Effect of hypercalcemia-producing tumor on 1,25(OH)2D3 biosynthesis in athymic mice

Abstract

Serum 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] levels are low in patients with malignancy-associated hypercalcemia (MAH), whereas murine models of MAH have high circulating 1,25(OH)2D3. To determine the effects of a hypercalcemia-producing tumor on circulating 1,25(OH)2D3, in vitro 25-hydroxyvitamin D1-hydroxylase (1OHase) activity was measured in kidneys from BALB/c athymic mice implanted with a hypercalcemia-producing human lung tumor. Twelve days of low-phosphorus diet (LPD) in control animals lowered serum phosphorus to levels found in tumor-bearing mice fed normal phosphorus diet (NPD; 4.1 +/- 0.3 vs. 4.4 +/- 0.7 mg/dl, P = NS) and increased 1OHase activity (1.6 +/- 0.2 vs. 3.9 +/- 0.7 pmol.mg protein-1.5 min-1, NPD vs. LPD, P less than 0.05). 1OHase activity was greater in tumor-bearing animals fed NPD compared with control animals fed LPD (8.4 +/- 0.6 vs. 3.9 +/- 0.7 pmol.mg protein-1.5 min-1, P less than 0.01). High-phosphorus intake suppressed 1OHase activity in both control and tumor-bearing animals. Seven days of parathyroid hormone infusion in control animals fed NPD raised serum calcium (9.4 +/- 0.2 vs. 13.3 +/- 1.6 mg/dl, P less than 0.05) and suppressed 1OHase activity (0.25 +/- 0.02 vs. 0.02 +/- 0.002 pmol.mg protein-1.5 min-1, P less than 0.001). The inverse relationship of serum phosphorus and 1OHase activity was much steeper in the tumor-bearing animals, with greater enzyme activity at comparable levels of serum phosphorus. The present study indicates that 1) factors produced by the tumor stimulate 1OHase activity, and 2) hypophosphatemia is required for expression of enhanced enzyme activity.