AJP - Endocrinology and Metabolism, Vol 256, Issue 2 E309-E314, Copyright © 1989 by American Physiological Society
Effect of hypercalcemia-producing tumor on 1,25(OH)2D3 biosynthesis in athymic mice
S. C. Kukreja, P. A. York, C. Nalbantian-Brandt, D. H. Shevrin and M. J. Favus
Department of Medicine, Veterans Administration, Chicago, Illinois 60680.
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.
