Copies of author's previously published articles inserted. / Bibliography: leaves 103-119. / viii, 199, [87] leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Aims to understand at the transcriptional level how 1,25-dihydroxyvitamin D3 up-regulates the mitochondrial cytochrome P450 enzyme. / Thesis (Ph.D.)--University of Adelaide, Dept. of Biochemistry, 1998?

The maximum daily dose of vitamin D currently recommended is 2000 IU. Ergocalciferol (D2) 50,000 IU orally weekly for 8-12 weeks is often used to treat vitamin D deficient patients (25(OH) vitamin D <20 ng/mL). The lack of vitamin D toxicity after massive doses of ergocalciferol has yet to be reported in the literature. We report a case of a 56-year-old woman who received supratherapeutic doses of ergocalciferol (150,000 IU orally daily) for 28 years without toxicity. We discuss the possible mechanisms which may account for a lack of toxicity despite intake of massive daily doses of ergocalciferol in this patient.

Vitamin D deficiency in patients with chronic kidney disease, measured by reduced serum concentrations of 25 hydroxy vitamin D, is highly prevalent and associated with both endothelial dysfunction and an increased risk of cardiovascular disease. Observational studies in chronic kidney disease have demonstrated that vitamin D therapy reduces the risk of cardiovascular disease. In patients with chronic kidney disease and concomitant vitamin D deficiency, the effect of vitamin D therapy on endothelial function, which is associated with cardiovascular disease, is poorly understood. The mechanism by which vitamin D affects endothelial function is unclear. Methods Presented in this thesis, two studies have addressed these issues: 1. A double blind, randomized controlled trial evaluating the effect of ergocalciferol compared to placebo on microcirculatory endothelial function in patients with non-dialysis chronic kidney disease and concomitant vitamin D deficiency 2. In vitro and in vivo experiments to determine the mechanistic effect of ergocalciferol on endothelial function in an experimental model of uraemia. Results In the clinical study, ergocalciferol increased vitamin D serum concentrations and improved microcirculatory endothelial function measured by laser Doppler flowmetry after iontophoresis of acetylcholine. Oxidative stress measured by skin autofluorescence for advanced glycation end products did not change in the ergocalciferol group but increased significantly in the placebo group. Ergocalciferol increased endothelial nitric oxide synthase expression and activity in cultured human endothelial cells and improved endothelial function in an in vivo model of mild uraemia. The findings from the in vivo and clinical studies occurred independently of changes in blood pressure, conduit artery function, serum calcium, phosphate and parathyroid hormone supporting in vitro findings that ergocalciferol acts directly on the endothelium. Conclusion Ergocalciferol improved endothelial function in both rodent and human subjects with chronic kidney disease. Experimental evidence suggests this effect occurs through an endothelium dependent mechanism involving changes in the upregulation and function of endothelial nitric oxide synthase.

Aim: VitaminD deficiency is a global health issue associated with increased health-care costs, and could play a role in the pathogenesis and management of inflammatory bowel disease. Prior studies show a high prevalence of vitaminD deficiency in veterans with inflammatory bowel disease. We aimed to examine the outcome differences in patients with inflammatory bowel disease, comparing treatment with ergocalciferol to cholecalciferol. Methods: A retrospective review of electronic medical records of patients with inflammatory bowel disease at a Veterans Affairs Medical Facility in the Southeastern United States was carried out. Those with at least one serum 25(OH) vitaminD level were included. Initial and follow-up vitamin D values were recorded. The type of vitaminD supplementation, whether cholecalciferol or ergocalciferol, was documented. Costs in the year after measurement of vitaminD were divided into separate inpatient and outpatient categories. Results: Veterans (n=108) with ulcerative colitis or Crohn's disease and an available 25(OH) vitaminD level were studied. There were differences in follow-up vitaminD levels; those who received weekly ergocalciferol had higher subsequent levels than those who received cholecalciferol, especially at a second follow up, although differences did not achieve statistical significance. However, those who received vitaminD3 were less likely to use laboratory, pharmacy, radiology and fee-based services, and had lower laboratory and pharmacy costs. Conclusions: Our data suggest that cholecalciferol replacement might improve outcomes to a greater extent than ergocalciferol, and might be better in limiting health-care costs and expenses in patients with inflammatory bowel disease.