Pharmacology of vitamin D Anything new?

A main source of food for ancient humans (hunter-gatherers) was fresh meat. It contains much more 25(OH) vitamin D-3 (25[OH]D-3) than vitamin D-3. 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)D-3: excellent oral bioavailability (60-80%) and little inter-individual variation. 25(OH)D-3 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 D-3 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 D-3 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)D-3 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.