1 alpha-hydroxylase and the action of vitamin D

The active form of vitamin D, 1,25-dihydroxvitamin Dg (1,25(OH)2D3), is a p leiotropic hormone whose actions include the regulation of calcium homeosta sis, control of bone cell differentiation and modification of immune respon ses. 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-la-hydroxylase (1 alpha -OHase). Although 1 alpha -OHase is expressed predominantly in the kidney, extra-renal produc tion of 1,25(OH),D, has also been demonstrated in tissues such as lymph nod es and skin. The tight regulation of 1 alpha -OHase which occurs in both re nal and peripheral tissues has made studies of the expression and regulatio n of this enzyme remarkably difficult. However, the recent cloning of mouse , rat and human cDNAs for 1 alpha -OHase (CYP1 alpha /Cyp1 alpha) has enabl ed a more thorough characterization of this enzyme. In particular, analysis of the CYP1 alpha gene has identified mutations causing the inherited diso rder vitamin other issues are discussed in the current review. D-dependent rickets type 1, also known as pseudo-vitamin D deficiency rickets. Studies from our own group have focused on the distribution of 1 alpha -OHase in bo th renal and extra-renal tissues. Data indicate that the enzyme is expresse d throughout the nephron, suggesting discrete endocrine and paracrine/autoc rine functions. Further immunohistochemical analyses have shown that the en zyme is widely distributed in extra-renal tissues, and this appears to be d ue to the same gene product as the kidney. Collectively, these observations have raised important new questions concerning the role of 1 alpha -OHase in vitamin D signalling at a local level. The relationship between expressi on of protein for 1 alpha -OHase and enzyme activity has yet to be fully ch aracterized and may be dependent on membrane proteins such as megalin. Simi larly, 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 u nderstanding of the tissue-specific functions of 1 alpha -OHase. These and other issues are discussed in the current review.