The 25(OH)D-3/1 alpha,25(OH)(2)D-3-24R-hydroxylase: a catabolic or biosynthetic enzyme?

The kidney is the major source of the circulating dihydroxylated metabolite s of vitamin D, 1 alpha ,25-dihydroxyvitamin D-3 [1 alpha ,25(OH)(2)D-3] an d 24R,25-dihydroxyvitamin D-3 [24R,25(OH)(2)D-3]. The enzymes which catalyz e 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 th e fundamental importance of the la-hydroxylase in the production of the ste roid hormone 1 alpha ,25(OH)(2)D-3, the biologic significance of the 24R-hy droxylase has been, the subject of ongoing discussion. Some hold that it is strictly catabolic, leading to side chain oxidation and cleavage of 25-hyd roxylated vitamin D sterols, and others hold that it plays a biosynthetic r ole in the production of 24R,25(OH)(2)D-3 which has biologic activities dis tinct from those of 1 alpha ,25(OH)(2)D-3. The 24R-hydroxylase has properti es in common with other multicatalytic steroidogenic enzymes: (I)the enzyme carries out multiple oxidative and carbon-carbon bond cleavages; (2) it ut ilizes two natural substrates; (3) its regulation varies depending on the c ell or tissue in which it occurs. The purpose of this paper is to review th e current literature relevant to the characteristics of the 24R-hydroxylase and its regulation in the context of other multicatalytic steroid hydroxyl ases in order to provide a perspective regarding its possible function as b oth a catabolic and activating enzyme in the vitamin D endocrine system. (C ) 2001 Elsevier Science Inc. All rights reserved.