Influence of Vitamin D - Metabolites and -Analogs on Growth and Apoptosis of C6-Rat-Glioma-Cells

Josef Elias

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Diploma Thesis from the year 2002 in the subject Chemistry - Bio-chemistry, grade: very good, University of Vienna (Institute for...

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Diploma Thesis from the year 2002 in the subject Chemistry - Bio-chemistry, grade: very good, University of Vienna (Institute for pharmaceutical Chemistry), language: English, abstract: 1. INTRODUCTION 1.1. General aspects of Vitamin D 1.1.1. Synthesis and Metabolism Vitamin D in the human body exists in two forms, derived from two sources. In the form of Vitamin D3, it is generated from 7-dehydrocholesterol in the skin by exposure to ultraviolet light (270-300 nm range), and in the form of Vitamin D2 or Vitamin D3 (Fig. 1), it can be derived from diet. [...] Both forms of Vitamin D are precursor of functionally active hormones and undergo the same two-step activation process leading to 1a,25-(OH)2-D2 or 1a,25-(OH)2-D3, respectively. These metabolic activations of Vitamin D3 are carried out a by specific P-450-containing enzymes, the vitamin D3-25- hydroxylase (CYP27A) and the 25-hydroxyvitamin D-1a-hydroxylase (CYP27B1). Both hydroxylases are located in the inner mitochondrial membrane of cells (Fig. 2).There is little evidence that the two hormones differ in their mode of action (Jones et al. (1998)). In contrast to earlier assumptions, which strictly localized 25- hydroxylation in the liver and sequential 1a-hydroxylation in the kidney (Blunt et al. (1968)), many different cell types were shown to be capable of the two-step activation process too. Regulation of both enzymes appears to be tissuespecific: CYP27A is only loosely regulated (Bhattacharyya et DeLuca (1973)) or constitutively expressed (Schüssler et al. (2001)). 1a-Hydroxylase in the kidney is tightly regulated by the levels of plasma 1,25-(OH)2D3 and calcium (via the parathyroid hormone (PTH)) (reviewed by Jones et al. (1998)), however constitutively expressed in skin (Schüssler et al. (2001)). A third vitamin Drelated mitochondrial cytochrome P-450-containing enzyme is the 25- hydroxyvitamin D-24-hydroxylase (CYP24). This enzyme is strongly inducible by 1a,25-(OH)2-D3 in practically all cell types of the body, prefers 1a,25-(OH)2- D3 as a substrate over 25-OH-D3, and catalyzes several steps of 1a,25-(OH)2- D3 - metabolism, collectively known as the C-24 oxidation pathway (Fig.3., Reddy and Tserng, 1989; Makin et al., 1989). [...]