The Metabolism and Function of 1α-Hydroxyvitamin D₃

Abstract

In 1968 25-hydroxyvitamin D₃ (25-OH-D₃) was isolated in pure form and chemically identified (4). During the ensuing years it was demonstrated that this hydroxylation occurs in the liver prior to the initiation of intestinal calcium transport or bone calcium mobilization (20, 5). Following this initial demonstration that vitamin D is not active as such but must be metabolically altered before it can function, it was soon learned that a metabolite of vitamin D more polar than 25-OH-D₃ appeared in the target tissues prior to response (19, 17, 9). This conversion was demonstrated by Fraser and Kodicek to occur in the kidney (8). In 1970 and 1971 this compound was isolated in pure form and identified as 1,25-dihydroxyvitamin D₃ (1,25-(OH)₂ D₃) (12). It was subsequently synthesized to confirm its structure and to provide evidence for the la configuration for the hydroxyl placed on ring A (22). During the course of this synthesis an important new analog was prepared, namely la-hydroxyvitamin D₃ (lα-OH-D₃) (13) (Fig. 1). Perhaps not surprising in retrospect is the fact that this compound proved to be almost equally as active as 1,25-(OH)₂ D₃ in the chick (10) but approximately one-half as active as the natural metabolite in the rat (14). The time course of onset of responses to the lα-OH-D₃ was remarkably similar to the 1,25-(OH)₂ D₃ (13) and in the case of the chick (10), virtually identical. Of great interest was the fact that the lα-OH-D₃ was much more effective when given in oil solutions orally to the rat than was the corresponding 1,25-(OH)₂ D₃, leading to the idea that perhaps the lα-OH-D₃ in some species is more easily absorbed (14). Its ease of synthesis (13, 2, 16) and the relative inexpensiveness of the starting material led to its application to such diseases as chronic renal failure and hypoparathyroidism in which there is a clear indication of impared ability to carry out the 1-hydroxylation of 25-OH-D₃. This has met with marked success in virtually every clinical center (6, 1, 7, 21). However, the surprising fact that the lα-OH-D₃ produced a response almost identical in time course to the 1,25-(OH)₂ D₃ in animals led to the suggestion that lα-OH-D₃ might function without the necessity of 25-hydroxylation. On the other hand it also seemed possible that the lα-OH-D₃ might be hydroxylated on carbon 25 very rapidly. Although work by Zerwekh et al. (26) indicated that 25-hydroxylation of lα-OH-D₃ does take place in the chick, the methods used to detect 1,25-(OH)₂ D₃ were indirect and not conclusive as they themselves stated.