![]() ![]() PTH effects renal tubular reabsorption of calcium, renal production of 1,25-(OH) 2D 3 and promotes osteoclastogenesis. PTH synthesis and secretion is induced by decreased serum calcium levels, which are detected by the calcium sensing receptor of the parathyroid gland. Further, 1,25-(OH) 2D 3 decreases the production and secretion of PTH. 1,25-(OH) 2D 3 itself works as its own negative feedback regulator by induction of the expression of a 24-hydydroxylase (CYP24A1). Calcitonin, cortisol, high phosphate levels and 25-(OH)D 3 suppress the 25-hydroxyvitamin D-1α-hydroxylase activity. The 1α-hydroxylation of 25-(OH)D 3 is upregulated by parathyroid hormone (PTH), calcitonin, low calcium- and phosphate levels as well as by estrogen, prolactin and growth hormone. DBP polymorphisms (Gc phenotype) are related to the DBP concentration and VitD status. In the blood, VitD and the inactive, relatively stable 25-(OH)D 3 metabolite are bound in 99% to the vitamin D binding protein (DBP). The serum concentration of 25-(OH)D 3 reflects the organism's VitD supply. This latter step is mainly localized to the proximal kidney tubule, however, many other cell types, including lung epithelial cells, are capable to perform this reaction. The inactive 25-(OH)-vitamin D 3 (25-(OH)D 3) metabolite is further hydroxylated at position 1α by the mitochondrial cytochrome P450 enzyme 25-hydroxyvitamin-D-1α-hydroxylase (gene name: CYP27B1) and converted to the bioactive 1α,25-dihydroxyvitamin D(1,25-(OH) 2D 3). ![]() In the human liver, the first hydroxylation of VitD on C-25 is performed by mitochondrial 25-hydroxylase enzymes (gene names: CYP27A1 and/or CYP2R1 ) that both belong to the cytochrome P450 family. The metabolizing enzymes belong to a group of cytochrome P450 hydroxylases, which can be found in eukaryotes, bacteria, fungi and plants. VitD, which is photosynthesized in the skin or has been derived from nutrition, is metabolized two times, before it mediates its calcemic effects by binding to the nuclear VitD receptor (VDR) (Figure 1). The precursors of VitD in those organisms may function as a natural sunscreen to protect the host against UV-radiation, since the absorption spectra of pro-vitamin D and their photoproducts overlap with the absorption maxima of DNA, RNA, and proteins. Functional VitD hydroxylases have also been characterized in bacteria like strains of actinomyces and streptomyces. VitD precursors have been found in ancient organisms like phytoplankton and zooplankton, some of which exist unchanged for at least 750 million years. VDRs were also identified in animals with a naturally impoverished VitD status like the subterranean mole rat and a frugivorous nocturnal mammal, the Egyptian fruit bat Cavaleros. Surprisingly, functional VitD receptors (VDRs) have also been found in lampreys, an ancient vertebrate that lacks a calcified skeleton. These animals possess a calcified skeleton and depend on a functional VitD hormone system for calcium and phosphorus homeostasis. Variants of VitD and its receptors have been identified in higher terrestrial vertebrates like humans, rodents, birds, amphibia, reptiles, as well as in zebrafish. The fact that precursors of VitD are found in ancient organisms like krill and phytoplankton that existed unchanged for at least 750 million years highlights its importance in physiologic and homeostatic processes. VitD and its receptors are found throughout the animal kingdom and are often linked to bone and calcium metabolisms. This review summarizes the knowledge on the classical and newly discovered functions of VitD, the molecular and cellular mechanism of action and the available data on the relationship between lung disease and VitD status. The exact mechanisms underlying these data are unknown, however, VitD appears to impact on the function of inflammatory and structural cells, including dendritic cells, lymphocytes, monocytes, and epithelial cells. Several lung diseases, all inflammatory in nature, may be related to activities of VitD including asthma, COPD and cancer. Epidemiological data indicate that low levels of serum VitD is associated with impaired pulmonary function, increased incidence of inflammatory, infectious or neoplastic diseases. Especially patients with lung diseases have often low VitD serum levels. VitD deficiency appears to be frequent in industrialized countries. In the last years, it has been recognized that in addition to this classical function, VitD modulates a variety of processes and regulatory systems including host defense, inflammation, immunity, and repair. The role of vitamin D (VitD) in calcium and bone homeostasis is well described. ![]()
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