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

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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., and DeLuca, 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 .fwdarw. 1,24,25-trihydroxyvitamin D3 .fwdarw. 1,25-dihydroxy-24-oxovitamin D3 .fwdarw. 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., and Norman, A. W. (1987) Biochemistry 26, 324]. In this present study, we investigated the metabolic fate of 1,25-dihydroxyvitamin D3 (3 .times. 10-10 M) in the perfused rat kidney and identified calcitroic acid as the major water-soluble metabolite of 1,25-dihydroxyvitamin D3. Furthermore, we also established C-23 alcohol as the immediate precursor of calcitroic acid (C-23) and finally concluded that 1,25-dihydroxyvitamin D3 is metabolized in the kidney through the C-24 oxidation pathway according to the following steps: 1,25-dihydroxyvitamin D3 .fwdarw. 1,24,25-trihydroxyvitamin D3 .fwdarw. 1,25-dihydroxy-24-oxovitamin D3 .fwdarw. 1,23,25-trihydroxy-24-oxovitamin D3 .fwdarw. C-23 alcohol .fwdarw. calcitroic acid. It now appears that the C-24 oxidation pathway for 1,25-dihydroxyvitamin D3 probably exists in all the target tissues that respond to 1,25-dihydroxyvitamin D3 and plays an important role in inactivating 1,25-dihydroxyvitamin D3 and thereby regulates the tissue concentration of the active hormone, 1,25-dihydroxyvitamin D3.