S-1-2 Further Metabolism of 1 a, 25-Dihydroxyvitamin D3 in Target Cells

Abstract

Work in DeLuca's laboratory in the late 1970's showed that the hormone, calcitriol (1,25-(OH)2D3), is subject to side chain cleavage [1] before it is excreted in the bile as the C23-acid, calcitroic acid [2]. Esvelt et al [3] showed that calcitroic acid is found in a variety of tissues in the body. Subsequent work using a series of in vitro cell systems including intestinal and kidney homogenates and the perfused rat kidney revealed the existence of a number of side chain-modified metabolites [4,5,6] derived from l,24,25-(OH)3D3, which might be precursors of calcitroic acid.Work in our laboratory [7] demonstrating the existence of a C23-alcohol derived from 25-OH-D3 strengthened the theory that calcitroic acid was derived from the C-24 oxidation pathway. Recently two groups [8,9] have achieved the generation of calcitroic acid from l,25-(OH)2D3 using in vitro models of kidney and bone. Figure 1 illustrates our current concept of the steps involved in this pathway. In this paper we describe some of our work to study the distribution of this pathway, to further delineate the biochemical steps of the pathway, and to study the regulation of this pathway by hormones and growth factors. We speculate on the implications of our work to the metabolism and effectiveness of the newer analogs of vitamin D being developed currently. © 1992, Center for Academic Publications Japan. All rights reserved.