Vitamin D: Metabolism

The biologically active metabolite of vitamin D, 1,25(OH) ₂D ₃, affects mineral homeostasis and has numerous other diverse physiologic functions including effects on growth of cancer cells and protection against certain immune disorders. This article reviews the role of vitamin D hydroxylases in providing a tightly regulated supply of 1,25(OH) ₂D ₃. The role of extrarenal 1α(OH)ase in placenta and macrophages is also discussed, as well as regulation of vitamin D hydroxylases in aging and chronic kidney disease. Understanding specific factors involved in regulating the hydroxylases may lead to the design of drugs that can selectively modulate the hydroxylases. The ability to alter levels of these enzymes would have therapeutic potential for the treatment of various diseases, including bone loss disorders and certain immune diseases.

Synthesis of 1,25(OH) ₂D ₃from vitamin D ₃

Vitamin D ₃(cholecalciferol) is taken in the diet (from fortified dairy products and fish oils) or is synthesized in the skin from 7-dehydrocholesterol by ultraviolet irradiation. The vitamin D produced by 7-dehydrocholesterol depends on the intensity of UV irradiation, which varies with season and latitude. Sunscreen and clothing have been reported to prevent the conversion of 7-dehydrocholesterol to vitamin D ₃. To be biologically active and affect mineral metabolism, and to have effects on numerous other diverse physiologic functions including inhibition of growth of cancer cells and protection against certain immune mediated disorders, vitamin D most be converted to its active form. Vitamin D is transported in the blood by the vitamin D binding protein (DBP, a specific binding protein for vitamin D and its metabolites in serum) to the liver. In the liver vitamin D is hydroxylated at C-25 by one or more cytochrome P450 vitamin D 25-hydroxylases (including CYP2R1, CYP2D11, and CYP2D25), resulting in the formation of 25-hydroxyvitamin D ₃(25(OH)D ₃). It has been suggested that CYP2R1 is the key enzyme required for 25-hydroxylation of vitamin D since a homozygous mutation of the CYP2R1 gene was found in a patient with low circulating levels of 25(OH)D ₃and classic symptoms of vitamin D deficiency. 25(OH)D ₃, the major circulating form of vitamin D, is transported by the DBP to the kidney. In the kidney, magalin, a member of the low-density lipoprotein receptor superfamily, plays an essential role in endocytic internalization of 25(OH)D ₃. In the proximal renal tubule 25(OH)D ₃is hydroxylated at the position of carbon 1 of the A ring, resulting in the hormonally active from of vitamin D, 1,25-dihydroxyvitamin D ₃(1,25(OH) ₂D ₃), which is responsible for most, if not all of the biologic actions of vitamin D ( Fig. 1 ). The cytochrome P450 monooxygenase 25(OH)D 1α hydroxylase (CYP27B1; 1α(OH)ase), which metabolizes 25(OH)D ₃to 1,25(OH) ₂D ₃, is present predominantly in kidney. This enzyme is also found in extrarenal sites including placenta, monocytes, and macrophages. As with all mitochondrial P450 containing enzymes, during the 1α(OH)ase reaction electrons are transferred from reduced nicotinamide adenine dinucleotide phosphate (NADPH) to NADPH-ferrodoxin reductase through ferrodoxin. Inactivating mutations in the 1α(OH)ase gene result in vitamin D dependency rickets (VDDR) type 1 despite normal intake of vitamin D, indicating the importance of the 1α(OH)ase enzyme. Type 1 VDDR is characterized by growth failure, hypocalcemia, elevated parathyroid hormone (PTH), muscle weakness, and radiologic findings typical of rickets. The 1α(OH)ase null mutant mouse has provided a mouse model of VDDR type 1. It is of interest that in these mice, in addition to rickets, reproductive and immune defects have been noted. Further studies are needed to test the role of 1α(OH)ase in extrarenal sites, which has been a matter of debate.