Effect of uremic serum on 1,25-dihydroxyvitamin D3-induced differentiation of human promyelocytic leukemia cell, HL-60.
The mechanism by which resistance to 1,25-(OH)2D3 occurs in patients with chronic renal failure was studied. 1,25-(OH)2D3 causes the induction of differentiation and of 1,25-(OH)2D3-24-hydroxylase activity in the mitochondria of the human promyelocytic leukemia cell line, HL-60, via a steroid hormone-receptor mechanism. Treatment of these cells with 10(-8) M 1,25-(OH)2D3 for 5 days in a medium containing 10% uremic serum from 4 patients with chronic renal failure resulted in maturation of the cells amounting to 30.3 +/- 18.7 (mean +/- SD) and 32.5 +/- 11.2% maturation by the nitroblue tetrazolium reduction assay and the nonspecific esterase assay, respectively. These values were significantly lower than those obtained with 10% normal serum from 3 normal controls (66.6 +/- 12.8 and 58.3 +/- 10.9%, p < 0.02). The occurrence of resistance to 1,25-(OH)2D3 in uremic serum-treated cells was also confirmed when the effect of 1,25-(OH)2D3 was assessed by the induction of the cell's ability to hydroxylate the C-24 position of 1,25-(OH)2[3H]D3. Treatment of HL-60 cells with a mixture of 5% uremic plus 5% normal serum impaired 1,25-(OH)2D3-induced cell differentiation to the levels as those in 10% uremic serum, strongly suggesting the occurrence of a substance(s) having 1,25-(OH)2D3-inhibitory activity in the uremic serum. A significant reduction in 1,25-(OH)2D3 receptor levels was observed in uremic serum-treated cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Second Department of Internal Medicine, Osaka City University Medical School, Japan.
M
M
Inaba
S
S
Okuno
H
H
Koyama
E
E
Ishimura
Y
Y
Nishizawa
H
H
Morii
D001798:Blood Proteins / Q000494:pharmacology*; D002117:Calcitriol / Q000378:metabolism / Q000494:pharmacology*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000473:pathology*; D000242:Cyclic AMP / Q000032:analysis / Q000378:metabolism; D006801:Humans; D007676:Kidney Failure, Chronic / Q000097:blood; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism / Q000473:pathology*; D011956:Receptors, Cell Surface / Q000032:analysis / Q000187:drug effects; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D014511:Uremia / Q000097:blood*
D001798:Blood Proteins; D011956:Receptors, Cell Surface; D000242:Cyclic AMP; D002117:Calcitriol