At present, the importance of vitamin D should be
considered a global issue [1, 2]. The functions of vitamin
D extend far beyond its participation in the bone tissue
metabolism . The vast majority of people and animals
receive only a small amount of vitamin D (~10% or even
less) with food . In humans, the main source of vitamin
D3is its synthesis in skin from the precursor 7dehydro
cholesterol (7DHC) upon exposure to UV radiation.
Unlike cholecalciferol (vitamin D3), humans and animals
receive ergocalciferol (vitamin D2) exclusively from food.
Therefore, ergocalciferol,in contrast to cholecalciferol,is a
true vitamin for them.
A scheme that is widely used when discussing vitamin
D synthesis was suggested by Holick et al. . This scheme
was primarily developed for vitamin D synthesis in humans.
Further in this paper, we will discuss the problem of vitamin
D formation in a broader sense, since new data have recent
ly appeared in the published literature that should be taken
into consideration. In particular, it was found that vitamin
Ddependent organisms can exist under a wide variety of
conditions, for example, at ambient temperatures below
1516°C and at very low intensity of UV radiation [5, 6].
The stages of calcitriol synthesis are shown in the
scheme. Let us consider in more detail the part of this
scheme that preceeds vitamin D3formation.
VITAMIN D PRECURSORS
It is generally accepted that 7DHC and ergosterol
are two initial compounds in the chain of reactions of
ISSN 00062979, Biochemistry (Moscow), 2018, Vol. 83, No. 11, pp. 13501357. © Pleiades Publishing, Ltd., 2018.
Original Russian Text © H. Göring, 2018, published in Biokhimiya, 2018, Vol. 83, No. 11, pp. 16631672.
Abbreviations: 7DHC, 7dehydrocholesterol; UV, ultraviolet;
vitamin D2, ergocalciferol; vitamin D3, cholecalciferol.
Vitamin D in Nature: A Product of Synthesis
and/or Degradation of Cell Membrane Components
1Göring Consulting, De 12555, Berlin, Germany
Received June 4, 2018
Revision received July 3, 2018
Abstract—The review discusses the data on vitamin D accumulation in animals, plants, and other organisms. 7Dehydro
cholesterol (7DHC) and ergosterol are considered to be the only true precursors of vitamin D, although even vitamin D2
(ergocalciferol) is not fully comparable to vitamin D3(cholecalciferol) in regard to their functions. These precursors are
converted by UV radiation into the corresponding D vitamins. There are a few published reports that this reaction can also
occur in the dark or under blue light, which is unexpected and requires explanation. Another unexpected result is conver
sion of provitamins D (7DHC and ergosterol) into vitamin D3and D2via previtamin D at low temperatures (<16°C) in
the lichen Cladonia rangiferina. An extensive survey of literature data leads to the conclusion that vitamin D is synthesized
from (1) 7DHC via lanosterol (D3) in land animals; (2) 7DHC via cycloartenol (D3) in plants; (3) ergosterol via lano
sterol (D2) in fungi; and (4) 7DHC or ergosterol (D3or D2) in algae. Vitamin D primarily accumulates in organisms, in
which it acts as a prohormone, e.g., land animals. It can also be found as a degradation product in many other species, in
which spontaneous conversion of some membrane sterols upon UV irradiation leads to the formation of vitamins D3or D2,
even if they are not necessarily needed by the organism. Such products accumulate due to the absence of metabolizing
enzymes, e.g., in algae, fungi, or lichens. Other organisms (e.g., zooplankton and fish) receive vitamins D with food; in this
case, vitamins D do not seem to carry out biological functions; they are not metabolized but stored in cells. A few excep
tions were found: the rainbow trout and at least four plant species that accumulate active hormone calcitriol (but not vita
min D) in relatively high amounts. As a result, these plants are very toxic for grazing animals (cause enzootic calcinosis). In
connection with the proposal of some scientists to produce large quantities of vitamin D with the help of plants, the accu
mulation of calcitriol in some plants is discussed.
Keywords: vitamin D synthesis, UV radiation, vitamin D precursors, vitamin D thermal isomerization, vitamin D accumu
lation, vitamin D degradation product, plant calcitriol
VITAMIN D SYNTHESIS IN NATURE 1351
BIOCHEMISTRY (Moscow) Vol. 83 No. 11 2018
vitamin D synthesis. However, if we discuss this issue in
more general terms, i.e., search for the precursors of
compounds that possess the properties or functions of
vitamin D, the range of such precursors becomes much
Firstly, there is a group of other sterols that could be
converted into substances similar to vitamin D in the UV
induced photochemical reaction :
22,23dehydroergosterol → vitamin D4;
7dehydrositosterol →vitamin D5;
7dehydrostigmasterol → vitamin D6;
7dehydrocampesterol → vitamin D7.
As early as 1968, the first study was published that
compared distribution and functions of vitamins D4and
D3in rat tissues . Unfortunately, no results were
obtained that would have allowed the representatives of
this group to be considered functionally similar to vita
mins D3or D2. Therefore, there is no reason to consider
the original sterols as vitamin D precursors as well.
Secondly, 7DHC is hydroxylated by CYP11A1 with
the formation of 22(OH)7DHC and 20,22(OH)27
DHC that are further converted into 7dehydropreg
nenolon and, finally, into Δ7steroids. In skin, Δ7
steroids form secosteroids under UV radiation. Their
physiological activity is similar to the activity of some
vitamin D metabolites. For example, 21(OH)pregnacal
ciferol inhibits formation of melanoma cell colonies to
the same extent as 1,25(OH)2D3. At the same time,
these compounds display no typical hormonal effects on
bone metabolism and other organism functions.
Assuming that we are searching for a precursor in the
synthesis of active calcitriol hormone or a functionally simi
lar compound,we can reliably refer only to 7DHC and
VITAMIN D AND UV RADIATION
In our earlier review, we concluded that “without the
UV part of the solar radiation spectrum, no vitamin D
would be present on the Earth at all!” . This statement
is based on the data of many papers published already in
the first years of studying vitamin D . It is assumed
that the B ring in the 7DHC molecule can be opened by
the energy of photons (18 mJ/cm2) in the 282310 nm
range, which corresponds to UVB radiation [14, 15].
However, the results of some studies contradict this
view. A new mechanism of vitamin D synthesis in the
Scheme of calcitriol synthesis (based on the study by Chen et al.  with modifications)
1) 7DHC (provitamin D) “previtamin D”
2) “previtamin D” vitamin D3
3) vitamin D325(OH)D3(calcidiol)
(Hormone active form)
(Inactive circulating form?)
(At what temperature can thermal isomerization take place?
Is vitamin D3inactive intermediate?)
(Are there other precursors? Is UV radiation necessary?)
BIOCHEMISTRY (Moscow) Vol. 83 No. 11 2018
absence of UV radiation was discovered in cultured
Solanum glaucophyllum cells [16, 17]. In these cells (both
in tissue culture and in suspension), the B ring in 7DHC
was opened in the dark. Unfortunately, the cited studies
did not provide explanation for the observed phenome
Several years ago, the effect of UVB radiation on the
accumulation of vitamin D and its hydroxylated metabo
lites in plants from the Solanaceae family was studied in
special climatic chambers . In these experiments,
control plants were grown at a 16 h light/8 h dark cycle
without UV irradiation. If even a small fraction of UV
were present in the light source, photochemical forma
tion of certain amounts of vitamin D and 25(OH)D
should have been expected. And if not? In the review 
published soon after, the authors wrote that “vitamin D3
synthesis without the action of UVB has also been report
Another interesting example is formation of vitamin
D from 7DHC in the skin of rainbow trout
(Oncorhynchus mykiss) under blue light (380480 nm). It
is interesting that in this case as well, 1,25(OH)2D3was
accumulated instead of vitamin D3or 25(OH)D3. It
should also be noted that in trout, calcitriol is synthesized
in the liver and not in kidneys (as in land animals) .
Nevertheless, considering a large number of pub
lished works and theoretical considerations, one should
proceed from the assumption that UV radiation is essen
tial for the photochemical reaction of 7DHC and ergo
sterol conversion. Under its action, photolysis of 7DHC
and ergosterol can occur even in a test tube with hexane
 or other solvents of lipids. This reaction proceeds
faster by an order of magnitude when the sterols are
embedded in biological membranes. It also takes place
under the sunlight in biological waste (e.g., in feces) or,
for example, in hay . At the same time, the rate of this
process largely depends on already existing conditions
VITAMIN D FORMATION AND CONDITIONS
FOR THERMAL ISOMERIZATION
The optimal condition for the previtamin D ther
mal isomerization is considered to be at a temperature of
≥25°C [13, 21]. Such temperature conditions may fully
explain the wide occurrence of vitamin D in nature: in the
skin of warmblooded (homoiothermic) animals, on
land, and in the upper layers of the oceans, reservoirs and
rivers in equatorial areas inhabited by vast amounts of
plankton organisms of various phylogenetic origin. The
membranes of plankton cells contain many different
sterols, including 7DHC and ergosterol.
However, humans and animals also live in colder ter
ritories away from the coasts, for example, in the Arctic
and Subarctic tundra. Although the intensity of UV radi
ation in the farnorth regions is low, it remains sufficient
for the synthesis of vitamin D from sterols [22, 23], espe
cially in summer, when the sun shines for almost 24 h a
Another important question is the role of thermal
isomerization in the process of vitamin D formation from
the previtamin in arctic conditions. According to the
scheme, a temperature of ≥25°C is required for previta
min D thermal isomerization . However, in this case,
specific conditions of isomerization are important . If
conversion of 50% previtamin D into vitamin D at 37°C
in hexane solution takes 30 h, achieving the same result in
human skin at the same temperature takes only 2.5 h [24,
25]. Not only the equilibrium of this reaction is shifted
toward the vitamin D formation, but the reaction rate is
increased by more than 10 times . The reaction rate
changes significantly in aqueous medium in the presence
of βcyclodextrin . Under these conditions, the reac
tion rate constant for previtamin D conversion into vita
min D, as well as the reaction rate constant for the reverse
reaction, increases more than 40 and 600 times, respec
tively, compared to the reaction in nhexane.
It is known that vitamins D2and D3are accumulat
ed, for example, in the reindeer lichen Cladonia rangiferi
na in the Arctic and Subarctic regions [5, 27], where the
maximum temperature rarely exceeds 16°C (mostly stays
within 510°C in summer). Unfortunately, there are little
data on the rate of vitamin D formation under these con
ditions, when all biological processes occur at extremely
slow rates. The annual growth rate of reindeer lichen is
~15 mm at its best. The vitamin D content in the lichen
depends not only on the rate of its synthesis, but also on
the rate of its metabolism (see the next section).
In some organisms, thermal isomerization of previta
min D into vitamin D occurs at temperatures significantly
C. Do these organisms possess specific adaptations
or “catalysts” for the thermal isomerization of previtamin D
into vitamin D at low temperatures? Might vitamin D accu
mulation occur due to its lowrate formation in the absence
of metabolization or at its significant slowdown?
WHICH ORGANISMS SYNTHESIZE
VITAMIN D PRECURSOR?
It is obvious that the formation of the precursor is a
prerequisite for vitamin D synthesis, since the next stage
of this process is carried out without any contribution
from specific enzymes. Certainly, one can expect that
morphological and anatomical features, as well as intra
cellular compartmentalization of the reaction compo
nents, may influence the rate of formation and the quan
tity of the reaction products. Plants synthesize a large
variety of chemical compounds, but this does not mean
that these compounds may be found in tissues in more or
less significant amounts, since they may be intermediate
VITAMIN D SYNTHESIS IN NATURE 1353
BIOCHEMISTRY (Moscow) Vol. 83 No. 11 2018
products in the chains of reactions. On the other hand, if
a compound is consumed with food by an organism lack
ing enzymes for further metabolization of this compound,
it simply accumulates in the cells. Fatsoluble products
accumulate in special fat cells (adipocytes), as vitamin D
does in animals .
To illustrate this, let us consider an organism that is
often mentioned in literature on vitamin D, namely the
planktonic coccolithophore Emiliania huxleyi. This species
of plankton has existed in the Sargasso Sea for over 750
million years [11, 31]. In terms of dry weight, E. huxleyi
contains up to 0.1% ergosterol. Ergosterol is an essential
component of cell membranes of many organisms. If
plankton accidentally enters the upper layers of the ocean,
a certain portion of ergosterol is converted into vitamin D2
by UV radiation at sufficiently high temperatures. This
process occurs without any participation of specific
enzymes. The product of this accidental exposure to UV
radiation does not undergo further metabolization, since
cells do not have the necessary enzymes. In this case,vita
min D2is most likely a product of damage or even degradation
of biological membranes under the action of UV radiation.
Which organisms are capable of vitamin D synthesis
and which organisms accumulate it as a degradation prod
uct? 7DHC and animals. The fact that in the animal
world, 7DHC serves as a precursor for the synthesis of
vitamin D under the action of UV light is generally
accepted. This process takes place in most land animals,
from amphibians to primates . In animals, cholesterol
is formed from lanosterol [32, 33]. At the same time, 7
DHC and cholesterol are also found in many plants,
algae, and cyanobacteria.
7DHC and plants. For a long time, it had been
assumed that only vitamin D2is synthesized in plants.
The synthesis of vitamin D3was discovered later . In
fact, all data demonstrating vitamin D2formation in
plants result from contamination of plant material with
fungal hyphae . Although plants possess a fairly
high number of sterols, they lack ergosterol and, conse
quently, vitamin D2. In plants, 7DHC is commonly
found in very low concentrations, amounting to only 1
2% of the total content of sterols, although in some
plants, the concentration of 7DHC can be approximate
ly an order of magnitude higher .
Vitamin D3and its metabolites, including calcitriol
(1,25(OH)2D), were found in some plants. The following
plants contain vitamin D3and its metabolites, including
calcitriol, in relatively large amounts: Solanum malacoxy
lon , Lycopersicon esculentum [46, 47], S. tuberosum
[33, 46], S. melongena , Cucurbita pepo subsp. pepo
convar. giromontina , S. glaucophyllum (plants and
cell culture) [16, 17, 48], Nicotiana glauca [33, 49],
Cestrum diurnum , and Trisetum flavescens [51, 52]. It
is surprising that some of these plants not only synthesize
vitamin D3, but also accumulate extremely high concen
trations of calcitriol. This primarily applies to four
species: S. malacoxylon , S. glaucophyllum , C.
diurnum , and T. flavescens [51, 52] that prove to be
very dangerous for livestock (cows, sheep, horses, goats,
pigs, and other animals). After eating them, animals fall
ill with hypercalcemia (enzootic calcinosis). This disease
develops as a result of massive intake of vitamin D3, as
well as its active metabolite calcitriol. In Europe, a com
mon cause of hypercalcemia is the yellow oat grass T.
flavescens that typically grows in the European Alps and
the Caucasus [51, 52, 54, 55]. The toxic effect of this
plant is greatly increased after it dries in the sun . In
South America, the toxic effects of vitamin D in some
animals can result from consumption of S. glaucophyllum
and S. malacoxylon of the Solanaceae family. Cestrum
diurnum, which is another Solanaceae species often con
sumed by livestock, grows in North America (USA) .
It had been believed before that plants do not contain
vitamin D3. This view was based, on one hand, on a very
low vitamin D3content in most plants , and on the
other hand, the use of insufficiently sensitive analytical
methods . In recent years, some authors have come to
the conclusion that cholesterol is characteristic of all
plants, since it is an intermediate product in the synthesis
of steroid glycoalkaloids and phytoecdysteroids .
Cycloartenol is considered to be a precursor of 7DHC in
plants [32, 33].
7DHC and algae. Cholesterol was found in green
, brown  and red  algae . Seckbach and
Ikan  suggested that cholesterol apparently occurs in
all groups of plants, since it occupies a key position in the
biosynthesis of other steroids.
Ergosterol and fungi. The presence of ergosterol,
often in relatively high concentrations, is characteristic of
all fungi . Ergosterol is a dominant sterol in fruit bod
ies of wild and cultivated fungal species . Moreover,
three other sterols were found in fungi, although in low
concentrations: ergosta7,22dienol, ergosta5,7dienol,
and ergosta7enol. The content of vitamin D2in fungal
fruit bodies could be increased 9 to 14fold by UV irra
diation at 254 nm for 2 h at a distance of ~20 cm. Similar
data were obtained in other laboratories as well [62, 63].
These results demonstrate that fungi possess significant
reserves of ergosterol that could be converted into vitamin
D2by UV radiation. Ergosterol in fungi, like 7DHC in
animals, is synthesized from lanosterol .
Ergosterol and algae. Ergosterol was also found in
various species of algae, e.g., Dunaliella tertiolecta ,
Chlamydomonas reinhardtii [65, 66], Chlorella vulgaris
, and Cyanidium caldarium [59, 68] (see also the study
by Bjorn and Wang ).
Therefore, the pathways for the synthesis of vitamin D
precursors vary in different groups of organisms:
– land animals – 7DHC from lanosterol;
– higher plants – 7DHC from cycloartenol;
– fungi – ergosterol from lanosterol;
– algae – 7DHC or ergosterol.
BIOCHEMISTRY (Moscow) Vol. 83 No. 11 2018
WHICH ORGANISMS ACCUMULATE
Up to this moment, we have been mainly interested
in the occurrence of vitamin D and its precursors in vari
ous organisms and only briefly touched the issue of its
accumulation. After all, not all animals require vitamin
D; nevertheless, many of them can accumulate it in sig
For example, plankton, which is the first link in the
food chains for many animals, is rich in vitamins D2and
D3. This is particularly typical of plankton in tropical and
subtropical regions. Water circulation in the oceans, in
particular the Gulf Stream current, carries plankton to
distant oceans and seas. In this way, vitamin D is trans
ported, for example, far north, where it performs an
important function in land animals and humans .
However, this benefits only coastal regions, as well as
regions permanently covered with ice.
There are small nation populations inhabiting, for
example, the northern regions of Russia (between lati
tudes of 5767°N) . They live relatively far from sea
coasts and are almost completely deprived of vitamin D
sources from the sea plankton. UV radiation in farnorth
ern habitats is clearly insufficient for providing humans
(and animals?) with required amounts of vitamin D.
Their survival depends on the presence of vitamin D in
food. In this case, the initial source of vitamin D is
lichens. Ergosterol and 7DHC, as well as vitamins D2
and D3, were found in the reindeer lichen (Cladonia
rangiferina) that grows in the far north of Russia and other
countries (5770°N) [27, 69]. This symbiotic organism
consisting of a fungus and an alga accumulates vitamins
D2and D3. It forms the first link in a food chain, since it
is the main food source for reindeer in winter. Reindeer
accumulate D vitamins in muscle tissue, giving humans
and predatory animals an opportunity to receive vitamin
D in sufficient quantities.
The concentrations of vitamins D3and D2in the
reindeer lichen are within 67204 and 2255 μg per 100 g
of dry matter, respectively . Moreover, reindeer lichen
also has high ergosterol content. For example, let us
compare the known numbers for certain food products
with a high vitamin D concentration (μg per 100 g of fresh
matter): eggs – 0.412; cheese – 1.25; chicken liver –
1.20; beef liver – 014.1; herring – 2.238.0; trout – 4.2
34.5; fungi – 0.330.0. Reindeer lichen exceeds all the
abovementioned products in its vitamin D content.
A question arises on how can lichens form vitamin
D under these harsh conditions? Calculations demon
strate that even at 70°N, the daily dose of UV radiation in
summer may be quite sufficient for vitamin D biosynthe
sis in lichens . It should be emphasized that even if
the growth rate of reindeer lichen is very low (~320 mm
per year), it grows on vast areas of tundra and light forests
of taiga. In winter, reindeer lichen is the main food
source for reindeer, which consume only the uppermost
part of lichen branches. In addition to reindeer, foxes,
arctic foxes, snow sheep, wolves, lemmings, brown hares,
and some other animals can be found in northern
regions. These regions are sparsely inhabited, but people
began to populate them already ~45,000 years ago ,
when they moved from NorthEast Siberia to the west
and occupied these places as nomadic hunters or rein
There are many organisms in which the concentra
tions of vitamin D and its precursors are very low. Plants
are a good example. They possess these compounds only
as intermediates. In other cases, vitamin D can be accu
mulated in significant amounts, for example, in various
algae that use sterols as building materials for the mem
branes. Such sterols, including UVsensitive cholesterol
and ergosterol, are converted into vitamins D2and D3
under highintensity UV radiation at relatively high tem
peratures of water. The mechanism of formation of these
vitamins is clear; however, it is still unknown whether they
possess any function in these organisms. Most likely, they
do not. From an evolutionary viewpoint, as long as accu
mulated vitamin D does not harm the cells in which it is
formed, its excessive accumulation does not matter for the
natural selection. It may be assumed that similar passive
accumulation occurs in representatives from the protozoa
to aquatic lower vertebrates, as well as in fungi and lichens.
The situation is quite different in land animals,
including humans. These organisms can accumulate
additional amounts of vitamin D as a result of its synthe
sis under UV radiation or consumption with food. In this
case, a portion of vitamin D is accumulated as a reserve
together with other fatsoluble compounds (e.g., vitamins
A, E, and K) in adipocytes.
However, some cases were described that do not fit
into this scheme. For example, the blood levels of vitamin
D in naked mole rats living in the underground colonies
are very low, but at the same time, these animals have a
high content of the Klotho protein, a component of the
antiaging mechanism, whose role in life in the dark is
currently being studied . In his review ,
Dammann also discusses alterations in the Klotho levels
in another group of nocturnal animals, bats.
“IN PURSUIT OF VITAMIN D IN PLANTS”
Articles with similar titles have appeared in scientific
journals, in which the authors declare the urge for inten
sifying efforts for creating plant mutants capable of vita
min D synthesis and accumulation [19, 38, 73]. Some
researchers believe that plants can also synthesize vitamin
D in the dark  (see the section “Vitamin D and UV
radiation”); for this reason, they call for studying the
capacity of underground plant organs to synthesize vita
min D. Other scientists refer to the necessity for UV radi
VITAMIN D SYNTHESIS IN NATURE 1355
BIOCHEMISTRY (Moscow) Vol. 83 No. 11 2018
ation in this synthesis and emphasize that vitamin D is
synthesized in animal skin and plant leaves .
The idea of using plants as a source of organic vita
min D to meet human needs is tempting. Indeed, plants
with high vitamin D content have been found (four
species so far; see section “7DHC and plants”).
Unfortunately, these plants contain not only vitamin D3,
but even higher concentrations of active calcitriol. While
unicellular organisms accumulate vitamin D as the final
product and land animals accumulate it in the form of
25(OH)D3, in these four plant species, synthesized vita
min D is immediately hydroxylated, forming 25(OH)D3,
which is then converted into calcitriol.
The corresponding hydroxylases in plants are so
active that the entire chain of reactions of calcitriol for
mation occurs without any kind of reverse regulation. The
accumulation of significant amounts of calcitriol indi
cates the absence of its metabolization in plant tissues.
And how can the reaction chain be stopped at the vitamin
D stage? Cultivated plants with high calcitriol content
would be poisonous and unfit for human or animal con
sumption (see section “7DHC and plants”).
Using vitamin D from plant sources is likely to be
complicated. Is it possible that using algal cultures would be
a more promising approach to producing vitamin D
enriched food products?
If we proceed from the scheme, the last two reactions
remain out of our scope. They are rather linked to the
issue of the mechanism of vitamin D action. Neither the
role of vitamin D2, nor that of other D vitamins and their
analogs are discussed in this review. If we consider the
functions of vitamin D in treating rickets and some other
bone diseases, then D2should be obviously placed in the
group of D vitamins . In literature, vitamins D3and
D2are often compared with respect to the accumulation
of the corresponding forms of 25(OH)D . Some
authors believe that vitamins D2and D3are equally avail
able biologically, regardless of whether they are consumed
with food or taken in capsules . However, no direct
comparison of the effects of vitamins D2and D3has been
carried out . On the other hand, it has been convinc
ingly demonstrated that vitamin D3significantly improves
the overall level of 25(OH)D with much higher efficiency
than vitamin D2[76, 79, 80]. It should be emphasized
that this applies only to the accumulation of 25(OH)D2
and 25(OH)D3. It is not the formation of 25(OH)D2and
25(OH)D3from vitamins D2and D3that is of interest, but
rather the physiological responses caused by the action of
these two forms of vitamin D. Unfortunately, there are
still very little data regarding this issue .
Conflict of Interests
The author declares no conflict of interests.
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