The 25(OH)D3/1α,25(OH)2D3-24R-hydroxylase:: a catabolic or biosynthetic enzyme?

The kidney is the major source of the circulating dihydroxylated metabolites of vitamin D, 1 alpha ,25-dihydroxyvitamin D-3 [1 alpha ,25(OH)(2)D-3] and 24R,25-dihydroxyvitamin D-3 [24R,25(OH)(2)D-3]. The enzymes which catalyze the production of these two dihydroxylated vitamin D metabolites are the 25(OH)D-3-1 alpha -hydroxylase (1 alpha -hydroxylase) and -24R-hydroxylase (24R-hydroxylase), respectively. While there is no controversy regarding the fundamental importance of the la-hydroxylase in the production of the steroid hormone 1 alpha ,25(OH)(2)D-3, the biologic significance of the 24R-hydroxylase has been, the subject of ongoing discussion. Some hold that it is strictly catabolic, leading to side chain oxidation and cleavage of 25-hydroxylated vitamin D sterols, and others hold that it plays a biosynthetic role in the production of 24R,25(OH)(2)D-3 which has biologic activities distinct from those of 1 alpha ,25(OH)(2)D-3. The 24R-hydroxylase has properties in common with other multicatalytic steroidogenic enzymes: (I)the enzyme carries out multiple oxidative and carbon-carbon bond cleavages; (2) it utilizes two natural substrates; (3) its regulation varies depending on the cell or tissue in which it occurs. The purpose of this paper is to review the current literature relevant to the characteristics of the 24R-hydroxylase and its regulation in the context of other multicatalytic steroid hydroxylases in order to provide a perspective regarding its possible function as both a catabolic and activating enzyme in the vitamin D endocrine system. (C) 2001 Elsevier Science Inc. All rights reserved.