Large Doses Of Vitamin D3 Research Articles

20S-Hydroxyvitamin D3, a Secosteroid Produced in Humans, Is Anti-Inflammatory and Inhibits Murine Autoimmune Arthritis.

The ability to use large doses of vitamin D3 (D3) to chronically treat autoimmune diseases such as rheumatoid arthritis (RA) is prohibitive due to its calcemic effect which can damage vital organs. Cytochrome P450scc (CYP11A1) is able to convert D3 into the noncalcemic analog 20S-hydroxyvitamin D3 [20S(OH)D3]. We demonstrate that 20S(OH)D3 markedly suppresses clinical signs of arthritis and joint damage in a mouse model of RA. Furthermore, treatment with 20S(OH)D3 reduces lymphocyte subsets such as CD4+ T cells and CD19+ B cells leading to a significant reduction in inflammatory cytokines. The ratio of T reg cells (CD4+CD25+Foxp3+ T cells) to CD3+CD4+ T cells is increased while there is a decrease in critical complement-fixing anti-CII antibodies. Since pro-inflammatory cytokines and antibodies against type II collagen ordinarily lead to destruction of cartilage and bone, their decline explains why arthritis is attenuated by 20(OH) D3. These results provide a basis for further consideration of 20S(OH)D3 as a potential treatment for RA and other autoimmune disorders.

Identification of 24,25,26,27-tetranor-23-hydroxyvitamin D3 as a product of the renal metabolism of 24,25-dihydroxyvitamin D3.

By cochromatography, mass spectrometry, and chemical derivatization, we have shown that a metabolite isolated from the perfused rat kidney incubated with 24-(R),25-dihydroxyvitamin D3 is indistinguishable from chemically synthesized 24,25,26,27-tetranor-23-hydroxyvitamin D3. The new metabolite is also produced from 24-oxo-25-hydroxyvitamin D3 but not from 23(S),25-dihydroxyvitamin D3. Enzymes required for the synthesis of the new metabolite are absent in the vitamin D deplete animal but are induced along with the 25-hydroxyvitamin-D3 24-hydroxylase by vitamin D repletion. The pathway of 24,25-dihydroxyvitamin D3 metabolism in the perfused kidney is stimulated by pre-treatment of the rat with large doses of vitamin D3, suggesting that the pathway is a degradative one.

Biological activity assessment of 25-hydroxyvitamin D 3-26,23-lactone in the rat

A new metabolite of vitamin D3 has been isolated from the plasma of chickens, rats and pigs given large doses of vitamin D3 and identified as 25-hydroxyvitamin Ds-26,23-lactone (25OH-Da-26,23-lactone) [l-3]. Four possible diastereoisomers of 25OH-Da26,23-lactone have been synthesized [4-91; they have been directly compared to the natural 25OH-Da-26, 23-lactone by high pressure liquid chromatography. The stereochemical configurations of the natural 25-OH-D,-26,23-lactone at C-23 and C-25 positions were determined to be 23(S) and 25(R), respectively [9,10]. 23(5)25Dihydroxyvitamin D3 [23(S)25(OH),Da] is a far better substrate for production of 25-OH-Ds-26,23-lactone than is 25,26_dihydroxyvitamin Ds (25,26-(OH),Ds) [ 11].23(,!7)25@)26&ihydroxyvitamin D3 [23(5)25@)26-(OH)sDs] is a better substrate than 23(5)25-(OH),D, in the biosynthesis of the 25-OH-Da-26,23-lactone [ 121. Therefore, the 25-OH-Ds-26,23-lactone may be biosynthesized from 25-OH-D3 by way of 23@)25-(OH),D, to 23(S)25(R)26-(OH),D,. 2.1. Compounds We synthesized 25-OH-D3 and lo,25-(OH)2Ds as in [ 13].25-OH-Da-26,23-Lactone was isolated and purified from the serum of rats given large doses of vitamin D3 as in [lo].

23,24,25-Trihydroxyvitamin D3, 24,25,26-trihydroxyvitamin D3, 24-keto-25-hydroxyvitamin D3, and 23-dehydro-25-hydroxyvitamin D3: new in vivo metabolites of vitamin D3.

Four new in vivo metabolites of vitamin D3 were isolated from the blood plasma of chicks given large doses of vitamin D3. The metabolites were isolated by methanol-chloroform extraction and a series of chromatographic procedures. By use of mass spectrometry, ultraviolet absorption spectrophotometry, and specific chemical reactions, the metabolites were identified as 23,24,25-trihydroxyvitamin D3, 24,25,26-trihydroxyvitamin D3, 24-keto-25-hydroxyvitamin D3 and 23-dehydro-25-hydroxyvitamin D3.

Isolation of identification of 24(R)-hydroxyvitamin D3 from chicks give large doses of vitamin D3.

A new metabolite of vitamin D was isolated from the blood plasma of chicks given large doses of vitamin D3. The isolation involved methanol-chloroform extraction and four column chromatographic steps. The metabolite was identified by high- and low-resolution mass spectroscopy, chemical derivatization, an comigration with authentic standard as 3 beta, 24(R)-dihydroxy-9,10-seco-5,7,10(19)-cholestatriene [24(R)-hydroxyvitamin D3]. No detectable 24-(R)-hydroxyvitamin D3 was recovered from 16 L of plasma from chicks receiving physiologic levels of vitamin D3.

25-Hydroxyvitamin D3 26,23-lactone: a new in vivo metabolite of vitamin D

A major vitamin D metabolite was isolated in pure form from the blood plasma of chicks either maintenance levels or large doses of vitamin D3. The isolation involved methanol-chloroform extraction and five column chromatographic procedures. The metabolite purification and elution position on these columns were followed by a competitive protein binding assay. The metabolite was identified, using high- and low-resolution mass spectrometry, 270-MHz proton nuclear magnetic resonance spectrometry, ultraviolet absorption spectrophotometry, Fourier transform infrared spectrophotometry, and specific chemical reactions, as 3 beta,-25-dihydroxy-9,10-seco-5,7,10(19)-cholestatrieno-26,23-lactone. The trivial names 25-hydroxyvitamin D3 26,23-lactone or calcidiol 26,23-lactone are suggested for this compound.

THE VITAMIN D3 METABOLITE‐TYPE ACTIVITY OF SOLANUM MALACOXYLON

1. Administration of an aqueous extract of the dried leaves of Solanum malacoxylon (DLSM) to rats causes a rapid hyperphosphataemia and a decrease in plasma alkaline phosphatase activity; the two effects are typical of 1,25(OH)2D3, the hormonally active metabolite of vitamin D3. 2. DLSM, like both vitamin D3 and parathyroid hormone, increases plasma calcium and citrate levels in rats. The effect of DLSM in influencing plasma citrate, and the role of this important metabolite in mineral metabolism is discussed. 3. A decrease of plasma magnesium levels occurs in rats following treatment with DLSM. This decrease, which is associated with a renal loss of this cation, is remarkably similar to that produced by hypervitaminosis D3. 4. Prolonged administration of DLSM to vitamin D deficient rats causes a polyuria, hypercalciuria, hyperphosphaturia, hypermagnesuria, an increase in urinary total hydroxyproline, an increase in plasma total hexosamines, and a corresponding decrease in the bone total hexosamines. These effects, some of which can also be produced by hyperparathyroidism, or following the administration of parathyroid extract (PTE), large doses of vitamin D3, or 1,25(OH)2D3, suggest that DLSM, like the latter compounds, is capable of causing bone mineral mobilization, and the dissolution of bone organic matrix.

Interrelationships between thyrocalcitonin, parathyroid hormone and vitamin D: control of serum calcium in hypervitaminosis D.

Rats which are hypercalcemic due to large doses of vitamin D3 show an additional transient hypercalcemia following thyroparathyroidectomy. Parathyroidectomy did not duplicate this response. Thyroidectomy 8 hr after parathyroidectomy, however, also gave rise to the additional hypercalcemia. Removal of endogenous thyrocalcitonin appears to be responsible for this serum calcium elevation. The ability of thyrocalcitonin to prevent this hypercalcemia was demonstrated with exogenous thyrocalcitonin. Exogenous parathyroid hormone further amplified the serum calcium elevation following thyroparathyroidectomy, an effect which was counteracted with exogenous thyrocalcitonin. In the absence of both thyrocalcitonin and parathyroid hormone, vitamin D3 (20,000 IU/day) was able to induce mobilization of bone to maintain serum calcium at normal levels which might have been expected from the use of vitamin D in the treatment of hypoparathyroidism. (Endocrinology 85: 704, 1969)

The effect of cortisone on cardiovascular sclerosis induced in rats with cholesterol and vitamin D.

ABSTRACT The authors have studied the effect of cortisone on rats fed 3.5 % cholesterol and 0.01 % vitamin D3, together or separately as part of the regular diet for a period of 100 days. The dose of cortisone was at first 2.5 mg but was reduced after thirty days to 1 mg/day. Particular attention was paid both macroscopically and histologically to any changes observed in the cardiovascular system. The study showed that, when administered alone cortisone in the doses used is not capable of inducing any changes characteristic of sclerosis in the walls of the arteries or in the heart. When cholesterol had been added to the diet, it was noted that after some time slight degenerative changes occurred in the elastic fiber structure of the aorta among both the female and male rats. The feeding of cholesterol alone had not led to changes in the walls of the blood vessels in previously performed experiments. The addition of large doses of vitamin D3 to the basic diet however caused a massive Mönckeberg-type mediasclerosis. With the addition of cortisone, these changes developed more rapidly and spread over a more extensive area. The mediasclerosis was then also accompanied by local, reactive proliferative formations in the intima, subendocardial fibrosis, necrosis and calcification of the myocardium. In the coronary arteries, accumulation of calcium in the media, occlusions and thromboses were found. Cartilaginous metaplasia and dissecting aneurysms were observed in the aorta.