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Osteologie 2011; 20(04): 299-303
DOI: 10.1055/s-0037-1620006
Vitamin D
Schattauer GmbH

Pharmacology of vitamin D

Anything new?Was gibt es Neues in der Pharmakologie von Vitamin D?
H. H. Glossmann
1   Institute for Biochemical Pharmacology, Innsbruck Medical University, Innsbruck, Austria
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Publication History

received: 10 September 2011

accepted: 29 September 2011

Publication Date:
30 December 2017 (online)

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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 longchain 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.

Zusammenfassung

Für unsere Vorfahren („Jäger und Sammler”) war Fleisch ein Hauptnahrungsmittel. Es enthält wesentlich mehr 25-(OH)-Vitamin D3 als Vitamin D3. Es ist wahrscheinlich, dass sich im nördlichen Teil Europas wegen fehlender Vitaminbildung (über die Sonne) während der langen Wintermonate die intestinale Resorption des Prohormons evolutionär adaptierte und optimal wurde: Ausgezeichnete orale Bioverfügbarkeit und minimale inter-individuelle Variation. Daher kann Calcidiol als das ideale orale „Sonnenschein-Äquivalent” für die rasche und zuverlässige Anhebung eines insuffizienten „Vitamin-D-Status” z. B. in klinischen Situationen betrachtet werden. Vitamin D3 wird in pharmakologischen Dosen zwischen 60 – 100 % als „Blinder Passagier erster Ordnung” absorbiert. Voraussetzungen hierfür sind eine intakte Leber- und Pankreasfunktion sowie ein gesunder Dünndarm. Die Dosis muss entweder mit Fett (Triglyzeride mit langkettigen Fettsäuren) und/oder einer „normalen Mahlzeit” appliziert werden. Die Frage erhebt sich, wie kleine Mengen von Vitamin D, die üblicherweise in der Nahrung vorkommen, resorbiert werden und ob hier ein „aktiver Prozess” eine Rolle spielt. Zellkultur-Experimente weisen darauf hin, dass Vitamin D3 u. a. über die gleichen komplexen und eng kontrollierten Mechanismen aktiv (Prozess „zweiter Ordnung”) in Enterozyten aufgenommen werden kann wie z. B. Cholesterin. Hier spielt u. a. das Rezeptor-Protein für Ezetimibe, NPC1L1, eine Rolle. In Europa besteht ein Nord-Süd-Gradient für das Apolipoprotein E Epsilon 4 Allel (30 % in Finnland und etwa 5 % um das Mittelmeer). Dieser Genotyp wurde offensichtlich im Norden selektiert, um mehr Vitamin D3 aus der Nahrung aufzunehmen. Eine klare Assoziation höherer Spiegel von Serum-25-(OH)-Vitamin D mit diesem Allel wurde belegt und in „knock-in”-Mäusen bestätigt. In einigen Studien wurde eine Assoziation von hohen Serumspiegeln von Calcidiol mit Übersterblichkeit gefunden. Ob der (zu Alzheimer und erhöhter kardiovaskulärer Mortalität disponierende) Genotyp Apolipoprotein E Epsilon 4 hier eine Rolle spielt, ist bislang nicht erforscht. Für Mutationen im Enzym Delta-7-Dehydrocholesterin-Reduktase wurde ebenso ein Nord-Süd-Gradient gefunden. Dies weist ebenfalls auf evolutionäre Adaption der Vitamin-D3-Synthese in der Haut hin.

Keywords

Vitamin D - Apolipoprotein E - intestinal transport - calcidiol plasma levels

Schlüsselwörter

Vitamin D - Apolipoprotein E - intestinaler Transport - Calcidiol-Plasmaspiegel
 

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