The renal function of 25-hydroxyvitamin D-3-1 alpha-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 h omeostasis, control of bone cell differentiation and modification of immune responses. Synthesis of 1,25(OH)(2)D-3 from the major circulating metaboli te, 25-hydroxyvitamin D-3 (25(OH)D-3), is catalysed by the mitochondrial cy tochrome P450 enzyme 25-hydroxyvitamin D-1 alpha-hydroxylase (1 alpha-HYD). Although 1 alpha-HYD activity has been demonstrated at several ectopic sit es, circulating levels of 1,25(OH),D, appear to reflect the expression of t his 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 t his enzyme remarkably difficult. However, the recent cloning of mouse, rat and human cDNAs for 1 alpha-HYD has stimulated renewed interest in the mole cular endocrinology of 1,25(OH),D, production. Analysis of the 1 alpha-HYD sequence has revealed homology with the liver enzyme vitamin D-25-hydroxyla se, and the ubiquitously expressed vitamin D-24-hydroxylase. Furthermore, m utations 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 link age 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 tissu e distribution and regulatory pathways are discussed in this review, with p articular emphasis on the role of 1 alpha-HYD in renal calcium/phosphate ho meostasis. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.