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Pharmacokinetics of vitamin D toxicity.

Jones G.

Am J Clin Nutr. 2008 Aug;88(2):582S-586S. Free article

Although researchers first identified the fat-soluble vitamin cholecalciferol almost a century ago and studies have now largely elucidated the transcriptional mechanism of action of its hormonal form, 1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)], we know surprisingly little about mechanisms of vitamin D toxicity. The lipophilic nature of vitamin D explains its adipose tissue distribution and its slow turnover in the body (half-life approximately 2 mo). Its main transported metabolite, 25-hydroxyvitamin D(3) [25(OH)D(3)], shows a half-life of approximately 15 d and circulates at a concentration of 25-200 nmol/L, whereas the hormone 1alpha,25(OH)(2)D(3) has a half-life of approximately 15 h. Animal experiments involving vitamin D(3) intoxication have established that 25(OH)D(3) can reach concentrations up to 2.5 mumol/L, at which it is accompanied by hypercalcemia and other pathological sequelae resulting from a high Ca/PO(4) product. The rise in 25(OH)D(3) is accompanied by elevations of its precursor, vitamin D(3), as well as by rises in many of its dihydroxy- metabolites [24,25(OH)(2)D(3); 25,26(OH)(2)D(3); and 25(OH)D(3)-26,23-lactone] but not 1alpha,25(OH)(2)D(3). Early assumptions that 1alpha,25(OH)(2)D(3) might cause hypercalcemia in vitamin D toxicity have been replaced by the theories that 25(OH)D(3) at pharmacologic concentrations can overcome vitamin D receptor affinity disadvantages to directly stimulate transcription or that total vitamin D metabolite concentrations displace 1alpha,25(OH)(2)D from vitamin D binding, increasing its free concentration and thus increasing gene transcription. Occasional anecdotal reports from humans intoxicated with vitamin D appear to support the latter mechanism. Although current data support the viewpoint that the biomarker plasma 25(OH)D concentration must rise above 750 nmol/L to produce vitamin D toxicity, the more prudent upper limit of 250 nmol/L might be retained to ensure a wide safety margin.

Vitamin D Deficiency in Mice Impairs Colonic Antibacterial Activity and Predisposes to Colitis
Venu Lagishetty, Alexander V. Misharin, Nancy Q. Liu, Thomas S. Lisse, Rene F. Chun, Yi Ouyang, Sandra M. McLachlan, John S. Adams, and Martin Hewison
Orthopaedic Hospital Research Center (V.L., N.Q.L., T.S.L., R.F.C., J.S.A., M.H.) and Molecular Biology Institute (J.S.A., M.H.), University of California Los Angeles, Los Angeles, California 90095; Autoimmune Disease Unit (A.V.M., S.M.M.), Cedars-Sinai Research Institute and University of California Los Angeles School of Medicine, Los Angeles, California 90048; Department of Pathology (Y.O.), Veterans Affairs Medical Center, Long Beach, California 90822; and University of California Irvine (Y.O.), Irvine, California 92679

Vitamin D insufficiency is a global health issue. Although classically associated with rickets, low vitamin D levels have also been linked to aberrant immune function and associated health problems such as inflammatory bowel disease (IBD). To test the hypothesis that impaired vitamin D status predisposes to IBD, 8-wk-old C57BL/6 mice were raised from weaning on vitamin D-deficient or vitamin D-sufficient diets and then treated with dextran sodium sulphate (DSS) to induce colitis.
Vitamin D-deficient mice showed decreased serum levels of precursor 25-hydroxyvitamin D3 (2.5 ± 0.1 vs. 24.4 ±  1.8 ng/ml) and active 1,25-dihydroxyvitamin D3 (28.8 ± greater DSS-induced weight loss (9 vs. 5%), increased colitis (4.71 splenomegaly relative to mice on vitamin D-sufficient chow. DNA array analysis of colon tissue (n = 4 mice) identified 27 genes consistently (P ± 0.05) up-regulated or down-regulated more than 2-fold in vitamin D-deficient vs. vitamin D-sufficient mice, in the absence of DSS-induced colitis. This included angiogenin-4, an antimicrobial protein involved in host containment of enteric bacteria.
Immunohistochemistry confirmed that colonic angiogenin-4 protein was significantly decreased in vitamin D-deficient mice even in the absence of colitis. Moreover, the same animals showed elevated levels (50-fold) of bacteria in colonic tissue. These data show for the first time that simple vitamin D deficiency predisposes mice to colitis via dysregulated colonic antimicrobial activity and impaired homeostasis of enteric bacteria. This may be a pivotal mechanism linking vitamin D status with IBD in humans. (Endocrinology 151: 0000 – 0000, 2010)