1α,25-Dihydroxyvitamin D3Specifically Induces Its Own Metabolism in a Human Cancer Cell Line

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Abstract
Human breast cancer and malignant melanoma cells possess specific, high affinity receptors for 1.alpha.,25-dihydroxyvitamin D3 (1,25-(OH)2D3). The replication of these cells is affected by 1,25-(OH)2D3 with a biphasic dose response, i.e., stimulation at low concentration and inhibition at high concentration. Several 1,25-(OH)2D3 metabolites hydroxylated at the 23,24 and 26 carbons have reduced affinity for the receptors but are still able to inhibit cell replication at high concentrations; none of these metabolites are able to stimulate cell growth. In this context, it is of considerable interest that T47-D breast cancer cells in culture actively metabolize 1,25-(OH)2D3 to choloroform- and aqueous-soluble compounds. Based on multiple solvent high pressure liquid chromatography, double label studies, and periodate sensitivity it is apparent that metabolism occurs about the 23,24 and 26,27 carbon atoms. Three metabolites have been tentatively identified as 1,24,25-(OH)3D3 and the 24-oxo derivatives of 1,25-(OH)2D3 and 1,23,25-trihydroxyvitamin D3. Although calcitroic acid may be produced, other aqueous-soluble metabolites with partially intact side chains are major metabolic products. The metabolic activity is low in the 1,25-(OH)2D3-depleted cell and is induced in 3-4 h by a process requiring new protein synthesis. The induction by 1,25-(OH)2D3 is highly specific since 25-OH D3 is quite ineffective. The studies reported here carried out in intact cells in culture demonstrate unequivocally that 1,25-(OH)2D3 metabolism, through chloroform-soluble to aqueous-soluble metabolites, occurs entirely within a proven target cell of 1,25-(OH)2D3 action. Since other 1,25-(OH)2D3 metabolites hydroxylated at the 23,24 and 26 carbons lack the ability to stimulate cell replication, the hormone-inducible metabolic activity, may represent a sensitive mechanism for the control of cellular responsiveness to 1,25-(OH)2D3.