25-Hydroxyvitamin D3 Metabolism by Human T-Lymphotropic Virus-Transformed Lymphocytes*

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Abstract
Production of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] by human T-lymphotrophic virus-I (HTLV-I)-infected lymphocytes may be the cause of the hypercalcemia frequently found in HTLV-I-associated adult T-cell lymphoma/leukemia. We examined three HTLV-I-transformed lymphocyte cell lines, two HTLV-II-transformed lymphocyte cell lines, and six HTLV-negative B and T-lymphocyte leukemia cell lines for metabolism of 25-hydroxyvitamin D3 (25OHD3). One HTLV-I-positive cell line, designated S-LB1, converted the substrate 25OH-[3H]D3 to several more polar metabolites, which were identified by high performance liquid chromatographic analysis as putative 1,25-(OH)2D3, 24,25-dihydroxyvitamin D3 [24,25-(OH)2D3], and 1,24,25-trihydroxyvitamin D3 [1,24,25-(OH)3D3]. The other cell lines gave no evidence of 25OH-[3H]D3 metabolism. Likewise, phytohemagglutinin-stimulated normal human lymphocytes did not metabilize 25OH-[3H]D3. The characteristics of 25OHD3 metabolism by S-LB1 cells were investigated in more detail. Kinetic studies revealed average Km values of 92 and 383 nM for 25OHD3 1-hydroxylase and 24-hydroxylase, respectively. Time course studies showed that both 1,25(OH)2-[3H]D3 and 24,25-(OH)2-[3H]D3 were further metabolized by S-LB1 cells to more polar compounds [primarily 1,24,25-(OH)3D3] and to compounds from which part of the side-chain had been cleaved. Exogenous 1,25-(OH)2D3 (1) inhibited endogenous 1,25-(OH)2D3 production, (2) stimulated 24,25-(OH)2D3 production, and (3) stimulated production of compounds more polar than 1,25-(OH)2D3. Bovine PTH-(1-34) had no effect on 25OH-[3H]D3 metabolism by S-LB1 cells. Our results indicate that the 25OH-[3H]D3-metabolizing system of cultured HTLV-I-transformed S-LB1 lymphocytes is similar but not identical to that of kidney cell culture systems. It appears, however, that infection of lymphocytes with HTLV does not uniformly result in acquisition of the competence to metabolize 25OHD3.