COVID-19 and Vitamin D: A lesson from the skin
Exp Dermatol. 2020 Aug 11. doi: 10.1111/exd.14170
Radomir M Slominski 1, Joanna Stefan 2, Mohamad Athar 2, Michael F Holick 3, Anton M Jetten 4, Chander Raman 1 2, Andrzej T Slominski 2 5
e-mail: aslominski at uabmc.edu; chanderraman at uabmc.edu;
CYP11A1 is a little-discussed gene that can transform raw vitamin D
CYP11A1 exists in the adrenal glands, etc.
CYP11A1 generated metabolites may be particularly good at helping the immune system
UVB, topical, sublingual, inhaled, injected and IV Vitamin D appear to be especially good sources for CYP11A1
The forms of Vitamin D created by CYP11A1 are NOT tested by a Vitamin D blood test
Note: you can find all occurrences of a word, such as honey on any page, by hitting the keys cntl &F concurrently and typing the word into the box which appears in the upper right
Wonder how much increased Vitamin D to the cells
- Different dosing levels: say 2,000 IU, 25,000 IU, and 250,000 IU
- Topical vs oral nanoemulsion
- Might the topical form allow more Vitamin D to get to the Vitamin D receptor?
- Note: The founder of VitaminDWiki has used topical, sublingual and inhaled vitamin D nanoemulsion since 2017
- Health benefit of Sunlight is more than Vitamin D in the blood - many studies
- Nanoemulsion Vitamin D may be a substantially better form
- Nanoemulsion vitamin D is again found to be the best liquid form (for rats in this case) – June 2019
- Inhaling Vitamin D nanoemulsion through nose gets lots more to the brain (mice) – July 2020
- Inhaled nanoemulsion of Vitamin D killed lung bacteria – Sept 2017
- Vitamin D nanoemulsion, with comments on COVID-19 – June 2, 2020
- Bioavailability of nanoemulsion formulations of Vitamin D3 – Nov 2019
- The renaissance of vitamin D – Dec 2014 CYP11A1
- Novel activities of CYP11A1 and their potential physiological significance- 2015 one of the authors of current study
- A pathway for the metabolism of vitamin D3: Unique hydroxylated metabolites formed during catalysis with cytochrome P450scc (CYP11A1) - 2003
- The role of CYP11A1 in the production of vitamin D metabolites and their role in the regulation of epidermal functions - 2014 -one of the authors of current study
- Poor CYP11A1 associated with 6 types of cancer - 2016
- Association between the CYP11 family and six cancer types
-  Download the PDF from VitaminDWiki
- Poor CYP11A1 increases the risk of ischemic stroke by 1.5 X in male Han Chinese
OTHER in VitaminDWiki
- Injection category listing has
61 items along with related searches
- Topical Vitamin D
- CYTOKINE in VitaminDWiki 12 titles as of Aug 2021
- Vitamin D is activated by the lungs as well as most human tissues - no liver or kidney required This chart does NOT include CYP11A1
- Getting Vitamin D into your body has the following
Download the PDF from VitaminDWiki
The negative outcomes of COVID-19 diseases respiratory distress (ARDS) and the damage to other organs are secondary to a "cytokine storm" and to the attendant oxidative stress. Active hydroxyl-forms of vitamin D are anti-inflammatory, induce anti-oxidative responses, and stimulate innate immunity against infectious agents. These properties are shared by calcitriol and the CYP11A1-generated non-calcemic hydroxyderivatives. They inhibit the production of pro-inflammatory cytokines, downregulate NF-κΒ, show inverse agonism on RORγ and counteract oxidative stress through the activation of NRF-2. Therefore, a direct delivery of hydroxyderivatives of vitamin D deserves consideration in the treatment of COVID-19 or ARDS of different etiology.
We also recommend treatment of COVID-19 patients with high dose vitamin D since populations most vulnerable to this disease are likely vitamin D deficient and patients are already under supervision in the clinics. We hypothesize that different routes of delivery (oral and parenteral) will have different impact on the final outcome.
The COVID-19 is currently the foremost health issue in the world. SARS-CoV-2 (severe acute respiratory syndrome coronavirus) is an enveloped positive strain RNA virus in the family Coronaviridae, which also includes the virus SARS-CoV-1 (which was another outbreak in 2002- 2003)1. COVID-19 has a fatality rate up to ~5%, which is several times higher than influenza2,3. The leading cause of death in the patients is due to acute respiratory distress syndrome (ARDS)2 induced by proinflammatory responses and oxidative stress (Fig. 1A).
Vitamin D is a fat-soluble prohormone, which after production in the skin or oral delivery affects important physiological functions in the body including regulation of the innate and adaptive immunity4-6. Vitamin D can be activated through canonical and non-canonical pathways (Fig. 1A). In the former, it is metabolized to 25-hydroxyvitamin D3 (25(OH)D3) by CYP2R1 and CYP27A1 in the liver with further metabolism in the kidney to the biologically active 1,25-dihydroxyvitamin D3 (1,25(OH)2D3 ) by CYP27B17-9. This metabolism also occurs in a variety of organs, including skin and the immune system7,9.
An alternative pathway of vitamin D activation by CYP11A1 leads to production of more than 10 metabolites some of which are non-calcemic even at high doses8,10,11. These hydroxyderivatives, including 20(OH)D3 and 20,23(OH)2D3, are produced in humans 12-15. In addition, 20(OH)D3 has been detected in the honey, which defines it as a natural product16. CYP11A1 is expressed not only in adrenals, placenta and gonads but also in immune cells and other peripheral organs17.
Both 1,25(OH)2D3 and non-calcemic CYP11A1 derived metabolites use various, although partially overlapping, mechanisms in enacting their anti-inflammatory and anti-oxidative effects (Figure 1B). 1,25(OH)2D3 mediates many of its anti-inflammatory and anti-microbial effects through the vitamin D receptor (VDR) 6,9. 1,25(OH)2D3 can also inhibit the mitogen-activated protein kinase (MAPK) and NF-kB signaling4,9.
The non-calcemic CYP11A1-derived vitamin D compounds also have their own methods to fight inflammation (Fig. 1B). 20(OH)D3 and their downstream hydroxyderivatives act on VDR as biased agonists11,18,19. They also act as inverse agonists on the retinoic acid-related orphan receptors, RORa and RORy, transcription factors with critical roles in several immune cells and immune responses20-23 (Fig. 1B). In addition, CYP11A1-derived derived vitamin D3 derivatives and classical 1,25(OH)2D3 can act as agonists on aryl hydrocarbon receptor (AhR)24. Although binding pocket of this receptor can accommodate many different molecules, we believe that secosteroidal signal transduction can be linked to detoxification and anti-oxidative action11 or down-regulation of pro-inflammatory
ARDS and other adverse effects of COVID-19 are induced by cytokine storm
A leading cause of ARDS is “cytokine storm”，a hyperactive immune response triggered by the viral infection (Fig. 1A)2,26. It is initiated when the pattern recognition receptor of the innate immune cells recognize the pathogen-associated molecular pattern from a pathogen such as bacteria or virus 26,27. The immune cells then release all types of cytokines (interferons, interleukins 1, 6 and 17, chemokines, colony stimulating factors, and tumor necrosis factor (TNF)) leading to hyperinflammation and organ damage 27-29. In the lungs, alveolar cells are targeted leading to acute lung injury and subsequently ARDS 27,30. In severe cases of CoVID-19 other organs and systems are also damaged2,3. Thus, it is crucial to find ways to prevent the “cytokine storm” from going out of control. Although different drugs have been suggested to fight the cytokine storm26,27, they have mixed results and in certain cases can even worsen the disease27. Thus, there is a great need for alternative therapies.
Oxidative stress is also involved in the development of ARDS through action of reactive oxygen ies (ROS) and nitrogen species (NRS)31-33. The production of ROS and RNS can be triggered by ogens promoting the secretion of cytokines, which stimulate ROS production thereby producing sitive feedback loop (Fig. 1A)31,33-35. Nuclear factor erythroid 2p45-related factor 2 (NRF-2) is a transcription factor that plays a role in the detection of excessive ROS and RNS and induction of mechanisms counteracting the oxidative damage36. NRF-2 loss due to ROS can lead to elevation in proinflammatory cytokine levels and stronger inflammatory responses to stimuli31,36.
Anti-inflammatory and antioxidative activities of active forms of vitamin D There is a strong experimental evidence that active forms of vitamin D including the classical 1,25(OH)2D3, and novel CYP11A1-derived hydroxyderivatives8,11 exert potent anti-inflammatory activities including inhibition of IL-1, IL-6, IL-17, TNFa and INFy production or other proinflammatory pathways (Supplemental table 1) 11,18,20,37,38. The mechanism of action includes downregulation of NF-kB involving action on VDR and inverse agonism on RORy leading to attenuation of Th17 responses (Fig 1B)11,18,20,37-39. These compounds also induce antioxidative and reparative responses with mechanism of action involving activation of NRF-2 and p5311,39-41.
Antiviral effects of active forms of vitamin D
Low vitamin D status in winter permits viral epidemics and vitamin D supplementation could reduce the incidence, severity, and risk of viral diseases42-45. In addition, several reports have found a strong association between vitamin D deficiency/insufficiency and enhanced COVID-19 severity and mortality45-53 with the most recent study defining low plasma 25(OH)D3 as an independent risk factor for COVID-19 infection and hospitalization54. Therefore, we retrospectively analyzed microarray data of human epithelial cells treated with 20,23(OH)2D3 and 1,25(OH)2D324. We found the downregulation of pathways connected with influenza infection and viral RNA transcription, translation, replication, life cycle and of host interactions with influenza factors with 20,23(OH)2D3 expressing higher anti-viral potency (Table 1).
lWhile 1,25(OH)2D3 has the limitation imposed by the toxicity that includes hypercalcemia7,9, CPY11A1-derived 20(OH)D3, 20(OH)D2 and 20,23(OH)2D3 are not toxic and non-calcemic at very high doses (3-60 pg/ kg) at which 1,25(OH)2D3 and 25(OH)D3 are calcemic55-59.
The hyperinduction of proinflammatory cytokines production (cytokine storm), further magnified by oxidative stress induced by the viral infection or cytokines themselves, acting reciprocally in self- amplifying circuitry, gradually damage/destroy the affected organs leading to death in the severe cases of COVID-19 infection (Fig. 1A). A solution to the problem fulfilling above premises, are active forms of vitamin D including the classical 1,25(OH)2D3 and 25(OH)D3 (precursors to 1,25(OH)2D3) 5,7,9,45,60 and novel CYP11A1-derived hydroxyderivatives including 20(OH)D3 and 20,23(OH)2D3 8,11,61. The former are FDA approved and can immediately be used in the clinic, while the latter are still not approved yet although they fulfill the definition of natural products. They would both terminate “cytokine storm” and oxidative stress with possible anti-viral activity to rescue the patient from the death path (Fig. 1). Their preferable routes of delivery are listed in Fig. 1C to reach immediately the most affected organs. In this context, active hydroxyforms of vitamin D2 should also be considered59,62-64.
As relates to the vitamin D precursor it is reasonable to propose that patients being admitted with COVID-19 infection to receive as soon as possible 200,000 IU of vitamin D2 or vitamin D3 followed by 4,000-10,000 lU/day, if justifiable45,65. Vitamin D3 at 200,000IU orally has been used to attenuate inflammatory responses induced by the sunburn66. It must be noted that application of 250,000- )0 IU of vitamin D was reported be safe in critically ill patients and was associated with increased hospital length of stay and improved ability of the blood to carry oxygen (reviewed in 67,68)
Relevance and perspective
Different routes of delivery of vitamin D precursor can have a profound effect on the final panel of circulating in the body vitamin D derivatives (Fig. 1C). Vitamin D delivered orally during the passage through the liver is hydroxylated to 25(OH)D7, which is not recognized by CYP11A that only acts on its precursor, vitamin D itself 69. This likely results in 30 times lower concentration of 20(OH)D3 in serum in comparison to 25(OH)D314. However, its levels are higher than that of 25(OH)D3 in the epidermis, a peripheral site of vitamin D3 activation14. Therefore, adequate systemic (adrenal gland) or local (immune system) production of CYP11A1-derived vitamin D hydroxyderivatives would require parenteral delivery of vitamin D. These routes of vitamin D precursor delivery could include sublingual tablets, intra-muscular, subcutaneous or intravenous injections as well as its aerosolized form of delivery to the lung (Fig. 1C). As relates CYP11A1-derived products these would be predominantly generated in the adrenal gland for systemic purposes. However, they can also be generated in peripheral organs expressing CYP11A1 including skin and immune system17,70.
Since vitamin D is readily available, easy to use and relatively nontoxic, it can represent an immediate solution to the problems at relatively high doses, since populations most vulnerable to negative outcome of COVID-19 disease are likely vitamin D deficient and the patients are already under supervision in the hospital environment and are monitored for adverse effects. Vitamin D toxicity is typically not observed until extremely high doses of vitamin D in the range of 50,000 100,000 IUs daily for several months or years71. Doses up to 500,000 IUs have been routinely given to nursing home patients twice a year in Scandinavian countries to reduce risk for fracture without any evidence of vitamin D intoxication including hypercalcemia, hyperphosphatemia and soft tissue calcification71.
In addition, we believe that routes of delivery are likely to impact the final outcome, because bypassing liver vitamin D3 will also be accessible to CYP11A1 for metabolism in organs expressing this enzyme.
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- Slominski AT, Kim TK, Takeda Y, et al. RORalpha and ROR gamma are expressed in human skin and serve as receptors for endogenously produced noncalcemic 20-hydroxy- and 20,23- dihydroxyvitamin D. FASEB J. 2014;28(7):2775-2789.
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- Slominski AT, Kim TK, Janjetovic Z, et al. Differential and Overlapping Effects of 20,23(OH)(2)D3 and 1,25(OH)(2)D3 on Gene Expression in Human Epidermal Keratinocytes: Identification of AhR as an Alternative Receptor for 20,23(OH)(2)D3. Int J MolSci. 2018;19(10).
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- Chaiprasongsuk A, Janjetovic Z, Kim TK, et al. CYP11A1-derived vitamin D3 products protect against UVB-induced inflammation and promote keratinocytes differentiation. Free Radic Biol Med. 2020;155:87-98.
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- Slominski AT, Janjetovic Z, Kim TK, et al. Novel non-calcemic secosteroids that are produced by human epidermal keratinocytes protect against solar radiation. J Steroid Biochem Mol Biol. 2015;148:52-63.
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Newer publication by Slominski etc. - Sept 2021
Vitamin D and lumisterol novel metabolites can inhibit SARS-CoV-2 replication machinery enzymes
Download the PDF from VitaminDWiki
Update - Aug 2020
- Reply to Jakovac and to Rocha et al.: Can vitamin D prevent or manage COVID-19 illness - Aug 13, 2020
- X Andrzej T. Slominski,1,7 Radomir M. Slominski,2,3 Paul A. Goepfert,2,4 Tae-Kang Kim,1 Michael F. Holick,5 Anton M. Jetten,6 and Chander Raman2,3
-  Download the PDF from VitaminDWiki
Effectiveness of honey for symptomatic relief in upper respiratory tract infections: a systematic review and meta-analysis - Aug 2020
Vitamin D is not mentioned
Download the PDF from VitaminDWiki
Perhaps 100 IU of vitamin D in 10 grams of honey - June 2020
Detection of 7-Dehydrocholesterol and Vitamin D3 Derivatives in Honey - June 2020 doi: 10.3390/molecules25112583
256 ng/gram of honey = 2560 ng. 10 grams = 2.56 micrograms
ASSUMING (could be way off here) that there are 40 IUs/microgram for 20(OH)D3
Then 10 grams of honey would have 100 IUCOVID-19 cytokine storms perhaps better stopped by the CYP11A1 Vitamin D pathway – Aug 11, 2020
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