Authors: Yan-Ru Lou and Pentti Tuohimaa (University of Tampere, Finland)
Abstract: Vitamin D3 is produced in the skin during exposure to sunlight and is then 25-hydroxylated in the liver, yielding the major circulating metabolite 25-hydroxyvitamin D3 (25OHD3, calcidiol). Calcidiol is converted to 1ƒÑ,25-dihydroxyvitamin D3 (1ƒÑ,25-(OH)2D3) mainly in the kidney by 25OHD3-1ƒÑ-hydroxylase (1ƒÑ-hydroxylase). Calcidiol and 1ƒÑ,25-(OH)2D3 are further hydroxylated into less active metabolites by 25OHD3-24-hydroxylase (24-hydroxylase, CYP24). Vitamin D3 metabolites exert their effects by binding to the nuclear vitamin D receptor. 24-Hydroxylase is highly inducible by vitamin D3 metabolites at transcriptional level and it controls the biological action of calcidiol and 1ƒÑ,25-(OH)2D3. It has been proposed that the local production of vitamin D metabolites is important. Calcidiol is generally considered a prehormone, which is activated via 1ƒÑ-hydroxylation. 1ƒÑ,25-(OH)2D3 plays a central role in calcium homeostasis but only at hypercalcemic (pharmacological) concentrations it regulates the proliferation and differentiation of various cell types in vivo and in vitro. However, we show direct evidence that calcidiol at physiological concentration possesses an inherent hormonal activity. Other hormonal factors can enhance vitamin D action by inhibiting its degradation. 5ƒÑ-dihydrotestosterone (DHT) and all-trans-retinoic acid (ATRA) enhance antiproliferative activities of calcidiol and 1ƒÑ,25-(OH)2D3 by suppressing the expression of 24-hydroxylase, which suggests that both at physiological concentrations combined with DHT or ATRA are active and can be used for therapeutic purposes. The novel vitamin D3 endocrine system of calcidiol seems to explain the discrepancies of the epidemiological and clinical data on the association between vitamin D insufficiency and many chronic diseases. We propose that calcidiol is more potent hormone regulating cell proliferation and differentiation than calcitriol in the physiological condition. Therefore, seasonal fluctuation of calcidiol might be directly involved in the development of chronic diseases.