Pharmacology of vitamin D, Anything new?

Hartmut H. Glossmann, Hartmut.Glossmann at i-med.ac.at; Institute for Biochemical Pharmacology, Innsbruck, Medical University,Peter Mayr Str. 1, A-6020 Innsbruck, Austria
Osteologie 4/2011 © Schattauer 2011
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Dr. Glossmann also had an excellent slide presentation in Oct 2011 Glossmann - 2011.pdf

Here are a few samples:

CLICK HERE for Sports page containing the stress fractures and fitness slides]
CLICK HERE for separate page made on non-response]
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PDF preliminary and final versions are attached at bottom of this page

following text is from the preliminary version of the paper

Summary

A main source of food for ancient humans ("hunter-gatherers") was fresh meat. It contains much more 25-(OH)-vitamin D3 (25[OH]D3) than vitamin D3. It seems likely that in northern Europe, where vitamin D is in short supply during the extended winter season, evolutionary forces may have led to optimization of intestinal absorption of 25(OH)D3: excellent oral bioavailability (60-80%) and little inter-individual variation. 25(OH)D3 could be considered the ideal oral "sunshine equivalent" for rapid and reliable restoration of an adequate vitamin D status e. g. in clinical situations. Unless biliary and pancreatic secretion or epithelial function in the small intestine is compromised, vitamin D3 in „pharmacological doses" is absorbed by 60-100 % as a „blind passenger" together with long-chain fatty acids and cholesterol. The question is raised whether very low amounts of the vitamin (as in the diet) are absorbed by a more active ("second order") mechanism. Experimental evidence obtained from cell culture systems indeed suggests that vitamin D3 can be taken up in part from enterocytes via the same complex, tightly regulated and saturable transport system as is e.g. cholesterol. The ezetimibe drug receptor NPC1L1 may play a role in this process. The Apolipoprotein Epsilon 4 genotype occurs in a north-south gradient in Europe. Allele frequencies are as high as 30% in Finland and much lower, 5%, around the Mediterranean Sea.The Epsilon 4 genotype may have been selected in the north because it enables more vitamin D to be obtained from food. The association of higher levels of 25(OH)D3 in humans with the Epsilon 4 genotype, together with evidence from knock-in mice, supports this hypothesis. It is possible, but as yet unproven, that this "lipid-thrifty" genotype is the cause of excess cardiovascular mortality sometimes observed in cohorts with high serum concentrations of 25(OH)D. Latitudinal gradients for mutations in the enzyme delta-7-dehydrocholesterol reductase (DHCR-7) suggest that similar evolutionary adaptations occurred for vitamin D synthesized in the skin following sun exposure.

Data on the bioavailability of orally applied vitamin D3 in "pharmacological doses" are straightforward: The vitamin is absorbed almost completely into the general circulation with little inter-individual variation, provided epithelial function in the small intestine and pancreatic as well as biliary secretion are normal. The "vehicle" for the vitamin must contain long-chain fatty acids or it must be given with a "standard meal". Sunlight-derived vitamin D3 has a similarly high bioavailability, but always increases - in extreme contrast to the oral route- serum levels of 25(OH)D3, depending on prior status. The oral acquisition of very small amounts of the vitamin in the diet is not well understood. Perhaps, an evolutionary selection process of genes responsible for fatty acid and cholesterol absorption has occurred, also favoring vitamin D uptake. Here we will review recent findings which point in this direction.

Oral bioavailability of vitamin D3 and calcidiol Vitamin D3

In the early days of vitamin D research, radiolabelled cholecalciferol was employed to follow oral absorption, metabolism and tissue distribution in human volunteers or patients (1-3). Although by no means following today's scientific or ethical standards, the conclusions that can be drawn from these studies are:
First, the absorption of orally applied vitamin D3 between 3 |Jg and 1 mg (40000 I.U.) is between 60 and 99 %, if given with milk, long-chain fatty acid containing triglycerides or a "standard meal".
Second, the absorption of these doses depends on the bile acid and cholesterol secretion capacity of the liver, is dependent
on pancreatic sufficiency and, as mentioned above, is a function of the "vehicle" as also shown by non-radioactive assays (4). Vitamin D3 can be regarded as a "blind passenger" traveling with long- chain fatty acids, bile acids and cholesterol in the intestinal tract. It ends up in chylomicrons after passing through enterocytes in an uncontrolled "first-order" process: The dose absorbed is a linear function of the dose applied.
Third, whereas vitamin D3 resides mainly in adipose tissue, 25(OH) vitamin D3 in humans (and in some animals, see below) is mainly stored in skeletal muscle. As the authors put it: "by binding to tissue proteins".

There is one report in the literature where vitamin D3 was given to fasting volunteers with water. Surprisingly, in these conditions single-dose pharmacokinetics of vitamin D3 exhibit extreme variations (?Table 1) in AUC0-120h (Area Under the Curve) or AUC0-80h for 2800 or 5600 I.U. vitamin D3, respectively. AUC varies from ~ 64 to ~ 1700, about 25-fold. Cmax values, correspondingly, also varied between 1.5 and ~ 34 ng/ml. Both parameters were unadjusted for base-line levels, which were around 3 ng/ml (5). Apparently, fasting individuals differ in their ability to provide sufficient transport for the "blind passenger". Sufficient means: basal secretion of cholesterol, bile acids and phospholipids. We suspect that dispositions for (re-)absorbing cholesterol, in-cludingbile acid secretion (see e.g. [6]) or the extreme inter-individual variations in fatty acid and cholesterol transporter protein expression along the human intestinal tract (7) may play a role in these conditions.

Variability of vitamin D3 absorption between fasting individuals receiving water instead of a standard meal or oil with long chain fatty acids must not be confused with the extremely variable responses of the circulating metabolite 25(OH)D after oral, pharmacological doses of vitamin D3. For instance, a close inspection of Figure 3 in (8) reveals that of 16 volunteers (5 males, 11 females, average age 74 years, receiving 1600 I.U. daily) 7 (~ 50%) had no increase or even a decrease of serum 25(OH) vitamin D3.

Table 1

Properties of vitamin D3 and calcidiol: F.W. = Fasting volunteers; vitamin D3 given with Water. M. = volunteers received milk, or long-chain fatty acids containing triglycerides and/or a standard meal together with the vitamin. VDBP = Vitamin D Binding Protein (GC); n.d. = not determined; observed half-life and tmax (maximum concentration achieved after single oral doses) are dependent on the absorption constant. Hence, the decline in plasma concentration is not identical to the plasma elimination half-life. In addition, „body-half-life" of vitamin D3 (and, possibly, 25[OH] vitamin D) is much longer. As an example for intracellular high-affinity calcidiol binding proteins, heat shock protein 70 is mentioned (see text). Direct binding of vitamin D3 to proteins involved in cholesterol uptake and transport (e.g. NPC1L1) has not been investigated. The EC50 value for calcidiol refers to the concentration leading to 50% of a maximal response in a model system for non-genomic signal transduction via the "VDR-Alternative-Pocket" of the vitamin D receptor (VDR, see text). A single, still unconfirmed analysis demonstrated high-affinity binding of vitamin D3 to smoothened, a member of the Hedgehog signal transduction pathway (32).
ParameterVitamin D3 25(OH)vitamin D3
Bioavailability [F]
• skin(UV-B) • 1.0 • -
• oral
-oralF.W. -extreme variability(0-?) -0,8
-oralM -0.6-1.0 -0,8

Oral bioavailability of calcidiol

The oral bioavailability of calcidiol is high (?Table 1). Itis absorbed via the portal vein, exhibits very little inter-individual variation and - in contrast to oral vitamin D3 - leads to an almost immediate and predictable increase in the circulation (?Table 1). If daily or weekly doses of vitamin D3 are given, it takes several months (!) until a pseudo steady-state between input of the precursor and serum levels of its metabolite calcidiol is reached, not to mention "Non-Responders" (see the above example).
In contrast, as exemplified by a recent small study with female volunteers (BMI = 23.5 ±3.2kg/m2) receiving 500 |Ug (~ 1250 nMol) of calcidiol monthly (equivalent to 0.24 ng/kg/d, assuming a mean 70 kg body weight) raised average serum levels from ~ 45 nM to ~ 125 nM (difference: 80 nM) already on day 3 and on day 120 (9). The formula derived by (10) predicts that the increase in 25(OH)D3 should be: 327.5x0.24 = 78.6, which is almost too good to be true. Nevertheless, the results indicate the general validity of the equation. If the distribution volume is in the reported range of 0.12 to 0.2 l/kg BW (?Table 1), the observed total body increase is in the range of 700 to 1120 nMol. From the total body increase we can calculate an oral bioavailability of 60-90 %. Animal experiments indicate a significant pre-systemic catabolism to the 24-(OH) metabolite of calcidiol (11) but data for humans are missing.

25(OH)D3 (similarly to curcumin) has an additional binding site on the vitamin D receptor (?Table 1) termed "VDR-Alter-native-Pocket", VDR-AP (12). Calcidiol can exert with equal EC50 values as calcitriol so-called rapid (non-genomic) responses which may - in model systems - also amplify gene expression (13). Therefore, long term clinical trials are needed to establish benefits and risks of calcidiol as a complete substitute for vitamin D3.

Calcidiol - optimal supply for our "hunter ancestors"

It takes many months to build up calcidiol levels after pharmacological doses of vitamin D3. One wonders how our ancestors in northern Europe coped with the problem of vitamin D3 supply given the much smaller amounts present in their food. Most likely, the hunters' major source was calcidiol in meat.

Indeed, content of 25(OH)D3 in voluntary muscle ("meat") is high and in steaks up to 25 ng/g wet weight, if cows are raised on pasture in summer (14). The high content cannot be explained by plasma contamination and suggests intracellular binding proteins. A member of heat-shock protein family (hsp70) binds calcidiol with high affinity (15), but there probably are more candidates among other sterol (and oxysterol) binding proteins. Speculative, but interesting is that other natural steroid hormones (e. g. estradiol) have a very significant first-pass-effect. In contrast, the pro-hormone calcidiol (similar to calcitriol) is not destroyed before reaching the general circulation. Higher affinity and plasma concentration ("avidity") of the vitamin D binding protein may have resulted from an evolutionary selection process to obtain more of the hormone precursor from food.

A saturable (second order) process for absorption of dietary vitamin D3

Is Vitamin D3 not only a blind passenger?

Dietary cholesterol and vitamin D3 for humans are obtained exclusively from animal sources. Saltwater fish can also supply it, but mainly in esterified form. Vitamin D3 content in steaks (animal meat) is between 0.8 and 16 ng/g fresh tissue (14) and in lamb cuts up to ~ 1 ng/g (16). Meat and fish contain ~ 0.5 mg cholesterol per gram of fresh tissue. The ratio cholesterol: vitamin D3 is of such a magnitude that even the most sophisticated transport and sorting system cannot distinguish between the two. Can vitamin D3 enter the systemic circulation by specific uptake systems, responsible for cholesterol (17) and long-chain fatty acid transport?

Reboul et al. (18) report that vitamin D3 (and D2) transport in Caco-2 cells is a saturable, direction- and temperature-dependent ("second-order") process. In their experiments, cells were grown on transwells as a monolayer; apical chambers were exposed to mixed micelles containing (lyso-) phospholipids, oleic acid, 100 | M cholesterol and 0.01-10 uJM vitamin D. In these conditions, the maximal transport rate for both vitamin D3 and D2 was ~ 110 pmol/ h/mg of protein, with half-maximal concentrations for saturable uptake of ~ 0.2 | M. The authors demonstrated that uptake and transport were unidirectional (from apical to basolateral) and that at "pharmacological" concentrations (>2 to 4 | M), vitamin D uptake was no longer saturable but linearily related to the concentration, a seen in human studies. In addition, they demonstrated weak inhibition by ezetimibe glucuronide in the Caco-2 cell system and increased vitamin D3 uptake in human embryonic kidney (HEK) cells when Niemann-Pick C1-like 1 (NPC1L1) was overexpressed. The latter protein may not be the sole transporter as others (e.g. scavenger receptor class B type I), when overexpressed in HEK cells, facilitated vitamin D directional transport as well. Surprisingly, within the limits of the concentration range of cholesterol in the micelles (zero to 200 | M), there was little competition with 0.5 | M vitamin D3.

In a second publication, (19) P-sitoste-rol and cholesterol impaired the micellar concentration of vitamin D3. Furthermore, force-feeding mice with vitamin D3 (100 ug) and 10 mg of P-sitosterol reduced the plasma concentrations of cholecalciferol dramatically. Vegetarians may possibly suffer from low absorption of vitamin D3 in supplements - but this still remains to be proven.

Caco-2 cells are not an ideal system to study the direct role of NPC1L1 in sterol transport, as most of it is expressed intra-cellularly. Merck researchers have developed cell lines in which flux of sterols (bound to albumin) can be studied as a function of NPC1L1 expression on the apical plasma membrane (20). In these optimized cells, both cholesterol and P-sitosterol flux are exquisitely sensitive to P-lac-tame-based ezetimibe analogues and ezetimibe glucuronide. Such a system could be useful to study NPC1L1-mediated vitamin D uptake in a more direct manner. The sterol binding domains of NPC1L1 (21, 22) and NPC1 can be also directly explored with respect to affinity and specificity for vitamin D.

Uptake into enterocytes is a necessary but by no means sufficient step for absorption (i.e. entry into the systemic circulation). Phytosterols are a good example: they are taken up but enter the general circulation only in minute amounts (23).

Phytosterols, serum 25(OH)D levels and HDL-cholesterol

The idea is intriguing that for the very low amounts of food-derived (dietary) vitamin D3, saturable uptake processes play a significant role. In this context, please note that low and high absorbers of dietary cholesterol differed most significantly in their serum HDL-levels: High absorbers had higher levels (24, 25). It is tempting to speculate that the high absorbers import vitamin D3 twice as well as the low absorbers. In 22 cross-sectional studies, serum 25(OH)D levels were positively associated with HDL-C (26). Do higher levels of serum 25(OH)D and phytosterols reflect better absorption of dietary sterols including vitamin D? If so, there maybe no causal relationship between (phytosterol or) 25(OH)D levels and HDL-C.

Genome-wide-association studies, serum calcidiol levels and Apolipoprotein E

Genome-wide association studies so far have identified three main players determining vitamin D status in populations (27), among them two enzymes involved in vitamin D metabolism and catabolism (?Fig. 1) or determining the steady-state level of the precursor 7-dehydrocholesterol in the skin (3-P-hydroxysterol-delta-7-re-ductase, DHCR-7). The third player is the vitamin D Binding protein (VDBP = GC) which transports cholecalciferol from the skin into the general circulation and calci-diol from the intestine to the liver as well as to other tissues and cells. The carrier frequency of DHCR-7 mutations in Caucasians, which can be as high as 2.3 %, was suggested to be advantageous for obtaining vitamin D3 from the sun (28). Correlations between serum 25(OH)D levels and carriers are not yet investigated. As humans in addition to UV-B may obtain vitamin D3 (or 25(OH)D3) orally, one wonders whether correlations to transport systems in the intestine and the lipoproteins involved in cholesterol and lipid traffic as well as bile acid production would also showup in these studies.

Apolipoprotein Allele e4 - better bones but earlier death?

In 2003, Lars Ulrik Gerdes (29) published an opinion paper in which he speculated that the geographical distribution of the apolipoprotein E (APOE) allele £4 in Europe (south to north gradient) protected against vitamin D deficiency. Eisenberg et al. (30) recently analyzed the worldwide frequencies of the £4 allele of apolipoprotein E gene under the hypothesis that this allele would protect against low cholesterol levels. They concluded that natural selection has been responsible for the observed frequencies - both south and north of the equator. The relative effects of skin colour and UV-B irradiance were not considered. Interestingly, when increasing elevation (which increases skin vitamin D production via higher UV-B levels) was included in the various models (in order to account for lower temperature) the result was opposite to the expected but is clearly in support of the vitamin D hypothesis. If the association between APOE £4 status and serum 25(OH)D levels in a general population sample and a small number of subjects for an interventional study are investigated, APOE £4 carriers had significantly higher levels, especially when APOE £2 allele carriers were excluded. APOE £4 carriers had lower PTH and higher serum calcium levels (31). In support of these findings, knock-in mice (APOE 4) had significantly higher serum 25(OH)D levels (~71 nM) than found in wild-type (~28 nM), APOE-2- or APO-3-mice. Indirect evidence was provided for increased calcitriol effects including higher femoral calcium and increased expression levels of genes involved in calcium absorption. Most interestingly, there was increased bile production, higher expression levels of CYP 7A1 (key enzyme in bile production) and higher mRNA expression for vitamin D binding protein.
Taken altogether, the association data in humans and the phenotype of the APOE £4 knock-in mice establish the APO £4 allele as novel modifier of the vitamin D status.

Acknowledgements

Oliver Gillie provided valuable advice and we thank him very much for his efforts.
Fig. 1
Gene loci so far identified for 25(OH) vitamin D serum levels

Note added in proof

The view expressed above, namely that 25-(OH)-vitamin D3 (and not vitamin D3) is the ideal oral „sunshine equivalent" was mainly based on pharmacokinetic data. A comparative, double-blind study (33) with otherwise healthy postmenopausal women but an average baseline level of calcidiol of 13.2 ng/ml not only confirms now the superior bioavailability and almost immediate action for the prohormone but surprisingly suggests that there may be major differences to oral vitamin D3 with respect to pharmacodynamics (improved muscle function, lowering of systolic blood pressure, decreases of markers of innate immunity). Speculative explanations are that the majority of oral vitamin D3 (the fate of which is still unknown) may be metabolized into a more „antago-nistic" compound or that it triggers as a li-gand (hedgehog pathway?) activities which may not be identical and even opposite to calcidiol.

Last-but not least we acknowledge the expert assistance in preparation of this manuscript (including style, figures and references) by Johannes Werner.

Conflict of interest - The author declares that there is no conflict of interest.

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See also VitaminDWiki

• All items in category Genetics and Vitamin D 343 items
• Search for Glossman on VitaminDWiki 32 items as of May 2013
• Seniors, like everyone else, need vitamin D and should avoid sunburns – 2011
• The statin Crestor dramatically increases levels of vitamin D in the blood – Jan 2012
• Nice Overview of Vitamin D in 64 slides - Glossmann 2013