This Article Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by DUSSO, A. S. Articles by SLATOPOLSKY, E. Search for Related Content PubMed PubMed Citation Articles by DUSSO, A. S. Articles by SLATOPOLSKY, E.

Extrarenal Production of Calcitriol in Normal and Uremic Humans^*

Renal Division, Washington University School of Medicine St. Louis, Missouri 63110

Address all correspondence and requests for reprints to: Eduardo Slatopolsky, M.D., Chromalloy American Kidney Center, One Barnes Hospital Plaza, Box 8129, St. Louis, Missouri 63110.

We have previously reported low serum levels of 1,25-dihydroxyvitamin D₃ [1,25-(OH)₂D₃] and increased 1,25-(OH)₂D₃ production after the administration of 25-hydryoxyvitamin D (25OHD) to anephric humans. Since normal alveolar macrophages are known to synthesize l,25-(OH)₂D₃when stimulated with -interferon or lipopolysaccharide, we determined whether macrophages derived from peripheral blood monocytes could be an extrarenal source of 1,25-(OH)₂D₃. Our results demonstrated that macrophages from normal individuals synthesize 1,25-(OH)₂D₃. The apparent K_m for 25OHD₃ was 6.6 ± 0.5 nM and the maximum velocity was 47.4 ± 13.7 fmol 1,25-(OH)₂D₃/h·µg DNA. The activity of this enzyme was reduced 37.2 ± 3.1% by physiological concentrations (96 pmol/L) of 1,25-(OH)₂D₃in the incubation medium. Normal macrophages further hydroxylated 1,25-(OH)₂D₃ to more polar metabolites, and this catabolic activity was significantly enhanced by physiological concentrations of 1,25-(OH)₂D₃. In chronic renal failure, peripheral macrophages exhibited an enhanced l-hydroxylase activity (8.2 ± 0.8 vs. 4.2 ± 0.5 fmol 1,25-(OH)₂D₃/Mg DNA·h in controls) and a decreased capacity to degrade 1,25-(OH)₂D₃. Exogenous 1,25-(OH)₂D₃, in physiological concentrations, reduced 1,25-(OH)₂D₃ synthesis to a degree (23.6 ± 8.5%) comparable to that observed in normal cells. 1,25-(OH)₂D₃ production by macrophages did not correlate with the severity of hyperparathyroidism. Moreover, human PTH-(l-34) in supraphysiological concentrations (20,000 and 100,000 ng/L) did not stimulate the lahydroxylase activity of macrophages from either normal or uremic subjects. These results demonstrate that 1) normal peripheral macrophages metabolize 25OHD₃ and 1,25-(OH)₂D₃; 2) macrophages in uremia display higher rates of 1,25-(OH)₂D₃ synthesis and lower rates of catabolism than normal macrophages; and 3) 1,25-(OH)₂D₃ deficiency, but not hyperparathyroidism, may play a role in the stimulation of 1,25-(OH)₂D₃ production by macrophages in chronic renal failure.

^* This work was supported in part by grants (DK-09976, DK-07126, and RR-00036) from the USPHS, NIDDK.

Received March 19, 1990.

This article has been cited by other articles:

				K. Kalantar-Zadeh and C. P. Kovesdy Clinical Outcomes with Active versus Nutritional Vitamin D Compounds in Chronic Kidney Disease Clin. J. Am. Soc. Nephrol., September 1, 2009; 4(9): 1529 - 1539. [Abstract] [Full Text] [PDF]

				H. Eddington and J. G. Heaf Clinical management of disturbances of calcium and phosphate metabolism in dialysis patients NDT Plus, August 1, 2009; 2(4): 267 - 272. [Abstract] [Full Text] [PDF]

				G. Jean, J.-C. Terrat, T. Vanel, J.-M. Hurot, C. Lorriaux, B. Mayor, and C. Chazot Daily oral 25-hydroxycholecalciferol supplementation for vitamin D deficiency in haemodialysis patients: effects on mineral metabolism and bone markers Nephrol. Dial. Transplant., November 1, 2008; 23(11): 3670 - 3676. [Abstract] [Full Text] [PDF]

				M. V. Young, G. G. Schwartz, L. Wang, D. P. Jamieson, L. W. Whitlatch, J. N. Flanagan, B. L. Lokeshwar, M. F. Holick, and T. C. Chen The prostate 25-hydroxyvitamin D-1{alpha}-hydroxylase is not influenced by parathyroid hormone and calcium: implications for prostate cancer chemoprevention by vitamin D Carcinogenesis, June 1, 2004; 25(6): 967 - 971. [Abstract] [Full Text] [PDF]

				B.-W. Ogunkolade, B. J. Boucher, J. M. Prahl, S. A. Bustin, J. M. Burrin, K. Noonan, B. V. North, N. Mannan, M. F. McDermott, H. F. DeLuca, et al. Vitamin D Receptor (VDR) mRNA and VDR Protein Levels in Relation to Vitamin D Status, Insulin Secretory Capacity, and VDR Genotype in Bangladeshi Asians Diabetes, July 1, 2002; 51(7): 2294 - 2300. [Abstract] [Full Text] [PDF]

				J. W. Morgan, N. Kouttab, D. Ford, and A. L. Maizel Vitamin D-Mediated Gene Regulation in Phenotypically Defined Human B Cell Subpopulations Endocrinology, September 1, 2000; 141(9): 3225 - 3234. [Abstract] [Full Text] [PDF]

				J. S. Adams and V. Kantorovich Inability of Short-Term, Low-Dose Hydroxychloroquine to Resolve Vitamin D-Mediated Hypercalcemia in Patients with B-Cell Lymphoma J. Clin. Endocrinol. Metab., February 1, 1999; 84(2): 799 - 801. [Abstract] [Full Text]

				A.S. Dusso, S. Kamimura, M. Gallieni, M. Zhong, L. Negrea, S. Shapiro, and E. Slatopolsky {gamma}-Interferon-Induced Resistance to 1,25-(OH)2 D3 in Human Monocytes and Macrophages: A Mechanism for the Hypercalcemia of Various Granulomatoses J. Clin. Endocrinol. Metab., July 1, 1997; 82(7): 2222 - 2232. [Abstract] [Full Text] [PDF]

				S. Kamimura, M. Gallieni, M. Zhong, W. Beron, E. Slatopolsky, and A. Dusso Microtubules Mediate Cellular 25-Hydroxyvitamin D(3) Trafficking and the Genomic Response to 1,25-Dihydroxyvitamin D(3) in Normal Human Monocytes J. Biol. Chem., September 22, 1995; 270(38): 22160 - 22166. [Abstract] [Full Text] [PDF]