Effects of long-term administration of vitamin D3 analogs to mice

被引:30
作者
Smith, EA
Frankenburg, EP
Goldstein, SA
Koshizuka, K
Elstner, E
Said, J
Kubota, T
Uskokovic, M
Koeffler, HP
机构
[1] Univ Calif Los Angeles, Cedars Sinai Med Ctr, Sch Med, Dept Med, Los Angeles, CA 90048 USA
[2] Univ Calif Los Angeles, Cedars Sinai Med Ctr, Sch Med, Dept Pathol, Los Angeles, CA 90048 USA
[3] Univ Michigan, Orthoped Res Labs, Ann Arbor, MI 48109 USA
[4] Hoffmann La Roche Inc, Nutley, NJ 07110 USA
关键词
D O I
10.1677/joe.0.1650163
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
This study explores the effects of chronic administration of vitamin Dg compounds on several biological functions in mice. Knowledge of long-term tolerability of vitamin D-3, analogs may be of interest in view of their potential clinical utility in the management of various pathologies such as malignancies, immunobiological disorders and bone diseases. Four unique vitamin Dg analogs (code names, compounds V, EO, LH and LA) and 1,25-dihydroxyvitamin D3 (1,25(OH)(2)D-3) were administered i.p, for 55 weeks to Balb/c mice. Each analog had previously been shown to have potent in vitro activities. After 55 weeks of administration, the mice had a profound decrease in their serum levels of interleukin-2 (IL-2). Likewise, several analogs depressed serum immunoglobulin G concentrations (compounds LH and LA), but levels of blood lymphocytes and splenic lymphocyte subsets (CD4, CD8 and CD19) were not remarkably depressed. The percent of committed myeloid hematopoietic stem cells was 4- to 5-fold elevated in the bone marrow of the mice that received analogs LH and V; nevertheless, their peripheral blood white and red cell counts and platelets were not significantly different in any of the groups. The mice that received 1,25(OH)2D3 had a decrease in bone quantity and quality with a decrease in cross-sectional area and cortical thickness, and a 50% reduction in both stiffness and failure load compared with the control group. In contrast, the cohort that received a fluorinated analog (compound EO) developed bones with significantly larger cross-sectional area and cortical thickness as well as stronger mechanical properties compared with the control group. At the conclusion of the study, body weights were significantly decreased in all experimental mice. Their blood chemistries were normal. Extensive gross and microscopic autopsy analyses of the mice at the conclusion of the study were normal, including those of their kidneys. In conclusion, the vitamin D-3, analogs were fairly well tolerated. They did suppress immunity as measured by serum IL-2 and may provide a means to depress the immune response after organ transplantation and for autoimmune diseases. Use of these analogs prevented the detrimental effects of vitamin D-3, administration on mechanical and geometric properties of bone, while one analog (compound EO) actually enhanced bone properties. These results suggest that long-term clinical trials with the analogs are feasible.
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页码:163 / 172
页数:10
相关论文
共 42 条
[1]   A NOVEL VITAMIN-D3 ANALOG, 22-OXA-1,25-DIHYDROXYVITAMIN-D3, INHIBITS THE GROWTH OF HUMAN BREAST-CANCER INVITRO AND INVIVO WITHOUT CAUSING HYPERCALCEMIA [J].
ABE, J ;
NAKANO, T ;
NISHII, Y ;
MATSUMOTO, T ;
OGATA, E ;
IKEDA, K .
ENDOCRINOLOGY, 1991, 129 (02) :832-837
[2]   NONGENOMIC ACTIONS OF THE STEROID-HORMONE 1-ALPHA,25-DIHYDROXYVITAMIN D-3 [J].
BARAN, DT .
JOURNAL OF CELLULAR BIOCHEMISTRY, 1994, 56 (03) :303-306
[3]   DIFFERENTIAL-EFFECTS OF 1,25-DIHYDROXYVITAMIN D3 ON HUMAN-LYMPHOCYTES AND MONOCYTE MACROPHAGES - INHIBITION OF INTERLEUKIN-2 AND AUGMENTATION OF INTERLEUKIN-1 PRODUCTION [J].
BHALLA, AK ;
AMENTO, EP ;
KRANE, SM .
CELLULAR IMMUNOLOGY, 1986, 98 (02) :311-322
[4]   A MURINE SKELETAL ADAPTATION THAT SIGNIFICANTLY INCREASES CORTICAL BONE MECHANICAL-PROPERTIES - IMPLICATIONS FOR HUMAN SKELETAL FRAGILITY [J].
BONADIO, J ;
JEPSEN, KJ ;
MANSOURA, MK ;
JAENISCH, R ;
KUHN, JL ;
GOLDSTEIN, SA .
JOURNAL OF CLINICAL INVESTIGATION, 1993, 92 (04) :1697-1705
[5]  
BRAISTEANU DD, 1993, CLIN EXPT IMMUNOLOGY, V94, P412
[6]   Toward therapeutic intervention of cancer by vitamin D compounds [J].
Campbell, MJ ;
Koeffler, HP .
JOURNAL OF THE NATIONAL CANCER INSTITUTE, 1997, 89 (03) :182-185
[7]  
Colston K., 1997, Vitamin D., P1107
[8]   CYCLOSPORINE-A SPECIFICALLY INHIBITS FUNCTION OF NUCLEAR PROTEINS INVOLVED IN T-CELL ACTIVATION [J].
EMMEL, EA ;
VERWEIJ, CL ;
DURAND, DB ;
HIGGINS, KM ;
LACY, E ;
CRABTREE, GR .
SCIENCE, 1989, 246 (4937) :1617-1620
[9]   INVIVO BENEFICIAL-EFFECTS OF CYCLOSPORINE A AND 1,25-DIHYDROXYVITAMIN-D3 ON THE INDUCTION OF EXPERIMENTAL AUTOIMMUNE-THYROIDITIS [J].
FOURNIER, C ;
GEPNER, P ;
SADOUK, M ;
CHARREIRE, J .
CLINICAL IMMUNOLOGY AND IMMUNOPATHOLOGY, 1990, 54 (01) :53-63
[10]  
Gross C., 1997, Vitamin D., P1125