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Therapeutics Initiative (University of British Columbia)
Ben-Eltriki, Mohamed
Gayle, Erysa J.
Paras, Jhoanne M.
Nyame-Addo, Louisa
Chhabra, Manik
Deb, Subrata
Vitamin D is a promising anticancer agent for the prevention and treatment of several cancers, including melanoma. Low 25-hydroxyvitamin D levels, a routinely used marker for vitamin D, have been suggested as one of the factors in the development and progression of melanoma. The parent vitamin D needs activation by cytochrome P450 (CYP) enzymes to exert its actions via the vitamin D receptor (VDR). This review discusses the role of vitamin D in melanoma and how CYP-mediated metabolism can potentially affect the actions of vitamin D. Through interacting with the retinoid X receptor, VDR signaling leads to anti-inflammatory, antioxidative, and anticancer actions. Calcitriol, the dihydroxylated form of vitamin D₃, is the most active and potent ligand of VDR. CYP27A1, CYP27B1, and CYP2R1 are involved in the activation of vitamin D, whereas CYP24A1 and CYP3A4 are responsible for the degradation of the active vitamin D. CYP24A1, the primary catabolic enzyme of calcitriol, is overexpressed in melanoma tissues and cells. Several drug classes and natural health products can modulate vitamin D-related CYP enzymes and eventually cause lower levels of vitamin D and its active metabolites in tissues. Although the role of vitamin D in the development of melanoma is yet to be fully elucidated, it has been proposed that melanoma prevention may be significantly aided by increased vitamin D signaling. Furthermore, selective targeting of the catabolic enzymes responsible for vitamin D degradation could be a plausible strategy in melanoma therapy. Vitamin D signaling can be improved by utilizing dietary supplements or by modulating CYP metabolism. A positive association exists between the intake of vitamin D supplements and improved prognosis for melanoma patients. Further investigation is required to determine the function of vitamin D supplementation and specific enzyme targeting in the prevention of melanoma.
Citation: Ben-Eltriki, M.; Gayle, E.J.;Paras, J.M.; Nyame-Addo, L.;Chhabra, M.; Deb, S. Vitamin D inMelanoma: Potential Role ofCytochrome P450 Enzymes. Life 2024,14, 510. https://doi.org/10.3390/life14040510Academic Editor: Zhiwei HuReceived: 25 February 2024Revised: 1 April 2024Accepted: 9 April 2024Published: 15 April 2024Copyright: © 2024 by the authors.Licensee MDPI, Basel, Switzerland.This article is an open access articledistributed under the terms andconditions of the Creative CommonsAttribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).lifeReviewVitamin D in Melanoma: Potential Role of CytochromeP450 EnzymesMohamed Ben-Eltriki 1,2,* , Erysa J. Gayle 3 , Jhoanne M. Paras 3, Louisa Nyame-Addo 3, Manik Chhabra 1and Subrata Deb 4,*1 Clinical Pharmacology Lab, Department of Pharmacology and Therapeutics, Max Rady College of Medicine,University of Manitoba, Winnipeg, MB R3E 0T6, Canada2 Cochrane Hypertension Review Group, Therapeutic Initiative, University of British Columbia,Vancouver, BC V6T 1Z3, Canada3 College of Biomedical Sciences, Larkin University, Miami, FL 33169, USA; egayle@myularkin.org (E.J.G.);jparas@myularkin.org (J.M.P.)4 Department of Pharmaceutical Sciences, College of Pharmacy, Larkin University, Miami, FL 33169, USA* Correspondence: mbeneltriki@alumni.ubc.ca (M.B.-E.); sdeb@alumni.ubc.ca (S.D.);Tel.: +1-780-695-6692 (M.B.-E.); +1-224-310-7870 (S.D.)Abstract: Vitamin D is a promising anticancer agent for the prevention and treatment of severalcancers, including melanoma. Low 25-hydroxyvitamin D levels, a routinely used marker for vitaminD, have been suggested as one of the factors in the development and progression of melanoma.The parent vitamin D needs activation by cytochrome P450 (CYP) enzymes to exert its actions viathe vitamin D receptor (VDR). This review discusses the role of vitamin D in melanoma and howCYP-mediated metabolism can potentially affect the actions of vitamin D. Through interacting withthe retinoid X receptor, VDR signaling leads to anti-inflammatory, antioxidative, and anticanceractions. Calcitriol, the dihydroxylated form of vitamin D3, is the most active and potent ligandof VDR. CYP27A1, CYP27B1, and CYP2R1 are involved in the activation of vitamin D, whereasCYP24A1 and CYP3A4 are responsible for the degradation of the active vitamin D. CYP24A1, theprimary catabolic enzyme of calcitriol, is overexpressed in melanoma tissues and cells. Several drugclasses and natural health products can modulate vitamin D-related CYP enzymes and eventuallycause lower levels of vitamin D and its active metabolites in tissues. Although the role of vitamin Din the development of melanoma is yet to be fully elucidated, it has been proposed that melanomaprevention may be significantly aided by increased vitamin D signaling. Furthermore, selectivetargeting of the catabolic enzymes responsible for vitamin D degradation could be a plausible strategyin melanoma therapy. Vitamin D signaling can be improved by utilizing dietary supplements orby modulating CYP metabolism. A positive association exists between the intake of vitamin Dsupplements and improved prognosis for melanoma patients. Further investigation is required todetermine the function of vitamin D supplementation and specific enzyme targeting in the preventionof melanoma.Keywords: vitamin D; melanoma; cytochrome P450; therapeutic prevention; dermal expression;anticancer effects; supplementation1. BackgroundMelanoma is the fifth most frequently diagnosed malignancy type in both gendersin the United States and is considered one of the most fatal cancer types, especially aftermetastasis [1,2]. The incidence rates are much higher in other parts of the world, such asEurope and Australia. Melanoma accounts for only 2.3% of skin cancer cases; however, it isresponsible for 75% of skin cancer-related deaths, making it one of the most perilous typesof skin cancer [3]. With UV radiation exposure being the main environmental factor, familyhistory of melanoma, altered regulation of susceptibility genes, weight, and hair and skinLife 2024, 14, 510. https://doi.org/10.3390/life14040510 https://www.mdpi.com/journal/lifeLife 2024, 14, 510 2 of 25color are among some of the risk factors that epidemiological studies have discovered [4–6].When it comes to skin cancer, people with darker skin types are twenty times less likely toget it than lighter-skinned people living at the same latitude [4]. The prognosis of melanomadrops drastically once it starts to metastasize [2]. Aside from genetic and environmental riskfactors, the expression and regulation of genes involved in the anticancer protective effectsof melanoma can be a crucial factor in the development and progression of melanoma [4].Vitamin D, a lipid-soluble vitamin, can be obtained from animals (vitamin D3 orcholecalciferol) or plants (vitamin D2 or ergocalciferol). Cholecalciferol, or vitamin D3,is formed in the skin from 7-dehydrocholesterol (7-DHC) through UV exposure and isthe natural form of vitamin D [7,8]. The synthesis of vitamin D can vary based on theseason and length of daytime sunlight, the time of day, weather, usage of sunscreen, andthe amount of melanin found in the skin [9]. Vitamin D can be obtained from dietarycomponents, including fatty fish (e.g., mackerel, salmon, and tuna), mushrooms, fishliver oils, egg yolks, red meat, and cheese [10–13]. The endogenous vitamin D3 andexogenous vitamin D2/D3 get absorbed via simple diffusion and intestinal membranecarrier proteins, and subsequently, vitamin D binding protein (DBP) and albumin transportvitamin D and its metabolites in the bloodstream to the target organs [14,15]. CytochromeP450 (CYP) enzymes are a superfamily of enzymes that are primarily responsible for thebreakdown of xenobiotics, including medications, environmental pollutants, and naturalhealth products [16,17]. However, CYP enzymes also catalyze reactions involved in thebiosynthesis or breakdown of endogenous compounds such as hormones and vitamins.Select CYP enzymes are critical in the anabolism and catabolism of vitamin D, whichundergoes CYP-mediated activation and inactivation reactions [18,19]. The physiologicalfunctions of vitamin D are carried out by its active metabolites through the activation of thevitamin D receptor (VDR). At the same time, CYP enzymes are involved in the breakdownof the active metabolites of vitamin D [20,21].The endocrine functions of vitamin D specifically control a wide range of autonomousbiological processes, such as bone metabolism and cell division and proliferation. There isincreased evidence of lower vitamin D levels and corresponding vulnerability to differenttypes of cancers like prostate, colon, and skin [22–24]. In light of this, the ingestion ofvitamin D3 supplementation has exponentially grown over the last decade or so. VitaminD and its active metabolites demonstrate antitumor properties by regulating cancer celldifferentiation, growth, and death in in vitro and preclinical animal models [25]. With skinas the primary site of physiological vitamin D synthesis and a location of VDR expression,vitamin D homeostasis will likely have a profound effect on the development, treatment,and progression of melanoma. Indeed, vitamin D and its derivatives have anticancereffects against melanoma and may play a critical role in the prevention and treatment ofmelanoma [26–29]. Interestingly, low vitamin D levels have been proposed as one of thefactors responsible for the development of melanoma. Similarly, combining vitamin D withsynthetic anticancer drugs has been related to better treatment outcomes for melanoma.Vitamin D is a promising anticancer agent. Researchers have studied its potentialanticancer actions in several cancers, including melanoma [7,26,30–35]. It is intriguing thatlow vitamin D is a potential cause of a cancer type that develops from excessive exposureto the sun, and it is well established that exposure to the sun facilitates vitamin D synthesis.This suggests that synthesis or ingestion of vitamin D is not the only factor determining itsphysiological levels, and different components of pharmacokinetics, especially metabolism,play a key role in vitamin D homeostasis. CYP enzymes are the primary driver of vitamin Dbioactivation and catabolism. The objective of this review is to understand the role of vita-min D in melanoma and evaluate the involvement of CYP enzymes in modulating vitaminD action. Since CYP enzyme levels and functions are commonly affected by xenobiotics,CYP-mediated vitamin D metabolism can influence vitamin D actions in melanoma.Life 2024, 14, 510 3 of 252. Literature Search StrategyThe literature search for this narrative review was carried out utilizing specific key-words across prominent electronic databases until 1 February 2024. Variations of keyterms, such as vitamin D, melanoma, deficiency, cytochrome P450, therapeutic prevention,dermal expression, metabolism, anticancer effects, vitamin D supplementation, and theircombinations were considered. PubMed, Medline, and Google Scholar databases weresearched. Original research articles in English were included, whereas conference abstractsand unpublished materials were excluded. Titles and abstracts were initially screened,followed by a full-text examination. The literature search and reconciliation of resourceswere independently carried out by two authors (S.D. and M.B.E.), with any discrepanciesresolved through consensus.3. Cytochrome P450-Mediated Vitamin D MetabolismVitamin D functions as a hormone on numerous extraskeletal sites and exhibits anintricate multistep metabolism [36]. The parent vitamin D that first enters the human bodyor is synthesized is inactive and must undergo CYP-mediated activation via hydroxylationreactions to become active. Multiple CYP enzymes, including CYP27A1, CYP27B1, CYP2R1,CYP2J2, CYP24A1, and CYP3A4, are involved in the biotransformation of vitamin D, whichare expressed in multiple organs, including the skin (Figure 1). Table 1 summarizes relevantinformation on the CYPs involved in vitamin D activation and inactivation reactions.The bioactivation of vitamin D3 is facilitated by 25- and 1α-hydroxylation reactions toform 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] or calcitriol, the most active and potentVDR ligand [15]. In contrast, the inactivation steps of 1α,25(OH)2D3 involve 24- and 23-hydroxylation [20,37]. The epidermis layer containing keratinocytes can locally produce theactive form of vitamin D and can also facilitate the inactivation of active vitamin D [38–40].However, the liver and kidney are the primary sites of activation and inactivation after DBPtransports the parent vitamin D to systemic organs [18,20,41]. The hepatic CYP enzymeshydroxylate vitamin D to produce 25-hydroxyvitamin D3 [25(OH)D3], which is the widelyaccepted clinical serum marker of vitamin D. Subsequently, DBP transports 25(OH)D3 to thekidneys for further hydroxylation to 1α,25(OH)2D3 [15]. CYP11A1 enzyme attacks the sidechains and D-ring of 7-DHC and vitamin D3 to produce atypical vitamin D derivatives [19].Table 1. Properties of cytochrome P450 enzymes relevant to vitamin D.CYP TissueLocalization SubstrateRole(Anabolism/Catabolism)TissueExpressionPolymorphic(Yes/No) Refs.CYP11A1 Mitochondria D3 Catabolism Brain, GI tract, Skin Yes [2,42,43]CYP24A1 MitochondriaCalcitriol25(OH)D31α,24,25(OH)3D31α,23,25(OH)3D3CatabolismHydroxylationKidney,Intestine, Skin Yes [15,37,44]CYP27A1 Mitochondria D31α(OH)D3Anabolism andCatabolismPharmacologicalHydroxylationLiver, Skin,Macrophage Yes [37,44–46]CYP27B1 Mitochondria 25(OH)D3Anabolism andCatabolismHydroxylationKidney, Skin Yes [15,37,44]CYP2R1 Microsomes D3PhysiologicalHydroxylation Liver, Skin Yes [37,46,47]CYP3A4 Microsomes CalcitriolD3Hydroxylation Liver, Intestine,Skin Yes [37,46]CYP2D25 Microsomes D3 Hydroxylation Liver, Kidney No [46]CYP2J2/3 Microsomes D3HydroxylationCatabolismLiver, Heart,Placenta, Brain Yes [36,46]Life 2024, 14, 510 4 of 25Life 2024, 14, x FOR PEER REVIEW 4 f Figure 1. Cytochrome P450 (CYP)-mediated metabolism (anabolism/catabolism) of vitamin D. Table 1. Properties of cytochrome P450 enzymes relevant to vitamin D. CYP Tissue Localiza-tion Substrate Role (Anabolism/Catabolism) Tissue Expression Polymorphic (Yes/No) Ref CYP11A1 Mitochondria D3 Catabolism Brain, GI tract, Skin Yes [2,42,43] CYP24A1 Mitochondria Calcitriol 25(OH)D3 1α,24,25(OH)3D3 1α,23,25(OH)3D3 Catabolism Hydroxylation Kidney, Intestine, Skin Yes [15,37,44] CYP27A1 Mitochondria D3 1α(OH)D3 Anabolism and Catabolism Pharma-cological Hydroxylation Liver, Skin, Macro-phage Yes [37,44–46] CYP27B1 Mitochondria 25(OH)D3 Anabolism and Catabolism Hydrox-ylation Kidney, Skin Yes [15,37,44] CYP2R1 Microsomes D3 Physiological Hydroxylation Liver, Skin Yes [37,46,47] CYP3A4 Microsomes Calcitriol D3 Hydroxylation Liver, Intestine, Skin Yes [37,46] CYP2D25 Microsomes D3 Hydroxylation Liver, Kidney No [46] CYP2J2/3 Microsomes D3 Hydroxylation Catabolism Liver, Heart, Placenta, Brain Yes [36,46] Calcitriol is the active and most potent form of vitamin D and is formed through two consecutive hydroxylation reactions. CYP27A1 is expressed in the liver, whereas CYP27B1 and CYP24A1 are primarily expressed in the kidneys. Similarly, for CYP2R1 and CYP3A4, the liver is the primary site of expression, along with their presence in dermal fibroblast [48]. Mitochondrial CYP27A1 is the major enzyme responsible for the C-25 hydroxylation Figure 1. Cytochrome P450 (CYP)-mediated metabolism (anabolism/catabolism) of vitamin D.Calcitriol is the active and most potent form of vitamin D and is formed throughtwo consecutive hydroxylati n reactions. CYP27A1 is expressed in the liver, whereasCYP27B1 and CYP24 1 are prim rily expressed in the k d eys. Similarly, for CYP2R1 andCYP3A4, the liver is the primary site of expression, along with their presence in dermalfibroblast [48]. Mitochondrial CYP27A1 is the major enzyme responsible for the C-25hydroxylation of vit min D3. In addition, microsomal CYP2R1 and CYP2J2/3 can alsocontribute to the formation of 25(OH)D3 [36]. In response to calcium homeostasis, CYP27B1,another mitochondrial enzyme, catalyzes the second hydroxylation step at C-1α in thebioactivation process to produce active calcitriol. Alternatively, calcitriol and other vitaminD3 derivatives are know to enhance CYP3A4 transcription via VDR [49]. Other cellsthroughout the body, including different cancer cells, can also synthesize calcitriol [50–52].Inactivation of the active forms of vitamin D primarily occurs through the CYP24A1enzyme in extrahepatic tissues, including the kidney and skin, whereas CYP3A4 is the majorvitamin D inactivating enzyme in the liver [19,20,53–55]. CYP24A1 catalyzes multistepreactions of converting calcitriol to inactive lactone and calcitroic acid through the C-23 and C-24 pathways, respectively [37]. In contrast, CYP3A4 inactivates calcitriol viahydroxylating at C-23, C-24, and potentially at another carbon on the side chain [20]. Itis worth recognizing that CYP3A4 is the major hepatic CYP enzyme, with majority of thedrugs in the c inic as its substrate. Its expression and activities are known to be modulatedby a divers class of medications, atural products, and dietary substances.Vitamin D derivatives can und rgo p ase II conjugation reactions involving uridinediphosphate (UDP)-glucuronosyltransferases (UGT) and sulfotransferases (SULTs), thoughthis area has not been explored comprehensively. Due to the presence of multiple hydroxylLife 2024, 14, 510 5 of 25groups in the vitamin D derivatives, they are suitable substrates of these conjugatingenzymes. Calcitriol has been identified as a substrate for UGT1A4, UGT2B4, and UGT2B7isoforms [56]. SULT2A1 catalyzes the sulfation reaction of several vitamin D3 derivatives,including 7-DHC, vitamin D3, 25(OH)D3, and calcitriol. In addition, calcitriol and 7-DHCare substrates of SULT1A1 and SULT2B1b, respectively [57].4. Dermal Expression of Vitamin D-Related CYP EnzymesSince the skin is the primary site of vitamin D synthesis, the dermal expression ofCYP enzymes can play a critical role in the homeostasis of vitamin D (Table 2). Thoughextradermal organs have the highest expression of vitamin D-related CYP enzymes, it isimportant to recognize that CYP27A1, CYP27B1, and CYP24A1 are present in differentlayers of skin with all the three enzymes present in the epidermis (keratinocytes) andCYP27A1 and CYP24A1 expressed in the dermis (fibroblast) [38]. CYP11A1, CYP24A1,CYP27B1, CYP2R1, and CYP3A4 are expressed in WM98 and A375 human melanoma celllines [58]. The 25-hydroxylase, 1α-hydroxylase, and 24-hydroxylase activities for vitaminD were modulated by vitamin D derivatives in MeWo melanoma cells but not in SkMel5cells [59]. CYP27A1 and CYP27B1 are expressed in MeWo, SK-Mel28, SM, SK-Mel-5, SK-Mel-25, IGR, and MelJuso melanoma cell lines; however, the last four cell lines in thislist are not responsive to 25(OH)D3 and calcitriol treatment [60]. Interestingly, calcitriolupregulated CYP24A1 expression by 7000-fold in MeWo, SK-Mel28, and SM cell lines [60].CYP2R1 and CYP27A1, the enzymes responsible for C-25 hydroxylation of vitamin D,are expressed in dermal fibroblasts [48]. CYP27B1 was identified in human melanomatumor tissue [61]. CYP27B1 expressions have been reported to be inversely correlated withthe development of melanoma, and low or undetectable levels have been linked to poorprognosis [62,63].Table 2. Effects of vitamin D and its derivatives on dermal tissues and cell lines.Vitamin D Model Signaling Proteins Significance Refs.1α,25(OH)2D3-Human melanoma cell lines-A375-ME18-MeWo-RPMI 7951-SK Mel 28-SKMEL-188-WM35-WM1341-increase in Bcl-2 and Bcl-X(antiapoptotic)-decrease in BAX, GOS2, DAP-3,FADD, and caspases(proapoptotic)-upregulation of beclin-1prodifferentiation [2,58]1,25,26(OH)3D3-malignant melanoma MM96cells-mouse B16 hamsterBomirski melanomas-increasing the expression ofTGFβ-blockade ofepithelial–mesenchymaltransition (EMT)-blocking of MMP-2 and MMP-9secretionsuppressedproliferation [2]21(OH)D-SKMEL-188-hamster Ab-AbC1 melanoma lines-decreased expression of VDR,RXR, PDIA3, and CYP2R1antiproliferativeactivity [2,58]20(OH)D3-in vitro assays-melanoma cells-melanocytes-hamster melanoma-inhibition of NFκβ activity-CYP24A1enhancedanti-melanoma activity [2]20(OH)D2-in vitro-malignant cells-melanocytes-hamster melanomaVDR-mediated antiproliferativeactivity [2]Life 2024, 14, 510 6 of 25Table 2. Cont.Vitamin D Model Signaling Proteins Significance Refs.20,23(OH)2D-in vitro assays-malignant cells-melanocytes-hamster melanoma-VDR-mediated-Albumin antiproliferative [2,58]20,23(OH)2D3 malignant cells -VDR-mediated antiproliferative [2]20,24(OH)2D3-in vitro-immunostaining ofmelanomas-CYP24A1 anti-melanoma activity [2]20,25(OH)2D3 -human melanoma cells -CYP24A1 inhibits proliferation [2,55]1,25(OH)2D325(OH)D3-human melanoma cell lines-MeWo-MeWo (EB1089)-SkMeI28-SkMeI28-(EB1089)2.05-SkMeI25-IGR-MeIJuso-VDR-mediated-CYP24A1 antiproliferative [60]1,25(OH)2D3-human melanoma cell lines-MeWo-SkMeI5VDR-mediated-CYP24A1 inhibits proliferation [59]1,25(OH)2D3-RPMI 7951 (high VDR)-SK-MEL-28 (low VDR) [64]1,25(OH)2D3 -B16-F10-increase in cleaved caspase-3,caspase 8, caspase 9, Beclin, andPARPantiproliferative [65]1,25(OH)2D3-human melanoma cell lines-MeWo-WM1341-VDR-mediated induce apoptosis [66]1,25(OH)2D3-human melanoma celllines-G-361/A3-VDR-mediated-nuclear factor KB (NF-KB)anti-inflammatoryaction [67]1,25(OH)2D3 -human melanoma cell line-blocks the formation of thesphingolipid degradationproduct sphingosine1-phosphate (S1P)induce apoptosis [68]1,25(OH)2D3 -CRL-1619-inhibition of oxidativeDNA/RNA damageanti-inflammatoryaction [69]CYP24A1, the most prominent catabolic enzyme, has been detected in tissues express-ing VDR and plays a vital role in the local regulation of vitamin D activity [36]. Severalhuman malignancies, including melanoma, have been shown to have higher CYP24A1 lev-els [55]. CYP24A1 protein levels are inversely linked with poor clinical outcomes in patientswith melanoma [55]. Maintaining homeostasis of 1α,25(OH)2D3 is the principal functionof 24-hydroxylase (CYP24A1) [26]. The CYP24A1-mediated inactivation of 1α,25(OH)2D3reduces the antitumorigenic capacity of the VDR signaling pathway [55]. Similar to VDRand CYP27B1, absent or diminished CYP24A1 was determined to be correlated with shorteroverall and disease-free survival [62]. Brozyna et al. also found that the expression ofCYP24A1 was greatest in patients with benign nevi and localized melanoma, while pa-tients with metastatic melanoma depicted lower levels. A clinical pathology study withmelanoma patients found that the occurrence of ulceration, necrosis, nodular type, andamelanotic phenotypes was related to lower CYP24A1 levels. It has been hypothesized thatLife 2024, 14, 510 7 of 25overexpressing CYP24A1 increases tolerance to the antiproliferative effects of calcitriol [55].Moreover, the suppression of CYP24A1 has been suggested as an adjuvant in vitaminD-based cancer treatments [55].A study carried out by Slominski et al. found that melanoma progression lowered theexpression of the VDR and CYP27B1, and melanization and melanogenesis had a detrimen-tal effect on stage III disease survival as well as overall survival [29]. Immunohistochemistrystudy of the human uveal tract and uveal melanoma, which is a tumor of the iris, indicatesthat CYP27B1 and CYP24A1 are expressed in the ocular compartment [70]. Interestingly, theexpression of CYP27B1 is downregulated in tumors that advance to metastasis comparedto the ones that did not metastasize [71]. CYP27B1 has been found to activate vitaminD, which protects against cancer [44]. Normal skin typically has high levels of CYP27B1expression (>10%); nevertheless, CYP27B1 enzymatic activity (0–5%) has been noted inaggressive forms of melanoma and non-melanoma skin malignancies, including basal cellcarcinoma [44]. The absence of CYP27B1 is linked to both disease-free progression andshorter overall survival. Due to the notable reduction in VDR and CYP27B1 expression,researchers believe that the low levels of these proteins promote melanoma developmentbecause of the lack of antiproliferative action of vitamin D [71]. Based on these findingsand their consistency with previous ovarian and colon cancer studies, it can be concludedthat CYP27B1 expression may be used as a biomarker for cancer presence and severity.5. Vitamin D Signaling in MelanomaThe physiological activities of vitamin D are carried out through the activation ofnuclear VDR by different vitamin D derivatives, followed by classical molecular signalingpathways (Figure 2). Though there are several natural and chemically synthesized vitaminD derivatives known to activate VDR, 1α,25(OH)2D3 is the most potent ligand of VDR [40].Apart from the main function of maintaining calcium concentration and skeletal health,vitamin D mediates a multitude of anticancer effects, including antiproliferation, inductionof apoptosis, and prodifferentiation [2,72]. Melanoma has been found to express VDR andrespond to activities of active vitamin D, such as cell proliferation. This cell proliferation isregulated by signaling pathways where active vitamin D affects growth factors and proteinsthat control the cell cycle [2]. Slominski et al. state that melanin content may impact vitaminD signaling and its anticancer efficacy, which is consistent with the idea that blockingmelanin formation would make melanoma cells more susceptible to antitumor therapy andprolong life. 1α,25(OH)2D3 suppressed cell growth in vitro transcriptional downregulationin human melanoma cell lines [25,36]. Wasiewicz et al. found that vitamin D signalingdefects were correlated with worse prognosis or more advanced stages of melanoma [58].As depicted in Figure 2, the metabolites of vitamin D carry out the physiological actionsof vitamin D by activating the vitamin D receptor. When the VDR forms a heterodimerwith retinoid X receptor, it binds to vitamin D response elements (VDREs) [58]. Theresulting complex then downregulates the cytokines and signaling mediators, leading tothe driving of anti-inflammatory and antioxidative actions. Furthermore, as concentrationsvary, the complex that forms between VDR, RXR, and VDREs modulates the expression ofspecific cell cycle-controlling proteins, leading to cell cycle arrest. Activation of RXR andvitamin D and its metabolites has also been shown to exhibit anticancer activity such asantiproliferation, apoptosis, and DNA repair. To prevent oxidative DNA damage, activeforms of vitamin D3 promote DNA repair by upregulating the expression of the p53 tumorsuppressor gene [2].Life 2024, 14, 510 8 of 25Life 2024, 14, x FOR PEER REVIEW 8 of 25 Activation of RXR and vitamin D and its metabolites has also been shown to exhibit anti-cancer activity such as antiproliferation, apoptosis, and DNA repair. To prevent oxidative DNA damage, active forms of vitamin D3 promote DNA repair by upregulating the ex-pression of the p53 tumor suppressor gene [2]. Figure 2. Anticancer signaling of vitamin D and its active metabolites. Changes in vitamin D activation, local and systemic levels, and VDR signaling path-ways can all lead to a loss of vitamin D anticancer protection, which may also promote the development of melanoma. Clinical data indicates that in cases of advanced melanoma, the VDR exhibits the lowest expression, whereas it is highest in normal skin. Patients with a clinical melanoma diagnosis and ulceration who have higher VDR expression seem to have better overall survival rates compared to those who have lower VDR expression since VDR expression is usually highest in normal cells [26]. The VDR is expressed in both mel-anocytes and keratinocytes, which respond to 1,25(OH)2D with decreased proliferation and enhanced differentiation. Major regulators of 1,25(OH)2D, such as interferon-γ (INFγ) and tumor necrosis factor-α (TNFα), are present in keratinocytes. Both TNFα and INFγ are activated by UVB, which increases the substrate through increased vitamin D production [40]. When tumors stop responding to vitamin D, it means that either the pro-duction of 1,25(OH)2D is suppressed or that posttranscriptional changes have eliminated VDR transcriptional activity [40]. The proliferation of both normal and pathological mel-anocytes, including melanoma cells, has been linked to modifications in the vitamin D endocrine system, which includes the VDR [72]. While signaling resulting from VDR ac-tivation regulates around 3% of the mammalian genome either directly or indirectly, al-ternative binding sites and receptors exist as well [2]. The VDR has the ability to carry out nongenomic functions, such as a variety of signaling pathways that could support topical 1,25(OH)2D protective effects [40]. An alternative binding pocket for 1α,25(OH)2D3 exists on the VDR, which induces prompt nongenomic reactions at the membrane level when occupied. Furthermore, as inverse agonists, active hydroxylated forms of vitamin D3 can interact with retinoic acid-related orphan receptors (RORs). They can thereby alter the physiological and molecular processes, such as cancer, that are controlled by these recep-tors. Inverse RORα/γ agonists may suppress tumor growth activity while also decreasing antitumor immunity [2]. When there is a deletion of CYP27B1 or VDR, defects in differentiation and increased proliferation of the epidermis are pronounced. In addition to the VDR, at least two other pathways modify vitamin D signaling and cause tumor growth in VDR null mice. The hedgehog (Hh) and Wnt/β-catenin pathways have both been implicated in this process [40]. The components of the Hh signaling pathway are overexpressed in the epidermis of animals lacking VDR. When Hh signaling is disrupted, basal cell carcinomic tumors will Figure 2. Anti ancer signaling of in D and its active metabolites.Changes in vitamin D activation, local and systemic levels, and VDR signaling path-ways can all lead to a loss of vitamin D anticancer protection, which may also promote thedevelopment of melanoma. Clinical dat indicates that in cases of advanced melan ma,the VDR exhibits the lowest expression, whereas it is highest in normal skin. Patientswith a clinical melanoma diagnosis and ulceration who have higher VDR expression seemto have better overall survival rates compared to those who have lower VDR expressionsince VDR expression is usually highest in normal cells [26]. The VDR is expressed in bothmelanocytes and keratinocytes, which respond to 1,25(OH)2D with decreased proliferationand enhanced differentiation. Major regulators of 1,25(OH)2D, such as interferon-γ (INFγ)and tumor necrosis factor-α (TNFα), are present in keratinocytes. Both TNFα and INFγare activated by UVB, which increases the substrate through increased vitamin D produc-tion [40]. When tumors stop responding to vitamin D, it means that either the productionof 1,25(OH)2D is suppressed or that posttranscriptional changes have eliminated VDRtranscriptional activity [40]. The proliferation of both normal and pathological melanocytes,including melanoma cells, has been linked to modifications in the vitamin D endocrine sys-tem, which includes the VDR [72]. While signaling resulting from VDR activation regulatesaround 3% of the mammalian genome either directly or indirectly, alternative binding sitesand receptors exist as well [2]. The VDR has the ability to carry out nongenomic functions,such as a variety of signaling pathways that could support topical 1,25(OH)2D protectiveeffects [40]. An alternative binding pocket for 1α,25(OH)2D3 exists on the VDR, whichinduces prompt nongenomic reactions at the membrane level when occupied. Furthermore,as inverse agonists, active hydroxylated forms of vitamin D3 can interact with retinoic acid-related orphan receptors (RORs). They can thereby alter the physiological and molecularprocesses, such as cancer, that are controlled by these receptors. Inverse RORα/γ agonistsmay sup ress tumor growth activity while also decr as g a titumor immunity [ ].When there is a deletion of CYP27B1 or VDR, defects in differentiation and increasedproliferation of the epidermis are pronounced. In addition to the VDR, at least two otherpathways modify vitamin D signaling and cause tumor growth in VDR null mice. Thehedgehog (Hh) and Wnt/β-catenin pathways have both been implicated in this process [40].The components of the Hh signaling pathway are overexpressed in the epidermis of animalslacking VDR. When Hh signaling is disrupt d, basal cell carcinomi umors will arise. Anessential function of the Wnt/β-Catenin signaling system is to control the interactionsbetween keratinocytes and melanocytes [39]. However, the exact function of this pathway inVDR function is still unknown. The Wnt/β-Catenin signaling pathway is unclear becauseLife 2024, 14, 510 9 of 25certain research has linked its activation to a reduction in the growth of melanoma. Whenthis pathway is inhibited, melanogenesis may be induced. Conversely, opposing studieshave shown that Wnt/β-Catenin signaling is necessary for metastatic melanoma survival,and its inhibition leads to decreased proliferation, among other things [39]. Wnt signalingblocks the phosphorylation of serine within the β-Catenin exon. Due to this hindrance,β-Catenin is more readily available in the nucleus, where it interacts with the transcriptionfactors to encourage the production of genes that are essential for cell division [40]. β-Catenin forms a junction complex with E-cadherin, which is increased by 1,25(OH)2D.When mutations or overexpression of the β-Catenin are present, skin tumors arise due toan increase in proliferation [40].The long noncoding RNAs (LncRNAs) make up about 80% of the transcriptome andhave been found to be master regulators of processes such as differentiation, embryonicpluripotency, and regulating histone modifications. Vitamin D signaling in the skin canalso inhibit tumor growth by using LncRNAs. When abnormally expressed, LncRNAsare typically associated with cancer [40]. Various LncRNAs were noticeably elevatedafter studying the function of LncRNAs in VDR defense against skin cancers in mice. InVDR null mice, there is a shift in the expression of LncRNAs towards a more oncogenicprofile [73]. In order to preserve the protective factors of VDR, the ratio of oncogenic totumor suppressor LncRNAs must be maintained [40].6. Vitamin D Deficiency and MelanomaStudies have demonstrated a link between vitamin D deficiency and an increased riskof developing melanomas (Table 3). Lower plasma vitamin D levels are associated withthe development of melanoma and/or reduced survival time in patients with metastaticmelanoma [74–80]. Additionally, studies have also explored the relationship betweendietary vitamin D supplements and the incidence of melanoma [11]. The findings indicatedthat while vitamin D and its metabolites have antiproliferative properties, there is nodiscernible pattern in the risk of melanoma associated with the length of time taken asa supplement, the daily dosage, or the average intake over ten years [11]. A new meta-analysis involving data from 211,230 patients showed that supplementation of vitaminD and blood 25(OH)D3 levels are modestly related to the risk of melanoma despite theuncertain relationship between melanoma risk and vitamin D intake. Nonetheless, afavorable association was discovered between vitamin D intake and an improved prognosisfor melanoma patients [81]. Intake of vitamin D supplements was protective against thedevelopment of melanoma. Table 3 lists the studies exploring the association betweenvitamin D plasma levels and melanoma [6,63,82].It is important to point out that there is an ongoing scientific debate between healthsocieties on what the optimal vitamin D serum levels are. Optimal levels are not welldefined. There is not yet a consensus on optimal levels and cut-off points. Differentorganizations have different definitions of vitamin D deficiency. Vitamin D levels arecategorized as sufficient or optimal levels if the levels are more than 30 ng/mL, insuffi-cient levels if between 12 and 20 ng/mL, and vitamin D deficiency if levels are less than12–20 ng/mL [83]. However, there is still a lack of consensus on the appropriate vitaminD intake. Different recommendations have been made by various expert groups. TheInstitute of Medicine (IOM) advised a threshold value of 20 ng/mL with 600 IU per dayto be adequate, whereas others suggest a benefit for a higher threshold of 25(OH)D levels≥ 30 ng/mL. The recommendations from European and American Societies for ClinicalNutrition and Metabolism (ESPEN and ASPEN), the European Food Safety Authority,the National Institute for Health and Care Excellence (NICE), Australian high-priority,and the American Institute of Medicine guidelines recommend 1000 IU per day. In addi-tion, the Endocrine Society recommended up to 2000 IU daily to reach adequate serumlevels [84–90].The retrospective review, cohort studies, cross-sectional studies, and randomizedcontrolled trial studies explored the plasma levels of vitamin D in a population >50 yearsLife 2024, 14, 510 10 of 25of age. Piotrowska et al. reported that vitamin D deficiency in melanoma was associatedwith poor prognosis [91]. In a 2020 study with approximately 1600 patients, the frequencyof low vitamin D was significantly greater in individuals with melanoma compared to themelanoma-free subjects (OR, 2.12; 95% CI, 1.15–3.89) [92]. Furthermore, the literature alsoreports that greater vitamin D levels at diagnosis are associated with a better prognosis formelanoma and lower Breslow thickness (melanoma thickness) (p value = 0.002). Serumvitamin D levels are estimated to be considerably higher in patients with tumor thicknessesof less than 1 mm than in individuals with tumor thicknesses greater than 1 mm. The factthat individuals with melanoma with low vitamin D levels had much greater death ratesthan those with higher vitamin D levels is not surprising, considering these findings [92].These findings are coherent with other studies conducted across the globe [3,39,93]. Recentresearch also claims that lower vitamin D (25 nmol/L) reduces the survival time in patientssuffering from melanoma [39]. Similarly, Lombardo et al. (2021) reported that vitaminD deficiency was correlated with a higher risk of developing more advanced melanomatumors [94].Various studies have demonstrated an association between obesity and low 25(OH)D3levels. It is thought that because vitamin D is fat-soluble and has a reduced bioavailability,overweight people are disposed to have lower vitamin D levels than people of normalweight. Therefore, some studies propose to use body mass index (BMI) as a possibleconfounding factor in analyzing the relationship between melanoma and obesity. Althoughthe relationship between weight and BMI and the occurrence of melanoma is not entirelyknown, it is thought to be less important than exposure to UV radiation [5]. In a similarstudy comparing individuals with cutaneous melanoma to those with normal BMI levels(≥18.5–<25 kg/m2), it was discovered that a BMI of ≥25–30 kg/m2 or >30 kg/m2 wasa critical reason for 25(OH)D3 levels < 20 ng/mL. This negative association between25(OH)D3 levels and BMI is consistent among adults and children from varying ethnicbackgrounds and geographic areas [82].Globally, fair-skinned populations are experiencing an increase in the incidence andfatality rates of cutaneous melanoma [5]. In Northern Europe, serum 25(OH)D3 levels tendto be higher than those in Southern Europe. Comparable results are observed in Westernand Eastern Europe, with greater 25(OH)D3 levels in the former region. The different skinphototypes found in European populations are thought to be the cause of this variationin 25(OH)D3 levels [93]. When groups have increased pigmentation, there tends to bea safeguard against the negative effects of UV radiation, UV-B-induced sunburn, DNAdamage, and skin carcinogenesis [73]. When compared to people with lighter characteristics,this conclusion is illustrated in those with light complexion and dark hair. Individuals withcutaneous melanoma who had light skin and dark-brown or black hair compared to thosewith light skin and blonde or light brown hair had a decreased chance of plasma 25(OH)D3levels below 20 ng/mL (OR 0.47, 95% CI 0.29–0.77, p = 0.003) [82]. Low vitamin D levelsare concerning as <20 ng/mL or less of blood total 25(OH)D3 is considered deficient [93].Approximately 21–29 ng/mL is considered insufficient, while greater than 30 ng/mL isconsidered adequate [93].Life 2024, 14, 510 11 of 25Table 3. Examples of clinical studies on vitamin D levels and melanoma risk.Author Study Design Sample Size Location Study Population Duration ofFollow Up Mean Age Objective Intervention Study FindingsAsgari et al.,2009 [11] Cohort studyMale: 37,382,Female: 40,337 USAMen and womenfrom westernWashington50–76 years10 years62 years (range,50–76yearsTo examine theassociationbetween vitaminD intake andmelanoma riskAverage intake inµg/day over 10years from multi-vitamin andindividualsupplementsourcesNo associationbetween totalintake of vitaminD and melanomariskDe Smedt et al.,2022 [82]Multicentrerandomizeddouble-blindplacebo-controlled phaseIII trialMale: 78,Female: 77 Belgium, HungaryPatients with stageIB to III Cutaneousmelanoma(according to the7th AJCCstaging), age 18–80NAGroup A 56(47–66), Group B54 (45–64)To investigate theconnectionbetween25(OH)D3levels,tumor-node-metastasis (TNM)stage andhistopathologicalparameters25(OH)D3 plasmalevelsLow levels of25(OH)D3 wereassociated with aworse outcome inpatients withmelanomaLiyanage et al.,2020 [6]MendelianrandomizationstudyCases: 12,874 andControls: 23,203 AustraliaSummary datafrom a largegenome-wideassociation studyNA NATo investigate acausal associationbetweengeneticallypredicted25(OH)D3concentrationsand melanomausing a Mendelianrandomization(MR) approachGeneticallypredicted25(OH)D3concentrationsLow levels of25(OH)D3 werenot associatedwith the risk ofmelanoma[(OR) 1.06, 95%confidenceinterval (CI)0.95–1.19]Reichrath et al.,2022 [63]Prospective,comparative, non-interventionalside-by-sidestudy83 GermanyTreatment withCTLA-4i, PD-1i, orBRAFi/MEKi forhistologically andclinicallyconfirmedadvancedmelanoma2013–until death 63.43 yearsTo investigatewhether vitaminD status ispredictive ofefficacy and safetyin patients treatedwith immunecheckpoint orBRAF/MEKinhibitorsVitamin D levelsin plasmaVitamin Ddeficiency wasassociated withpoor clinicaloutcomes inpatients treated formetastasizedmelanoma withBRAF/MEKinhibitors orimmunotherapyLife 2024, 14, 510 12 of 25Table 3. Cont.Author Study Design Sample Size Location Study Population Duration ofFollow Up Mean Age Objective Intervention Study FindingsBefon et al.,2020 [93]Prospective cohortstudy105, Male: 46,Female: 53 GreeceConsecutivepatientsdiagnosed withprimaryinvasive CMM ofany stage wereenrolled.42–78 months ≤40 years: 31 ±31.31Association ofserum total25(OH)D3levels atmelanomadiagnosis withknown risk andprognostic factorsfor CMMSerum 25-hydroxyvitamin D levels ofmelanomapatientsLow levels of25(OH)D3 werefound in Greekcohort ofmelanomapatients vs.healthy controlsStenehjem et al.,2020 [5] Case-control study1416, Case: 708,Control: 708 NorwayCases werehistologicallyverifiedmelanomas< 75 years of ageYear 1972–2003 to31 December 2009Cases: 42 (22–67),Control: 42 (22–67To study25(OH)D3 andmelanoma risk inthepopulation-basedJanusSerum BankCohortConcentrations of25(OH)D3 weremeasured during2016–2017Adequate vitaminD levels wereassociated with areduced risk ofmelanomaFearfield et al.,2019 [74]Retrospectivestudy 104 patients UKPatients withprimary andmetastaticmelanomaMay 2016 toOctober 2017.Range: 23–85yearsTo determinelevels of25(OH)D3 inpatients withprimary andmetastaticmelanomaPlasma levels ofvitamin D80% of patientswith melanomahad vitamin DdeficiencyTimerman et al.,2017 [75]retrospective,single-centerstudy252, Male: 144,Female: 108 USAPatients withmelanoma and atleastone serum25(OH)D3measurementwithinone year after thediagnosisJanuary 2007 toJune 2013 55.4 ± 14.7The initial serum25(OH)D3concentrationsand the changein 25(OH)D3levels wereassociated withmelanomaprognosisSerum 25(OH)D3concentrationsVitamin Ddeficiency wasassociated with aworse prognosisin patients withmetastaticmelanomaLife 2024, 14, 510 13 of 25Table 3. Cont.Author Study Design Sample Size Location Study Population Duration ofFollow Up Mean Age Objective Intervention Study FindingsLombardo et al.,2021 [94]retrospective,single-centerstudy154, Male: 78,Female: 76 ItalyPatients withmelanoma withlow Vitamin Dserum levels.Control groupswith a negativemelanoma history3-year period2016 to 2019 59.7 ± 15.5To study theassociationbetween vitaminD serum levelsand germaneprognostic fac-tors/pathologicalparameters inmelanoma25(OH)D3 serumlevels weremeasured during2016–2019Vitamin Ddeficiency is apossiblepredisposingfactor for thedevelopment ofmelanomaMoreno-Arroneset al.,2019 [78]cross-sectional,single-centerstudy204patients SpainPatients withprimary invasivemelanoma2013 to 2017 -To investigate theassociationbetween vitaminD serum levelsand pathologicalparameters inmelanomaSerum 25(OH)D3concentrationsThere was asignificantassociationbetween lowvitamin D levelsand an increasedrisk of developingaggressivemelanomaBade et al.,2014 [76]retrospective,single-centerstudy324 melanomapatients,141 healthycontrolsGermany MelanomapatientsFebruary 2000 andApril 2004 56.3To study theassociationbetween lowvitamin D serumlevels and risk formelanomaprognosisSerum 25(OH)D3concentrationsLow serum25(OH)D3concentrationswere associatedwith pooroutcomes inmelanomapatients,predicting riskand prognosis ofmelanomaGambichler et al.,2013 [77] Prospective study764patients GermanyMalignantmelanoma - -To study theassociationbetween vitaminD serum levelsand clinicalparameters inmelanomapatientsSerum 25(OH)D3concentrationsLow levels ofvitamin D wereassociated withadvanced tumorstageLife 2024, 14, 510 14 of 25Table 3. Cont.Author Study Design Sample Size Location Study Population Duration ofFollow Up Mean Age Objective Intervention Study FindingsNurnberg et al.,2009 [79] Prospective study205Patients, 141health controlsGermany Stage 4 melanomapatientsDecember 1997 toMarch 2007 -To study theassociationbetween vitaminD levels andclinical andhistopathologicalparameters amongmelanomapatientsSerum 25(OH)D3concentrationsPatients withmetastasizedmelanoma stage 4had significantlylower vitamin DlevelsMoro et al.,2022 [80]Retrospective,observational,longitudinal286 patients withhistory withmelanoma;SpainPatients with ahistologicalmelanomaFollow-up periodof 39.4 months -To study theprognostic valueof vitamin Dserum levels inmelanomapatientsSerum 25(OH)D3concentrationsLow vitamin Dlevels wereassociated withulceration inmelanomaLife 2024, 14, 510 15 of 25The relationships between sun exposure, vitamin D levels, and melanoma risks arecomplex and not fully understood. It is known that increasing sun exposure maximizesvitamin D production and boosts serum vitamin D levels while minimizing skin cancerrisk [95]. However, studies have shown that people with adequate exposure have beenreported to have low vitamin D levels [96]. The antioxidant actions of vitamin D incancer are well established (Figure 2). Low vitamin D levels were associated with anincrease in oxidative stress marks in many human diseases [97,98]. However, vitamin Dsupplementation reduces oxidative stress [99,100]. Studies have linked melanoma withan increase in oxidative stress [101,102]. It has been demonstrated that patients withNMSC and melanoma presented with an overproduction of free radicals [103]. Karampiniset al. studied the role of vitamin D levels in non-melanoma skin cancer (NMSC) patients.The results revealed that the majority of the included NMSC patients had low vitaminD levels and were presented with higher levels of systematic oxidative stress markers.However, the higher vitamin D levels were positively correlated with lower oxidative stressmarkers [104].Another study reported by Reichrath et al. in melanoma patients found that lowervitamin D levels (25(OH)D3 s.c. 10 ng/mL) were correlated with worse overall survival(OS) and progress-free survival (PFS), increased tumor load, and risk of adverse events [63].Although all these results validate the correlation between vitamin D and clinical outcomes,including a connection between a smaller Breslow tumor thickness and a higher 25(OH)D3level, published reports have shown inconsistent results [5,26,82,92]. The competing roles ofUVR in the etiology of cancer and vitamin D production mean that, despite ongoing studieson melanoma, the causal link between vitamin D and melanoma remains unclear [6].Furthermore, the precise role of vitamin D in the development of melanoma remainsunknown. However, due to the complex connection between melanoma and vitaminD levels, along with its resulting inconsistent outcomes, it is reasonable to assume thatcorrelation does not amount to causation [92]. In fact, a Mendelian randomization (MR)study was conducted in 2020 to ascertain the plausibility of a causal relationship betweenvitamin D and the incidence of melanoma. While researchers found no evidence of acausal link to melanoma, both direct and reverse causality cannot be definitively ruledout. According to reverse causality, the cancer diagnosis itself could be the reason fordecreased 25(OH)D3 levels [5,63]. As researchers continue to explore the pathogenesisbehind melanoma, it may be inferred that vitamin D is more significant in slowing theprogression of melanoma than in preventing its development [92].7. Factors Affecting CYP-Mediated Vitamin D Metabolism and Vitamin D EffectsThe modulation of CYP enzymes that facilitate vitamin D activation or inactiva-tion can have a significant effect on its plasma concentration. Activation of vitamin Doccurs in the liver and kidneys by sequential reactions of 25-hydroxylation (CYP27A1,CYP2R1) to form 25(OH)D3 (liver); further, it undergoes another 1α hydroxylation (CYP27B1)to form 1α,25(OH)2D3 (kidneys). In contrast, 24-hydroxylation (CYP24A1) of the 25(OH)D3 or1α,25(OH)2D3 in the kidney plays a major in the catabolism or inactivation of vitamin D [21,105].Vitamin D-metabolizing CYP enzymes are regulated via multiple receptors, including VDR,pregnane X receptor (PXR), and steroid and xenobiotic receptor (SXR) [18,21,106–108]. Factorsthat influence the activation of these receptors and the regulation/function of CYP enzymescatalyzing vitamin D metabolism can eventually affect vitamin D levels and their actions.The polymorphism of VDR and vitamin D-related CYPs can influence vitamin D levels andactions. Similarly, different disease conditions can also affect vitamin D activation.7.1. Xenobiotics as Inducers of Vitamin D MetabolismCYP enzymes that facilitate vitamin D anabolism or catabolism are susceptible toinduction by numerous medications and natural health products. Several studies haveinvestigated the impact of CYP induction on tissue-specific vitamin D metabolism andplasma levels, as those enzymes are expressed in a variety of tissues [109]. MultipleLife 2024, 14, 510 16 of 25receptors, such as the SXR and PXR, are involved in the regulation of CYP enzymes. Alarge number of drug classes (e.g., antiepileptics, St. John’s wort, Kava Kava, antibiotics,and HIV drugs) work as PXR ligands and can increase the breakdown of calcitriol throughCYP3A4 or CYP24A1 induction. Antiretrovirals such as ritonavir and saquinavir are knownto cause vitamin D deficiency, followed by other bone-related problems, through inductionof CYP-mediated active vitamin D metabolism [110]. Antiretroviral medications efavirenz,stavudine, and ritonavir have been shown to upregulate CYP24A1, leading to a lowercalcitriol level [109]. Drug-induced osteomalacia has been linked to increased CYP24A1in the liver and gut via phenobarbital-and rifampicin-mediated activation of human PXRand better metabolic clearance of 1α,25(OH)2D3 and 25(OH)D3 [18]. Activation of SXR hasbeen found to reduce the VDR-mediated CYP24A1 promotor function [21]. SXR-mediatedinduction of CYP24A1 leads to enhancement of vitamin D degradation, diminishing thebiological effects of vitamin D [21].Similarly, antituberculosis treatments such as isoniazid (INH) and rifampicin (RIH)induce the expression of CYP27A1 in hepatocytes. The data from coadministration of theanti-TB medications in mice suggests that RIF and INH have a negative effect on vitamin Dactions. RIF induces 24-hydroxylation in the kidney and accelerates vitamin D breakdown.Sheng et al., however, found that mice given single doses of RIF or combined RIF andINH exhibited increased 25-hydroxylase enzyme in the liver, which counteracted drug-mediated vitamin D catabolism and elevated serum 25(OH)D3 [111]. While administrationof each drug individually did not affect CYP2R1 transcription, combined treatment with100 mg/kg RIF and 50 mg/kg INH also showed a considerable increase in CYP2R1 mRNAexpression [111].Vitamin D levels can be affected by drugs and dietary supplements that work asCYP3A4 inhibitors or inducers [112]. Dexamethasone, a common anti-inflammatory gluco-corticoid, is often administered before chemotherapy for advanced malignancies. It wasfound to have a significant negative impact on 1α,25(OH)2D3 levels, calcium absorption,and bone metabolism in a study with infant pigs. Considering these findings, a studyassessing the effects of prednisolone and dexamethasone on mouse hepatic biotransfor-mation was carried out. Compared to prednisolone, the dexamethasone-treated animalsshowed a greater amount of 1α,25(OH)2D3 breakdown by CYP3A isoforms. The biologicaleffects of vitamin D3 may be impaired as a result of this enhanced hepatic breakdown [20].Antiepileptic medications such as phenobarbital and phenytoin upregulate CYP3A4 andCYP24AA1 expression in cell culture experiments, leading to a purported decrease in serum25(OH)D3 levels and enhancing the clearance of vitamin D metabolites [113]. Antiepilep-tic medications like carbamazepine or phenytoin have been shown to induce CYP3A4,leading to reduced benefits of vitamin D and the potential development of osteomala-cia [114–116]. Similarly, CYP3A4-mediated 4-hydroxylation of 25(OH)D3 was increasedby rifampin [114]. Autoinduction of CYP3A4-mediated metabolism of active vitamin D isanother phenomenon that can lower vitamin D levels [41,107]. The effect of a diverse classof drugs on vitamin D metabolism has been reviewed elsewhere [110,117].7.2. Xenobiotics as Inhibitors of Vitamin D MetabolismThe inhibitors of vitamin D metabolism-related CYP enzymes can influence the endoge-nous levels of parent and active vitamin D derivatives. The modulators can be classifiedas either inhibitory towards the bioactivation or the inactivation step. Antiretroviral med-ications efavirenz, stavudine, and ritonavir have been shown to downregulate CYP2R1,leading to a 30–45% reduction in cellular levels of calcitriol [109]. Several studies havereported antiretroviral therapy-mediated disruption of vitamin D activation, which couldaffect the efficiency of the skin as the first line of immune defense [109]. Interestingly, nu-merous studies have reported the association between low vitamin D levels and the risk ofdeveloping COVID-19 infection and its associated severe symptoms [118,119]. Ellfolk et al.showed that medications such as phenobarbital (antiepileptic) and efavirenz (anti-HIV)downregulated CYP2R1 expression; however, CYP27A1 expression was not affected byLife 2024, 14, 510 17 of 25these drugs [48]. In contrast, cyclosporine has been reported to be an inhibitor of CYP27A1in studies with cell culture and animal models [120]. Protease inhibitors (ritonavir, indi-navir, and nelfinavir) block the activation of vitamin D by inhibiting the 25-hydroxylationand 1α-hydroxylation reactions [121].A diverse class of medications, e.g., ritonavir, ketoconazole, clarithromycin, tamoxifen,and docetaxel, were able to inhibit hydroxylation-mediated deactivation of calcitriol [20].Several medications have been reported to inhibit CYP24A1 and CYP3A4, the enzymes re-sponsible for the breakdown of the active vitamin D. Ly et al. reported that 24-hydroxylationof calcitriol is blocked by liarozole [122]. Similarly, ketoconazole, either alone or in combina-tion with tetralone or dexamethasone, can inhibit CYP24A1 activity [105,123]. Consideringthe flexible active site of CYP3A4, several drugs and natural products can inhibit theCYP3A4-mediated breakdown of calcitriol. Ketoconazole, a potent inhibitor of CYP3A, wasshown to inhibit 1α,25(OH)2D3 hydroxylation in vitro in nanomolar concentration [20,116].Ginsenosides such as aPPD and aPPT can block the CYP3A4-mediated hydroxylation ofcalcitriol [124,125]. Similarly, abiraterone, a prostate cancer treatment, can exert inhibitoryeffects on vitamin D catabolism [126]. Troleandomycin and azamulin, known potent in-hibitors of CYP3A4, inhibited the CYPA4-mediated metabolism of 20(OH)D3, a vitamin Dderivative with a biological efficacy similar to calcitriol [127].7.3. ComorbiditiesThe presence of different diseases is another factor that can modify the vitamin D levelsand their effects on melanoma. Researchers discovered a higher frequency of osteomalacia,severe vitamin D insufficiency, and low bone mineral density in individuals receiving HIVtreatment. The combined use of antiretroviral medications, such as efavirenz, ritonavir,and stavudine, is thought to be the cause of this impact on bone and vitamin D levels [109].It is believed that these drugs disrupt vitamin D homeostasis via mechanisms that altergene expression. Protease inhibitors (PI), on the other hand, decreased the formationof 1α,25(OH)2D3 in monocyte-macrophage cell lines after HAART treatment [121]. Theinhibition of 1α,25(OH)2D3 induced by PI may have a role in the demineralization of boneinduced by PI-based therapy [36]. Obesity and type 2 diabetes are two metabolic disorderslinked to a decrease in 25(OH)D3 levels. While many researchers believe that vitamin Dlevels are low due to storage in adipose tissue, another ongoing theory suggests that areduction in CYP2R1 activity may be the source. Researchers looked at the obese animalmodels that were fed high-fat diets to verify this theory. CYP2R1 mRNA was shown to besubstantially reduced in these obese mice than in lean animals [36].7.4. PolymorphismThe endogenous vitamin D levels and their actions can be affected by polymorphismsin the gene encoding vitamin D metabolism-related CYP enzymes and VDR. Single nu-cleotide polymorphisms (SNPs) have been identified as frequent genetic risk factors formelanoma risk [53]. Studies have shown that VDR single nucleotide polymorphisms havebeen linked to poor survival rates in patients with melanoma [3,44]. The A allele of the VDRgene was shown to be substantially correlated with both metastasis and melanoma sus-ceptibility in a study that examined the significance of VDR polymorphisms in melanomarisk [53]. Researchers examined multiple VDR gene polymorphisms in a study involvingover 3600 individuals to identify that eight polymorphisms are statistically significantlyassociated with the risk of developing subsequent new primary melanomas [53]. Breslowtumor thickness is one of the most significant prognostic factors used for patients withcutaneous melanoma. The VDR polymorphism rs1544410 has been linked to an elevatedrisk of melanoma and an increased thickness of Breslow tumors. Reduced survival andthe possibility of metastasis increases with tumor thickness [53]. The FokI (C/T-rs2228570)and BsmI (rs1544410) mutations are among the several SNPs found in the VDR gene thathave been widely used in melanoma research. The FokI polymorphism results in a longerand less active VDR protein by generating a novel start codon upstream from the typicalLife 2024, 14, 510 18 of 25start codon. Conversely, the BsmI polymorphism limits the length of the fragment andcauses silent changes that may change the VDR gene transcription and the stability of themRNA [39].Similarly, polymorphism of CYP enzymes involved in vitamin D metabolism caninfluence vitamin D levels. The polymorphisms in CYP24A1 and CYP27B1 were linkedto prostate and colon cancer, respectively [39]. Despite there being few studies involvingCYP-related polymorphisms, a variant of rs4646536 in CYP27B1 was identified to haveprobable relevance in carcinogenesis [39]. The loss of CYP27B1 activity led to pooreroutcomes in melanoma [3]. Likewise, the CYP3A4 I301T mutation shows greater activityfor the inactivation of vitamin D metabolites, resulting in decreased vitamin D levels.Following the loss of CYP3A4 function, a link between the CYP3A4 rs2242480TT variantand elevated 1α,25(OH)2D3 levels were observed among an elderly study population inSingapore. Certain polymorphisms were shown to increase cancer risks among variousethnic groups. For instance, it is believed that Africans with the CYP3A4*1B mutation havea higher risk of developing cancer, with small cell lung and prostate cancer being the mostprevalent types [112].8. Therapeutic Prevention of Melanoma by Vitamin D Supplementation andModulation of CYPsThe development and progression of melanoma may be affected by VDR expressionand signaling [112]. Vitamin D may play a vital role in the prevention of cancer because ofits antiproliferative properties [128]. The prevention and treatment of melanoma can beinfluenced by vitamin D signaling in both local or systemic effects on vitamin D activationand inactivation. Over the last decade, substantial attention has been given to the roleof vitamin D in preventing cancers, particularly in reducing the risk of melanoma [4,58].Regarding epidemiological studies, the function of systemic vitamin D in melanoma pa-tients is undetermined due to ambiguous evidence. Though there are convincing clinicalreports about the effect of low vitamin D serum levels on the risk of development andprogression of melanomas, the causal relationship is not confirmatory [6,81,92,129–131]. Onthe contrary, experimental evidence amply supports the anti-melanoma capabilities of vita-min D and its derivatives [11,26]. Additionally, molecular and clinicopathological reportshave shown an association between deficiencies in vitamin D signaling and melanomadevelopment and prognosis. This indicates that vitamin D signaling may be significant intreating melanoma.Supplementation with vitamin D has been shown to reduce the development ofadvanced cancers and mortality [132]. Meta-analyses of randomized clinical trials (RCTs) ofvitamin D have shown that supplementation with vitamin D lowers cancer-related mortalityrates [133]. Improving vitamin D signaling could be one of the strategies to preventmelanoma. Vitamin D signaling may be augmented by either increasing or correcting lowplasma vitamin D levels by influencing the CYP-mediated metabolism of active vitaminD or through dietary supplementation. CYP24A1 and CYP3A4 are two key enzymes thatare accountable for the breakdown of 1α,25(OH)2D3, the most active form of vitamin D.Higher CYP24A1 levels are indicators of poor prognosis of melanoma [55]. It is plausiblethat inhibition of CYP24A1 can prevent the development of melanoma. In other cancertypes (e.g., prostate cancer and breast cancer), CYP24A1 or CYP3A4 inhibitors blockedthe degradation of active vitamin D3 and improved the treatment outcomes in preclinicalmodels or clinical studies [105,134–137]. Thus, CYP enzymes can be a viable target in theprevention or treatment of melanoma.In a study observing the consequences of targeting the vitamin D endocrine system inmalignant skin diseases, vitamin supplementation was explored as a therapeutic option.The intake of 1000 mg of calcium and 400 IU of vitamin D daily by women with a historyof non-melanoma skin cancer decreased their risk of developing melanoma compared tothe placebo group. These findings suggest that future therapy options for at-risk groups,such as those with a present or past diagnosis of non-melanoma skin cancer, may includeLife 2024, 14, 510 19 of 25vitamin D and calcium supplements [72]. Slominski et al. (2015) suggested that higherdoses of vitamin D (50,000 units/week or 10,000 units/day) can be administered to provideadjuvant (stage III/IV) or preventive benefits (stage I/II) [138]. The preventive effectsof vitamin D supplementation were further evidenced in a randomized controlled studywhere a 57% lowering of melanoma development was observed in postmenopausal womenwho took 400 IU and 1000 mg of calcium daily [139]. Smedt et al. (2022) reported thatmelanoma patients without vitamin D supplementation were at a higher risk of developinglow 25(OH)D3 levels [82]. Though the risk of low vitamin D levels and the develop-ment or progression of melanoma is relatively well accepted, the benefits of vitamin Dsupplementation in preventing melanoma development need more evidence.9. ConclusionsHere, we reviewed the available evidence on the role of vitamin D in melanomaand CYP-mediated metabolism, which can potentially affect the actions of vitamin D inmelanoma. There is mounting evidence that vitamin D supplementation has the potential toexhibit VDR-mediated anticancer properties in melanoma. Vitamin D-related CYP enzymesare present in the epidermis (keratinocytes) and dermis (fibroblast), which are the primarysites of vitamin D synthesis. Selective targeting of catabolic CYP enzymes appears to bepromising in the prevention of melanoma. Future studies on the combination of vitamin Ddietary supplementation or vitamin D-related CYP modulators and chemotherapy shouldbe undertaken to further our understanding of the prevention and treatment of melanoma.The influence of CYP polymorphic forms on the development and progression of melanomais an area that needs close attention. The findings and limitations from past vitamin Dstudies should be considered in designing future clinical studies.Author Contributions: Conceptualization, S.D.; methodology, S.D. and M.B.-E.; software, S.D.;resources, S.D.; data curation, M.B.-E., E.J.G., J.M.P., L.N.-A., M.C. and S.D.; writing—original draftpreparation, S.D., E.J.G., M.B.-E., J.M.P., L.N.-A. and M.C.; writing—review and editing, S.D., M.B.-E.and E.J.G.; supervision, S.D.; project administration, S.D. All authors have read and agreed to thepublished version of the manuscript.Funding: This research received no external funding.Institutional Review Board Statement: Not applicable.Informed Consent Statement: Not applicable.Data Availability Statement: Not applicable.Conflicts of Interest: The authors declare no conflicts of interest.References1. Siegel, R.L.; Giaquinto, A.N.; Jemal, A. Cancer statistics, 2024. CA Cancer J. Clin. 2024, 74, 12–49. [CrossRef] [PubMed]2. 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vitamin D
melanoma
cytochrome P450
therapeutic prevention
dermal expression
anticancer effects
supplementation
Vitamin D in Melanoma: Potential Role of Cytochrome P450 Enzymes
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