1alpha-Hydroxylase and the action of vitamin D

Abstract

The active form of vitamin D, 1,25-dihydroxvitamin D(3) (1, 25(OH)(2)D(3)), is a pleiotropic hormone whose actions include the regulation of calcium homeostasis, control of bone cell differentiation and modification of immune responses. Synthesis of 1, 25(OH)(2)D(3) from the major circulating metabolite, 25-hydroxyvitamin D(3) (25(OH)D(3)), is catalysed by a mitochondrial cytochrome P450 enzyme, 25-hydroxyvitamin D-1alpha-hydroxylase (1alpha-OHase). Although 1alpha-OHase is expressed predominantly in the kidney, extra-renal production of 1,25(OH)(2)D(3) has also been demonstrated in tissues such as lymph nodes and skin. The tight regulation of 1alpha-OHase which occurs in both renal and peripheral tissues has made studies of the expression and regulation of this enzyme remarkably difficult. However, the recent cloning of mouse, rat and human cDNAs for 1alpha-OHase (CYP1alpha/Cyp1alpha) has enabled a more thorough characterization of this enzyme. In particular, analysis of the CYP1alpha gene has identified mutations causing the inherited disorder vitamin D-dependent rickets type 1, also known as pseudo-vitamin D deficiency rickets. Studies from our own group have focused on the distribution of 1alpha-OHase in both renal and extra-renal tissues. Data indicate that the enzyme is expressed throughout the nephron, suggesting discrete endocrine and paracrine/autocrine functions. Further immunohistochemical analyses have shown that the enzyme is widely distributed in extra-renal tissues, and this appears to be due to the same gene product as the kidney. Collectively, these observations have raised important new questions concerning the role of 1alpha-OHase in vitamin D signalling at a local level. The relationship between expression of protein for 1alpha-OHase and enzyme activity has yet to be fully characterized and may be dependent on membrane proteins such as megalin. Similarly, elucidation of the mechanisms involved in differential regulation of renal and extra-renal 1,25(OH)(2)D(3) production will be essential to our understanding of the tissue-specific functions of 1alpha-OHase. These and other issues are discussed in the current review.