Calcitroic acid, end product of renal metabolism of 1,25-dihydroxyvitamin D3 through the C-24 oxidation pathway

Abstract

About a decade ago calcitroic acid was isolated as a major side chain cleaved water-soluble metabolite of 1,25-dihydroxyvitamin D3 [Esvelt, R. P., Schnoes, H. K., & Decula, H. F. (1979) Biochemistry 18, 3977]. Presently, calcitroic acid is being considered as the major excretory form of 1,25-dihydroxyvitamin D3. However, the exact site or sites of calcitroic acid production and the possible side chain modified intermediary metabolites that may be formed during the conversion of 1,25-dihydroxyvitamin D3 into calcitroic acid are not fully understood. In the mean time there have been many advances in our understanding of the side-chain metabolism of 1,25-dihydroxyvitamin D3. It is now well established that both the kidney and the intestine metabolize 1,25-dihydroxyvitamin D3 through the C-24 oxidation pathway according to the following steps: 1,25-dihydroxyvitamin D3----1,24,25-trihydroxyvitamin D3----1,25-dihydroxy-24-oxovitamin D3-----1,23,25-trihydroxy-24-oxovitamin D3. Recently, we identified 1,23-dihydroxy-24,25,26,27-tetranorvitamin D3 (C-23 alcohol) as a major side chain cleaved lipid-soluble metabolite of 1,25-dihydroxyvitamin D3 and further extended the aforementioned C-24 oxidation pathway in the kidney by demonstrating 1,23,25-trihydroxy-24-oxovitamin D3 as the precursor of C-23 alcohol [Reddy, G. S., Tserng, K. Y., Thomas, B. R., Dayal, R., & Norman, A. W. (1987) Biochemistry 26, 324]. In this present study, we investigated the metabolic fate of 1,25-dihydroxyvitamin D3 (3 X 10(-10) M) in the perfused rat kidney and identified calcitroic acid as the major water-soluble metabolite of 1,25-dihydroxyvitamin D3.(ABSTRACT TRUNCATED AT 250 WORDS)

Identification of a vitamin D-response element in the rat calcidiol (25-hydroxyvitamin D3) 24-hydroxylase gene.

“…This 24-hydroxylation is thought to be the first step in the catabolic pathway (2,3). In vivo studies have shown that the 24-hydroxylase is induced by 1,25-(OH)2D3 (4), essentially inducing its own inactivation.…”

Tissue-Specific Regulation of Sex Hormone Biosynthesis and Metabolism: Novel Aspects on Hormonal Signalling and Maintenance of Cellular Steroid Levels

“…Finally, after side chain cleavage, calcitroic acid is formed. Calcitroic acid is then excreted into the bile (Makin et al, 1989;Reddy and Tserng, 1989;Zimmerman et al, 2001). The expression of both the activating (25-and 1-hydroxylases) and the catabolizing (24-hydroxylase) enzymes by cells of certain tissues, indicates that the multifunctional hormone 1,25-dihydroxyvitamin D 3 can be produced locally in some tissues, including cells in the skin, breast, colon, prostate, lung, and various cells of the immune system.…”

Further Metabolism of 1α, 25-Dihydroxyvitamin D3in Target Cells

“…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 1,25-(OH)2D3 using in vitro models of kidney and bone. Figure 1 illustrates our current concept of the steps involved in this pathway.…”