The renal function of 25-hydroxyvitamin D3-1alpha-hydroxylase

The active, hormonal form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) has numerous pleiotropic actions including the regulation of calcium homeostasis, control of bone cell differentiation and modification of immune responses. Synthesis of 1,25(OH)2D3 from the major circulating metabolite, 25-hydroxyvitamin D3 (25(OH)D3), is catalysed by the mitochondrial cytochrome P450 enzyme 25-hydroxyvitamin D-1alpha-hydroxylase (1alpha-HYD). Although 1alpha-HYD activity has been demonstrated at several ectopic sites, circulating levels of 1,25(OH)2D3 appear to reflect the expression of this enzyme in the kidney. The tight regulation of 1alpha-HYD in both renal and ectopic 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-HYD has stimulated renewed interest in the molecular endocrinology of 1,25(OH)2D3 production. Analysis of the 1alpha-HYD sequence has revealed homology with the liver enzyme vitamin D-25-hydroxylase, and the ubiquitously expressed vitamin D-24-hydroxylase. Furthermore, mutations causing the inherited disorder vitamin D-dependent rickets type 1, also known as pseudo-vitamin D deficiency rickets have been described for the 1alpha-HYD gene and these have been mapped to chromosome 12q14 by linkage analysis. The availability of sequence information for the 1alpha-HYD gene has also facilitated the development of new molecular tools which will help to clarify key functions of the enzyme. Specific issues such as tissue distribution and regulatory pathways are discussed in this review, with particular emphasis on the role of 1alpha-HYD in renal calcium/phosphate homeostasis.