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

The active, hormonal form of vitamin D-3 1,25-dihydroxyvitamin D, (1,25(OH),D,) 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)(2)D-3 from the major circulating metabolite, 25-hydroxyvitamin D-3 (25(OH)D-3), is catalysed by the mitochondrial cytochrome P450 enzyme 25-hydroxyvitamin D-1 alpha-hydroxylase (1 alpha-HYD). Although 1 alpha-HYD activity has been demonstrated at several ectopic sites, circulating levels of 1,25(OH),D, appear to reflect the expression of this enzyme in the kidney. The tight regulation of 1 alpha-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 1 alpha-HYD has stimulated renewed interest in the molecular endocrinology of 1,25(OH),D, production. Analysis of the 1 alpha-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 1 alpha-HYD gene and these have been mapped to chromosome 12q14 by linkage analysis. The availability of sequence information for the 1 alpha-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 1 alpha-HYD in renal calcium/phosphate homeostasis. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.