Retinoid
Retinoids are a class of chemical compounds consisting of natural and synthetic molecules derived from vitamin A (retinol) or exhibiting structural and functional similarities to it, characterized by a polyene chain with four isoprene units in a head-to-tail arrangement and typically featuring a β-ionone ring.[1] These compounds bind to nuclear receptors such as retinoic acid receptors (RARs) and retinoid X receptors (RXRs) to modulate gene transcription, thereby regulating essential biological processes including cell proliferation, differentiation, apoptosis, embryogenesis, vision, reproduction, growth, and immune function.[1] Retinoids are vital for the development and maintenance of multiple organ systems, such as the nervous system, heart, kidneys, eyes, and limbs, where disruptions in their signaling pathways can lead to congenital defects or diseases like acute promyelocytic leukemia (APL), metabolic disorders, and skin conditions.[2] Retinoids are classified into four generations based on their chemical evolution and receptor selectivity: first-generation compounds like tretinoin (all-trans-retinoic acid) and isotretinoin (13-cis-retinoic acid), which are non-aromatic and broadly active; second-generation aromatic analogs such as etretinate; third-generation highly selective synthetic retinoids including adapalene, tazarotene, and bexarotene; and fourth-generation agents like seletinoid G, designed for minimal irritation and targeted RAR-γ binding.[3] Biologically, they exert effects through canonical genomic pathways involving RAR/RXR heterodimers that influence over 500 genes, as well as non-genomic mechanisms like rapid signaling and protein retinoylation, which contribute to homeostasis and repair processes.[2] In dermatology, retinoids are cornerstone therapies for acne vulgaris (e.g., isotretinoin achieving up to 87.6% remission rates at 0.5–1.0 mg/kg/day), psoriasis (e.g., acitretin), photoaging (e.g., tretinoin 0.05% cream reducing wrinkles and hyperpigmentation after 6–12 months), and pigmentation disorders by promoting epidermal turnover, collagen synthesis, and inhibition of matrix metalloproteinases (MMPs).[4][3] Beyond skin applications, retinoids have significant roles in oncology, with all-trans-retinoic acid (ATRA) inducing differentiation in APL by targeting the PML-RARα fusion protein, often combined with arsenic trioxide for cure rates exceeding 80%.[3] They also show promise in treating cutaneous T-cell lymphomas (e.g., bexarotene yielding 44% response rates), rosacea, ichthyosis, and preventing oral carcinogenesis, while ongoing research explores repurposing for autoimmune diseases and neurodegeneration due to their established safety profiles and anti-inflammatory properties.[3] Despite efficacy, common adverse effects include skin irritation (erythema, peeling), teratogenicity requiring strict contraception, and hypervitaminosis A risks, prompting development of less irritating formulations like nanoparticles or selective analogs.[4]Overview and Definition
Definition
Retinoids are a class of natural and synthetic compounds that are structurally and functionally related to vitamin A (retinol), typically featuring a β-ionone ring and a polyene chain consisting of four isoprene units, encompassing retinol itself, retinal (also known as retinaldehyde), retinoic acid, and various derivatives thereof.[5][1] These substances are structurally related to vitamin A and exhibit similar biological activities, including roles in cellular processes such as growth and differentiation.[6] Functionally, retinoids are defined as compounds that bind to and activate specific nuclear receptors, namely retinoic acid receptors (RARs) and retinoid X receptors (RXRs), thereby modulating gene expression through nuclear signaling pathways.[7] This receptor-mediated mechanism distinguishes retinoids as active signaling molecules in physiological regulation.[8] Unlike carotenoids, which are plant-derived pigments, retinoids represent the bioactive forms of vitamin A that arise from the metabolic conversion of provitamin A carotenoids, such as beta-carotene.[9] The term "retinoid" was coined in the mid-1970s by Michael B. Sporn and colleagues to broadly describe both naturally occurring vitamin A compounds and their synthetic counterparts with comparable structures and functions.[10]Nomenclature
Retinoids are named systematically according to IUPAC recommendations, using stereoparents such as retinal (an unsaturated aldehyde derived from vitamin A), retinol, and retinoic acid, which imply the all-trans configuration unless specified otherwise.[11] The recommended name for the all-trans form of this aldehyde is retinal, previously known as retinene or vitamin A aldehyde, while alternatives like retinaldehyde are used in nutritional contexts.[11] The carbon numbering system for retinoids follows conventions from carotenoid nomenclature, starting from the beta-ionone ring at one end and proceeding along the polyene chain to the terminal functional group. The beta-ionone ring comprises carbons 1 through 6, with the conjugated chain extending from carbon 7 to carbon 15 at the functional terminus; for example, in retinal, carbon 15 bears the aldehyde group.[11] This numbering facilitates identification of double bond positions, such as the critical 11-12 double bond.[12] Isomerism in retinoids primarily involves cis-trans configurations around the conjugated double bonds, with the all-trans form serving as the default stereoparent in nomenclature. The 11-cis isomer is particularly significant biologically, as 11-cis-retinal binds covalently to opsin in rod cells to form rhodopsin, the light-sensitive pigment in vision; upon photon absorption, it isomerizes to all-trans-retinal, initiating the phototransduction cascade.[13] Cis isomers are denoted by position, such as 11-cis-retinal or using E/Z notation for precision, like (11Z)-retinal.[11] Common names for retinoids often reflect their functional groups and historical association with vitamin A, contrasting with systematic IUPAC names that describe the full structure. For instance, retinol is commonly called vitamin A alcohol, retinal is the aldehyde form, and retinoic acid is the carboxylic acid derivative, whereas systematic names like (2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraen-1-ol apply to all-trans-retinol.[11] These common terms remain widely used in biochemical and medical literature for clarity.[14]Chemical Properties
Molecular Structure
Retinoids share a common molecular scaffold composed of four isoprenoid units linked head-to-tail, resulting in a β-ionone ring connected to a linear polyene chain featuring four conjugated double bonds and a polar functional group at the terminus.[11] This architecture, with the β-ionone ring providing a hydrophobic cyclohexene moiety substituted with three methyl groups, underpins the biological activity of retinoids across natural and synthetic variants.[14][12] The polyene chain consists of a nine-carbon backbone with alternating single and double bonds, forming an extended conjugated π-system that delocalizes electrons and imparts key optical properties.[12] This conjugation enables strong absorption of ultraviolet-visible light at approximately 325 nm, responsible for the yellow-orange coloration observed in retinoids.[14][12] In the prototypical retinoid retinol (vitamin A alcohol), the molecular formula is C_{20}H_{30}O, and the all-trans configuration features double bonds at positions 2E, 4E, 6E, and 8E along the chain, ensuring maximal planarity and conjugation with the ring's internal double bond.[14][11] The polar end group varies among retinoids, modulating their overall polarity and solubility. Retinol terminates in a hydroxyl (-OH) group, conferring lipophilicity suitable for membrane association; retinal features an aldehyde (-CHO), which is marginally more polar; and retinoic acid bears a carboxylic acid (-COOH), enhancing hydrophilicity and aqueous solubility through potential ionization at physiological pH.[12][15] These structural differences in the end group influence transport, binding, and metabolic handling without altering the core conjugated framework.[12]Physical and Chemical Characteristics
Retinoids exhibit high lipophilicity primarily due to their extended polyene chain, which confers hydrophobic character; for example, retinol has a calculated octanol-water partition coefficient (logP) of 5.68.[14] This property facilitates their incorporation into lipid membranes and transport via lipoproteins but limits their solubility in aqueous environments.[12] These compounds are inherently unstable, showing sensitivity to light, which induces photoisomerization from the all-trans to cis forms (e.g., 11-cis-retinal from all-trans-retinal with quantum yields of 0.1–0.7 depending on solvent), oxygen, which promotes oxidation and formation of reactive byproducts, and heat above 60°C, leading to degradation and discoloration.[12][16] To mitigate these issues, retinoids are typically stored under inert atmospheres (e.g., nitrogen or argon) at temperatures ≤ -20°C in amber containers or oil-based formulations to minimize exposure.[16] Solubility of retinoids is poor in water—for retinol, it is approximately 5 × 10^{-5} mg/mL (~0.05 mg/L)—but they dissolve readily in organic solvents such as ethanol, methanol, chloroform, ether, and lipids.[17] This amphiphilic profile, with a polar functional group (e.g., hydroxyl in retinol) and nonpolar chain, influences their formulation in pharmaceutical and cosmetic applications.[12] Spectral properties arise from the conjugated polyene system, enabling UV-Vis absorption; retinol shows a maximum at 325–328 nm in ethanol, while all-trans-retinoic acid absorbs at around 350 nm.[14][16] Retinoids also display intrinsic fluorescence, with retinol emitting yellow-green light under extreme UV irradiation, a trait exploited in analytical assays and imaging techniques.[14][12]Classification
Natural Retinoids
Natural retinoids encompass the biologically active forms of vitamin A that occur endogenously in living organisms, primarily including retinol, retinal, and retinoic acid. Retinol serves as the main storage and transport form, often esterified with fatty acids to form retinyl esters that are predominantly stored in the liver of vertebrates.[9] Retinal, an aldehyde derivative of retinol, functions as the key chromophore in visual phototransduction within the retina.[18] Retinoic acid, the oxidized form, acts as a critical signaling molecule that regulates gene expression during development and cellular differentiation.[19] In addition to these preformed retinoids, provitamin A carotenoids such as beta-carotene and alpha-carotene serve as dietary precursors that animals convert into active retinoids through enzymatic processes in the intestine and liver. Beta-carotene, the most abundant provitamin A carotenoid, is symmetrically cleaved by beta-carotene 15,15'-monooxygenase 1 (BCMO1) to yield two molecules of retinal, which can then be reduced to retinol.[20] Alpha-carotene undergoes central cleavage to produce one molecule of all-trans-retinal and one molecule of α-retinaldehyde, though with lower efficiency than beta-carotene.[21][18] These conversions provide a vital link between plant-derived pigments and animal retinoid pools, with efficiency varying by species and nutritional status.[22] Preformed retinoids like retinol and retinyl esters are predominantly found in animal-derived products, with the highest concentrations in organ meats such as liver, as well as in dairy products, eggs, and fish.[9] In contrast, provitamin A carotenoids occur almost exclusively in plant sources, including orange and green leafy vegetables like carrots, spinach, and sweet potatoes, where beta-carotene predominates.[23] This dichotomy reflects the biosynthetic capabilities of plants, which produce carotenoids via the mevalonate pathway, versus animals, which rely on dietary intake for retinoid supply.[18] Retinoids exhibit remarkable evolutionary conservation across all vertebrates, where they underpin essential physiological functions such as vision, embryonic development, and epithelial maintenance.[24] The core retinoid signaling pathway, involving retinoic acid receptors and binding proteins like interphotoreceptor retinoid-binding protein (IRBP), traces back to ancient gene duplications in early vertebrate lineages, ensuring its indispensability in diverse species from fish to mammals.[25] This conservation underscores the fundamental role of retinoids in vertebrate biology, with disruptions leading to severe developmental defects.[26]Synthetic Retinoids
Synthetic retinoids are man-made compounds designed to mimic the structure and function of natural retinoids, primarily to enhance therapeutic efficacy while minimizing side effects such as irritation and photodegradation. While many synthetic retinoids feature novel structures not found in nature, some first-generation compounds like tretinoin correspond to naturally occurring retinoic acid, and others like isotretinoin are stereoisomers occurring only in trace amounts biologically. These molecules are engineered through chemical modifications to the polyene chain or terminal rings, aiming for greater stability and targeted binding to retinoic acid receptors (RARs).[27][4] Unlike purely natural retinoids, synthetic variants are classified into generations based on structural evolution and receptor selectivity.[28] The first generation of synthetic retinoids, developed in the 1970s, includes pharmaceutical preparations of retinoic acid such as tretinoin (all-trans-retinoic acid) and synthetic isomers like isotretinoin (13-cis-retinoic acid).[4] Tretinoin, approved for acne and photoaging, binds non-selectively to all RAR subtypes but suffers from instability due to its polyene chain, leading to rapid degradation upon light exposure.[27] Isotretinoin, used orally for severe acne, features a cis configuration at the 13-position to improve bioavailability and reduce some toxicities associated with the all-trans form.[28] Second-generation synthetic retinoids introduced aromatic rings to replace the unstable polyene chain, enhancing chemical stability and lipophilicity.[4] Etretinate, an example from this era, is a monoaromatic ester derivative designed for psoriasis treatment, though its long half-life led to accumulation concerns; it was succeeded by acitretin's free-acid form for better elimination.[28] This shift from polyene to aromatic structures marked a key advancement, reducing photoinstability while maintaining retinoid activity.[27] Third-generation synthetic retinoids further refined aromatic designs for receptor selectivity, incorporating naphthoic acid or polyaromatic moieties.[4] Adapalene, a naphthoic acid derivative, selectively targets RAR-β and RAR-γ, offering improved tolerability for acne therapy compared to first-generation compounds.[27] Tazarotene, another polyaromatic example, also prefers RAR-β/γ and is used for acne and psoriasis.[27] Bexarotene, a distinct third-generation agent, acts as a selective agonist for retinoid X receptors (RXRs), employed in cutaneous T-cell lymphoma treatment due to its unique heterodimer modulation.[29] The fourth generation emphasizes hyper-selectivity, with trifarotene (approved in 2019) designed as a potent RAR-γ agonist through precise modifications to the aromatic scaffold, achieving high efficacy for acne on the face and trunk with minimal off-target effects.[27] Overall, these generational advancements prioritize modifications like cyclization of the polyene chain into stable rings and subtype-specific binding to optimize pharmacokinetics and reduce systemic toxicity.[28]Biological Roles
Role in Vision
Retinoids play a central role in vertebrate vision through their involvement in phototransduction, the process by which light is converted into electrical signals in the retina. The key retinoid, 11-cis-retinal—a derivative of vitamin A—binds covalently to opsin proteins in rod and cone photoreceptor cells to form visual pigments, such as rhodopsin in rods and iodopsins in cones. This binding occurs via a protonated Schiff base linkage, stabilizing the pigment in a conformation sensitive to light absorption.[30] Upon absorption of a photon, 11-cis-retinal undergoes a rapid cis-to-trans isomerization, converting to all-trans-retinal and initiating a conformational change in the opsin protein. This activated state, known as metarhodopsin II, triggers a G-protein-coupled signaling cascade involving transducin, phosphodiesterase, and cyclic GMP-gated channels, leading to hyperpolarization of the photoreceptor and signal transmission to bipolar cells. The isomerization step is highly efficient, with a quantum yield of approximately 0.65, meaning that about 65% of absorbed photons successfully induce the conformational shift, contributing to the remarkable sensitivity of rods that can detect single photons.[31][32] Following phototransduction, all-trans-retinal is released from the opsin and reduced to all-trans-retinol in the photoreceptor outer segments by enzymes such as retinol dehydrogenase 8 (RDH8). This all-trans-retinol is then transported to the adjacent retinal pigment epithelium (RPE), where it is re-esterified by lecithin:retinol acyltransferase (LRAT) into all-trans-retinyl esters. These esters serve as substrates for RPE65, an isomerohydrolase enzyme that catalyzes the conversion back to 11-cis-retinol, which is subsequently oxidized to 11-cis-retinal by 11-cis-retinol dehydrogenase 5 (RDH5). The regenerated 11-cis-retinal is shuttled back to the photoreceptors via the interphotoreceptor retinoid-binding protein (IRBP), completing the visual cycle and enabling continuous pigment renewal essential for sustained vision.[30][33] Disruptions in retinoid availability or the visual cycle impair rhodopsin formation and regeneration, leading to conditions such as night blindness (nyctalopia). In vitamin A deficiency, insufficient 11-cis-retinal limits visual pigment synthesis, particularly in rods, resulting in delayed dark adaptation and reduced low-light sensitivity. Similarly, mutations in genes encoding visual cycle enzymes, like RDH5, cause fundus albipunctatus, a form of stationary night blindness characterized by prolonged recovery after light exposure due to slowed 11-cis-retinal production.[34][35]Role in Development and Differentiation
Retinoids, particularly retinoic acid (RA), play a pivotal role in embryonic development by acting as morphogens that establish signaling gradients essential for patterning the anterior-posterior (A-P) axis. In vertebrate embryos, RA gradients formed through localized synthesis and degradation influence the spatiotemporal expression of developmental genes, thereby guiding tissue specification and organogenesis.[36] RA regulates Hox gene clusters, which are critical transcription factors organized in collinear domains along the A-P axis. As a morphogen, RA induces the expression of 3'-Hox genes (such as Hoxa1, Hoxb1, and Hoxd1) in a concentration-dependent manner, promoting hindbrain segmentation into rhombomeres and specifying cranial neural crest cell fates. This regulation ensures proper positioning of structures like the branchial arches and spinal cord, with disruptions altering Hox expression patterns and leading to axial defects.[37][38][39] The core signaling mechanism involves RA binding to retinoic acid receptors (RARs), which heterodimerize with retinoid X receptors (RXRs) to form RA-RAR complexes. These complexes bind to retinoic acid response elements (RAREs) in the promoter regions of target genes, recruiting coactivators to initiate transcription of developmental regulators such as Hox genes and those involved in cell fate determination. In the absence of RA, RAR-RXR binds RAREs with corepressors to maintain gene repression, highlighting RA's role in switching from repression to activation during differentiation.[36][37][38] In stem cell biology, RA promotes lineage commitment by directing pluripotent cells toward specific fates. For neuronal differentiation, RA treatment of human embryonic stem cells or neural progenitors enhances the expression of neurogenic markers like Nestin and β-III tubulin, facilitating the transition from progenitors to mature neurons. Similarly, in hematopoietic differentiation, RA signaling from human pluripotent stem cells boosts the generation of primitive blood progenitors while suppressing non-hematopoietic lineages, underscoring its instructive role in multilineage specification.[40][41][42] Excess RA exhibits teratogenic effects by perturbing these developmental gradients, particularly in limb and craniofacial regions. High RA levels inhibit Cyp26 enzymes, which normally degrade RA to maintain low concentrations in anterior domains, resulting in ectopic signaling that disrupts proximodistal limb patterning and causes malformations like phocomelia or craniosynostosis. In mouse models, Cyp26b1 deficiency mimics excess RA phenotypes, confirming that precise RA clearance is vital for preventing anterior shifts in Hox expression and ensuring normal skeletogenesis.[43][44][45]Role in Immunity and Reproduction
Retinoic acid (RA), the active metabolite of vitamin A, plays a pivotal role in modulating immune responses, particularly in promoting mucosal immunity through its actions on gut-associated lymphoid tissue (GALT). In the intestinal environment, RA produced by CD103+ dendritic cells induces the expression of gut-homing receptors such as α4β7 integrin and CCR9 on T and B lymphocytes, facilitating their migration to mucosal sites and enhancing IgA secretion by B cells, which is crucial for barrier defense against pathogens.[46] This process supports immune tolerance and homeostasis in the gut, where RA also promotes the differentiation of Foxp3+ regulatory T cells (Tregs) in conjunction with transforming growth factor-β (TGF-β), thereby balancing pro- and anti-inflammatory responses.[46] Additionally, RA exerts anti-inflammatory effects by suppressing Th17 cell differentiation under steady-state conditions and inhibiting proinflammatory cytokine production, such as TNF-α and IL-12, in macrophages via downregulation of NF-κB signaling.[46] In the context of reproduction, retinoids are indispensable for gametogenesis in both males and females. Retinol, transported to the testes, is converted to RA, which drives spermatogonial differentiation and the initiation of meiosis by upregulating Stra8 expression in spermatogonia, synchronizing the seminiferous epithelium cycle and ensuring continuous sperm production.[47] Vitamin A deficiency disrupts this process, leading to arrest at the undifferentiated spermatogonial stage and subsequent infertility in mammals, as demonstrated in rodent models where RA supplementation restores spermatogenesis.[47] Similarly, in females, RA is essential for ovarian follicle development; it promotes oocyte maturation and granulosa cell function postnatally, enhancing follicle growth and preventing apoptosis through pathways involving follicle-stimulating hormone (FSH) synergy.[47] Deficiency results in impaired meiosis and oocyte arrest, contributing to infertility, with evidence from mammalian studies showing RA's necessity for germ cell survival and progression.[47] Retinoids also contribute to skin barrier integrity as part of innate immunity, maintaining epithelial cohesion and antimicrobial defenses. RA regulates keratinocyte differentiation and proliferation, preserving the structural barrier against environmental insults, while vitamin A deficiency compromises this integrity, increasing infection susceptibility.[48] Furthermore, retinoids induce the production of antimicrobial peptides, such as resistin-like molecule α (RELMα) in keratinocytes and sebocytes, which disrupts bacterial membranes of pathogens like Staphylococcus aureus and Pseudomonas aeruginosa; this expression is RAR-dependent and enhanced by retinol, shaping the skin microbiota and bolstering resistance to invasion.[48] Systemically, retinoids influence metabolic and skeletal homeostasis through retinoid X receptor (RXR) heterodimers. In adipogenesis, RA inhibits preadipocyte differentiation by activating RXR heterodimers with peroxisome proliferator-activated receptor γ (PPARγ), suppressing key transcription factors like C/EBPβ and promoting anti-adipogenic genes such as PREF-1 and SOX9, thereby limiting fat accumulation and mitigating obesity risk.[49] In bone remodeling, RXR heterodimers with retinoic acid receptors (RARs) regulate osteoclastogenesis; RA stimulates RANKL expression via RARα/RXR, enhancing bone resorption while inhibiting osteoblast mineralization, with excessive levels linked to cortical bone loss in preclinical models.[50] These actions underscore retinoids' broader role in integrating immune, reproductive, and metabolic physiology.Sources and Metabolism
Dietary Sources
Retinoids, essential for various physiological functions, are obtained primarily through dietary sources in the form of preformed vitamin A (retinol and retinyl esters) or provitamin A carotenoids like beta-carotene. The nutritional content of these compounds is standardized using retinol activity equivalents (RAE), where 1 μg RAE equals 1 μg retinol or 12 μg dietary beta-carotene, accounting for differences in bioavailability and conversion efficiency.[9] Animal-derived foods provide preformed retinoids with high bioavailability, typically exceeding 80%, making them efficient sources for meeting nutritional needs. Liver is among the richest, with beef liver containing approximately 6,500 μg RAE per 100 g, while eggs offer about 150 μg RAE per 100 g and dairy products like whole milk provide around 50 μg RAE per 100 g, often higher in fortified varieties.[51][9] Plant-based sources supply provitamin A carotenoids, which the body converts to active retinoids, though absorption and conversion rates are lower, ranging from 10% to 30% depending on food matrix and dietary fat intake. Carrots contain about 8,000 μg beta-carotene per 100 g, and sweet potatoes provide around 8,300 μg beta-carotene per 100 g in baked form, serving as key contributors in vegetarian diets.[52][53] The recommended dietary allowance (RDA) for vitamin A is 900 μg RAE per day for adult men and 700 μg RAE per day for adult women, with higher needs during pregnancy and lactation. Deficiency remains a significant public health issue in developing countries, affecting approximately 190 million preschool-age children and increasing risks of blindness, infections, and mortality, particularly in regions with limited access to diverse foods.[9][54]| Food Source | Type | Approximate Content per 100 g | Bioavailability Notes |
|---|---|---|---|
| Beef liver (cooked) | Animal (preformed) | 6,500 μg RAE | >80% absorption |
| Eggs (whole, raw) | Animal (preformed) | 150 μg RAE | >80% absorption |
| Whole milk | Animal (preformed) | 50 μg RAE | >80% absorption; fortified options higher |
| Carrots (raw) | Plant (provitamin A) | 8,000 μg beta-carotene | 10-30% conversion to retinol |
| Sweet potatoes (baked) | Plant (provitamin A) | 8,300 μg beta-carotene | 10-30% conversion to retinol |