention" with ACR as the key drug has great potential to become an effective strategy for the prevention of liver carcinogenesis. In summary, both basic and clinical research strongly suggest that ACR plays a critical role in preventing the development of HCC and that "clonal deletion" therapy is one of the most practical approaches for this purpose.

[Retinoids: mechanisms of action]. / Rétinoïdes: mécanismes d'action.

Retinoids, vitamin A derivatives, are natural or synthetic molecules with pleiotropic effects, which regulate cell differentiation, proliferation and apoptosis. In target cell, the active natural metabolites retinoic acid (RA) and 9-cis-retinoic acid are synthetized from retinol by a two-step process with intermediate metabolite retinaldehyde. In 1987, the identification of the nuclear retinoic acid receptors that belong to the superfamily of nuclear receptors led to a significant progress in the comprehension of the mechanism of action of retinoids. There are two families of Retinoid Nuclear Receptors (RNR), the RA receptors (RAR), which natural ligand is RA, and the Retinoid X Receptors (RXR), which natural ligand is 9-cis-retinoic acid. Among synthetic retinoids, isotretinoin, acitretin, tazarotene and adapalene are ligands of the RAR, bexarotene is the first rexinoid (ligand of the RXR), alitretinoin the first panagonist (RAR+ RXR). For each family, there are 3 isotypes (α, ß, γ), and for each isotype several isoforms. Each NRR is composed of 6 regions (A-F). 3 regions are of importance: the A/B region has a ligand-independent transcriptional activation function, the C region harbors the DNA binding domain, the E region harbors the ligand binding domain. To regulate the expression of target genes, NRR have to dimerize. RXR are obligatory in dimers (heterodimers RAR-RXR, homodimers RXR-RXR). Dimers binds specific sequences of DNA, present in the promoters of target genes. When the ligand, natural or synthetic, bind to RNR, coactivators are recruited and transcription factors are activated. In target cell, retinoids not utilized are degradated in polar metabolites by enzymes of cytochrome P450.