Intestinal absorption of cholecalciferol and 25-hydroxycholecalciferol in chronic cholestatic liver disease

We compared the absorption of cholecalciferol and 25-hydroxycholecalciferol in normal subjects and in patients with mild and severe cholestatic liver disease. 3H-cholecalciferol and 3H-25-hydroxycholecalciferol were given orally and serial blood samples were drawn for measurement of the serum level of radiolabeled vitamin. Absorption of 25-hydroxycholecalciferol peaked earlier and was greater than absorption of cholecalciferol at all times in all three groups. Patients with mild cholestasis (normal bilirubin and fecal fat excretion) absorbed both forms of the vitamin normally. Those with severe cholestasis (jaundice and steatorrhea) had minimal absorption of cholecalciferol but relatively preserved absorption of 25-hydroxycholecalciferol. Absorption of cholecalciferol and 25-hydroxycholecalciferol was inversely related to fecal fat excretion. The superior absorption of 25-hydroxycholecalciferol may partly explain its greater efficacy in oral treatment of vitamin D deficiency in patients with severe cholestasis.     

Relative toxicity and metabolic effects of cholecalciferol and 25-hydroxycholecalciferol in chicks.

The relative toxicity and metabolic effectiveness of cholecalciferol (CC) and 25-hydroxycholecalciferol (25-HCC) in chicks were evaluated by feeding six graded levels of each and observing gross and microscopic pathology as well as several metabolic parameters of calcium metabolism. Renal tubular calcification was observed when CC was fed at the rate of 10.0 mg/kg of diet and when 25-HCC was fed at the rate of 0.1 mg/kg diet. Thus, 100-fold increase in toxicity results when the hydroxylated form of CC is fed. Both microscopic renal lesions and increased renal calcium and inorganic phosphate concentrations occurred in chicks with normal serum calcium concentrations.     

Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol

BACKGROUND: The cholecalciferol inputs required to achieve or maintain any given serum 25-hydroxycholecalciferol concentration are not known, particularly within ranges comparable to the probable physiologic supply of the vitamin. OBJECTIVES: The objectives were to establish the quantitative relation between steady state cholecalciferol input and the resulting serum 25-hydroxycholecalciferol concentration and to estimate the proportion of the daily requirement during winter that is met by cholecalciferol reserves in body tissue stores. DESIGN: Cholecalciferol was administered daily in controlled oral doses labeled at 0, 25, 125, and 250 micro g cholecalciferol for approximately 20 wk during the winter to 67 men living in Omaha (41.2 degrees N latitude). The time course of serum 25-hydroxycholecalciferol concentration was measured at intervals over the course of treatment. RESULTS: From a mean baseline value of 70.3 nmol/L, equilibrium concentrations of serum 25-hydroxycholecalciferol changed during the winter months in direct proportion to the dose, with a slope of approximately 0.70 nmol/L for each additional 1 micro g cholecalciferol input. The calculated oral input required to sustain the serum 25-hydroxycholecalciferol concentration present before the study (ie, in the autumn) was 12.5 micro g (500 IU)/d, whereas the total amount from all sources (supplement, food, tissue stores) needed to sustain the starting 25-hydroxycholecalciferol concentration was estimated at approximately 96 micro g (approximately 3800 IU)/d. By difference, the tissue stores provided approximately 78-82 micro g/d. CONCLUSIONS: Healthy men seem to use 3000-5000 IU cholecalciferol/d, apparently meeting > 80% of their winter cholecalciferol need with cutaneously synthesized accumulations from solar sources during the preceding summer months. Current recommended vitamin D inputs are inadequate to maintain serum 25-hydroxycholecalciferol concentration in the absence of substantial cutaneous production of vitamin D.     

Changes in plasma 25-hydroxycholecalciferol and selected blood parameters after injection of massive doses of cholecalciferol or 25-hydroxycholecalciferol in non-lactating dairy cows.

Plasma levels of 25-hydroxycholecalciferol, free hydroxyproline, calcium, phosphorus, and magnesium were determined in non-lactating, pregnant dairy cows injected intra-muscularly with 15 X 10(6) IU of cholecalciferol or 25 mg of 25-hydroxycholecalciferol. A lag in the conversion of cholecalciferol to 25-hydroxycholecalciferol was observed in the cows injected with cholecalciferol, while an immediate increase was observed when cows were injected with 25-hydroxycholecalciferol directly. The increased plasma levels of 25-hydroxycholecalciferol following injection of cholecalciferol were directly related to rises in plasma free hydroxy-proline, calcium, and phosphorus, while plasma magnesium was inversely related to plasma 25-hydroxycholecalciferol. Injection of 25-hydroxycholecalciferol caused an immediate increase in plasma calcium which persisted for the duration of the experiment. The biological half-life of 25-hydroxycholecalciferol in the injected cows was found to be 34 days. The data indicate the possibility of a feedback mechanism in which massive doses of cholecalciferol inhibit hydroxylation at the 25ths carbon preventing its conversion to 25-hydroxycholecalciferol until after 8 days post injection. The increase in plasma 25-hydroxycholecalciferol after 8 days resulted in increased bone resorption as indicated by plasma free hydroxyproline.     

Intestinal absorption of cholecalciferol and 25-hydroxycholecalciferol in patients with both Crohn's disease and intestinal resection.

We compared the intestinal absorption of cholecalciferol and 25-hydroxycholecalciferol in patients with Crohn's disease and resections of the small bowel. Patients were subgrouped into those with small (less than 100 cm), intermediate (100-300 cm), and large (greater than 300 cm) resections. [3H]cholecalciferol or [3H]25-hydroxycholecalciferol were given orally and serial blood samples were taken for measurement of plasma radiolabeled vitamin. Absorption of both forms of the vitamin decreased with extent of resection but 25-hydroxycholecalciferol absorption was always greater than that of cholecalciferol. When compared with normal control subjects, 25-hydroxycholecalciferol absorption in these patients was better maintained than that of cholecalciferol. These data indicate that vitamin D malabsorption reflects the extent of distal small-bowel resection in Crohn's disease. Treatment with oral cholecalciferol is sufficient in those with small or moderate resections but oral 25-hydroxycholecalciferol supplementation may be preferred in those with a severe short-bowel syndrome.     

The effect of dietary cholecalciferol, 25-hydroxycholecalciferol and 1,25-dihydroxycholecalciferol on the development of tibial dyschondroplasia in broiler chickens in the absence and presence of disulfiram

Four experiments were conducted to determine the effect of dietary cholecalciferol (vitamin D3), 25-hydroxycholecalciferol (25-OHD3) and 1,25-dihydroxycholecalciferol (1,25-(OH)2D3) on the changes in growth, feed efficiency and bone ash, and the incidence, severity and number of #3 scores of tibial dyschondroplasia caused by the addition of disulfiram to the diet. The basal diet used was low in calcium and high in phosphorus and chlorine and known to promote a high incidence of tibial dyschondroplasia in broiler chickens. The chickens in all experiments received enough ultraviolet radiation from fluorescent lights in the pens to nearly satisfy their need for vitamin D. The addition of disulfiram to the diet caused an increase in most of the measurements indicating development of tibial dyschondroplasia in all of the experiments, and caused a decrease in bone ash in two of the experiments and a decrease in growth and gain:feed in one experiment. The addition of D3 to a diet containing no D3 caused higher bone ash and lower incidence of tibial dyschondroplasia in the absence or presence of disulfiram. The effects of the addition of 25-OHD3 to diets containing approximately five times the requirement of D3 in the absence and presence of disulfiram caused variable results. The addition of 1,25-(OH)2D3 to the D3-supplemented diet in the absence or presence of disulfiram caused dramatic increases in bone ash and a decrease in most of the criteria used to measure development of tibial dyschondroplasia. There was no indication of interaction of the effects of D3, 25-OHD3 and 1,25-(OH)2D3 with the action of disulfiram.     

Biological activity of 24,24-difluoro-25-hydroxycholecalciferol in chicks

The biological activity of subcutaneously injected 24,24-difluoro-25-hydroxycholecalciferol was compared with that of 25-hydroxycholecalciferol in the vitamin D-deficient growing chick. 24,24-Difluoro-25-hydroxycholecalciferol is equal to 25-hydroxycholecalciferol in the stimulation of: 1) growth, 2) intestinal calcium absorption, 3) elevation of serum calcium and serum phosphorus, 4) healing of rachitic cartilage (radiography), and 5) mineralization of rachitic bone (bone ash). The response appears to be linear in the range of 13.0 to 325 pmol daily. Since 24,24-difluorocholecaliferol cannot be 24-hydroxylated to produce either 24,25-dihydroxycholecalciferol or 1,24,25-trihydroxycholecalciferol, while it can be 1 alpha-hydroxylated to produce 24,24-difluoro-1,25-dihydroxycholecalciferol, these results demonstrate that 24-hydroxylation is not required for the known functions of cholecalciferol in the chick.     

Serum 25-hydroxycholecalciferol levels in women using oral contraceptives

A study has been made of the serum 25-hydroxy cholecalciferol(25-HCC)levels in six groups of women. Significant differences were found between the one pregnant group and the two reference groups as well as between the one pregnant group and two of the three groups using oral contraceptives. No significant differences were found between the reference groups and the ones taking oral contraceptives with oestrogenic concentrations of 0.05 mg or 0.03 mg ethinyl oestradiol for more than one year.It can therefore be concluded that in contrast with most other vitamins, the serum 25-HCC levels are not influenced by the use of oral contraceptives with different oestrogenic concentrations, even over a long period of time.     

Low dietary calcium reduces 25-hydroxycholecalciferol in plasma of rats

We investigated whether dietary factors that are known to increase 1,25-(OH)2-cholecalciferol production can deplete plasma 25-OH-cholecalciferol. Plasma concentration of 25-OH-cholecalciferol, its metabolism in vivo and activities of renal mitochondrial 25-OH-cholecalciferol 1-hydroxylase (1-OHase) and 25-OH-cholecalciferol 24-hydroxylase (24-OHase) were measured in rats fed various amounts of calcium (Ca) and phosphorus (P). All diets contained 5 micrograms (200 IU) cholecalciferol per 100 g. For rats fed the "normal" diet (0.7% Ca and 1.2% P) the mean plasma 25-OH-cholecalciferol level was 11.0 +/- 0.8 nmol/L, and the mean 1-OHase activity was 30 +/- 5 fmol/(mg X min). All rats fed the low Ca (0.014%) diet had 1-OHase activities above 200 fmol/(mg X min) and undetectable plasma 25-OH-cholecalciferol levels (less than 2.5 nmol/L). The chi-square test interrelating plasma 25-OH-cholecalciferol and dietary Ca showed statistical significance (P less than 0.001). The high activity of 1-OHase that resulted from dietary Ca restriction increased utilization of 25-OH-cholecalciferol to the point of causing depletion of this metabolite in the circulation.     

Absorption, tissue distribution and excretion of pelargonidin and its metabolites following oral administration to rats

Recent reports have demonstrated various cardiovascular and neurological benefits associated with the consumption of foods rich in anthocyanidins. However, information regarding absorption, metabolism, and especially, tissue distribution are only beginning to accumulate. In the present study, we investigated the occurrence and the kinetics of various circulating pelargonidin metabolites, and we aimed at providing initial information with regard to tissue distribution. Based on HPLC and LC-MS analyses we demonstrate that pelargonidin is absorbed and present in plasma following oral gavage to rats. In addition, the main structurally related pelargonidin metabolite identified in plasma and urine was pelargonidin glucuronide. Furthermore, p-hydroxybenzoic acid, a ring fission product of pelargonidin, was detected in plasma and urine samples obtained at 2 and 18 h after ingestion. At 2 h post-gavage, pelargonidin glucuronide was the major metabolite detected in kidney and liver, with levels reaching 0.5 and 0.15 nmol pelargonidin equivalents/g tissue, respectively. Brain and lung tissues contained detectable levels of the aglycone, with the glucuronide also present in the lungs. Other tissues, including spleen and heart, did not contain detectable levels of pelargonidin or ensuing metabolites. At 18 h post-gavage, tissue analyses did not reveal detectable levels of the aglycone nor of pelargonidin glucuronides. Taken together, our results demonstrate that the overall uptake of the administered pelargonidin was 18 % after 2 h, with the majority of the detected levels located in the stomach. However, the amounts recovered dropped to 1.2 % only 18 h post-gavage, with the urine and faecal content constituting almost 90 % of the total recovered pelargonidin.     

Presence in human serum, associated with cancer, of an abnormal cholecalciferol derivative, the 1-ceto-24-methyl-25-hydroxycholecalciferol. Preliminary results of a prospective study

Using new techniques for micro-determinations of blood fat soluble vitamin concentrations, this study from a large population of cancer patients compared to healthy controls led to the finding, extraction and isolation of an abnormal cholecalciferol derivative the 1-ceto-24-methyl-25-hydroxycholecalciferol. This factor was shown to be present in serum from cancer patients and absent in most normal controls. A double blind study has confirmed the diagnostic value of this new marker of cancer. In the same time, an animal study was performed. The abnormal cholecalciferol derivative, absent in intact rats, was found in the blood of rats transplanted by the Ehrlich carcinoma. The compound, extracted from serum of human cancer patients, injected to transplanted rats significantly decreased their survival time. Injected to untransplanted rats it induced hypocalcemia. The genesis and the possible role of this factor in cancer development are discussed.     

Bread fortified with cholecalciferol increases the serum 25-hydroxyvitamin D concentration in women as effectively as a cholecalciferol supplement

Fortification of foods is a feasible way of preventing low vitamin D status. Bread could be a suitable vehicle for fortification because it is a common part of diets worldwide. The bioavailability of cholecalciferol from bread is not known. We studied cholecalciferol stability, the concentration of the added cholecalciferol, the dispersion of cholecalciferol in bread, and the bioavailability of cholecalciferol from fortified bread. Three batches of fortified low-fiber wheat and high-fiber rye breads were baked; from each batch, 3 samples of dough and bread were analyzed for their cholecalciferol content. In a single-blind bioavailability study, 41 healthy women, 25-45 y old, with mean serum 25-hydroxyvitamin D concentration 29 nmol/L (range 12-45 nmol/L), were randomly assigned to 4 study groups. Each group consumed fortified wheat bread, fortified rye bread, regular wheat bread (control), or regular wheat bread and a cholecalciferol supplement (vitamin D control) daily for 3 wk. The daily dose of vitamin D was 10 mug in all groups except the control group. The vitamin dispersed evenly in the breads and was stable. Both fortified breads increased serum 25-hydroxyvitamin D concentration as effectively as the cholecalciferol supplement. Supplementation or fortification did not affect serum intact parathyroid hormone concentration or urinary calcium excretion. In conclusion, fortified bread is a safe and feasible way to improve vitamin D nutrition.     

Effects of 1 alpha-hydroxylated metabolites of cholecalciferol on intestinal radiocalcium absorption in goats

Intestinal absorption of 47Ca was measured by a double-isotope technique in goats treated with 1, 5 or 25 micrograms of 1,25-dihydroxycholecalciferol (1,25(OH)2D3). The effects of giving 1,25(OH)2D3 by intravenous (iv) infusion for 30-36 h were compared at each dose level with the effects obtained by oral administration of 1,25(OH)2D3 either in ethanol or protected against rumen degradation in fatty acid pellets. Dose-dependent increments in absorption followed the treatments, with a doubling of absorption at the 1 microgram dose and three- to fivefold increases with the 5 and 25 micrograms doses. 47Ca absorption was equally stimulated 2 and 6 d after treatment but had returned to pretreatment levels 12-14 d after treatment. Intravenous and protected oral administration of 1,25(OH)2D3 stimulated 47Ca absorption to the same extent, in spite of two- to fivefold higher plasma concentrations of 1,25(OH)2D3 after iv treatment. Somewhat lower increments in 47Ca absorption were seen using ethanol as the vehicle for oral administration. The naturally occurring metabolites 1,24(R),25-trihydroxycholecalciferol and 1,25(S),26-trihydroxycholecalciferol had only one-tenth to one-fifteenth the potency of 1,25(OH)2D3 in stimulating 47Ca absorption, while synthetic 1 alpha-hydroxycholecalciferol appeared to be twice as effective as 1,25(OH)2D3 when tested at a high (10 micrograms) dose.     

Urinary excretion of n-hexane metabolites in rats and humans

Summary The urinary excretion of n-hexane metaboites was studied in rats which were either treated or not with phenobarbital before n-hexane treatment and in workers occupationally exposed to n-hexane.A new hexane metabolite, 3-hexanol, and 2-hexanol were found in rat urine, but not in workers' urine. The amount of 2-hexanol excreted during 24 h after n-hexane administration, was equal to 1.2 – l.7 % of the dose. The ratio between 3-hexanol excreted and n-hexane injected was much less than 1 %. Phenobarbital affected 3-hexanol excretion but not 2-hexanol excretion.The lack of n-hexane metabolites in workers' urine, which can be explained by the low ratio of metabolite excretion to the n-hexane absorbed, suggests that urine analysis is unsuitable for monitoring hexane exposure during work.     

Plasma 25-hydroxyvitamin D in growing kittens is related to dietary intake of cholecalciferol

Vitamin D synthesis by growing kittens exposed to ultraviolet light is ineffective. Concentration of 25-hydroxyvitamin D (25-OHD) in plasma (the most useful index of vitamin D status) was measured in six groups each of seven kittens given a purified diet (12 g calcium and 8 g phosphorus/kg, calculated metabolizable energy = 20 kJ/g) that contained either 0.0, 3.125, 6.25, 12.5, 18.75 or 25 microg of cholecalciferol/kg diet. All kittens received these diets from 9 to 22 wk of age, and the two groups given the 0.0 and 3.125 microg cholecalciferol/kg treatments continued to receive the diets until they were 34 wk old. Total and ionizable calcium and phosphorus in plasma were not affected by treatments. No adverse clinical changes were observed or found on radiographic examination of the kittens at 22 or 34 wk of age. Plasma concentration of 25-OHD was linearly related (r2 = 0.99, P < 0.001) to dietary intake of cholecalciferol. Plasma concentration of 25-OHD in kittens given the diet without added vitamin D was significantly less at 22 wk than at 9 wk, whereas kittens receiving the diet containing 3.125 microg cholecalciferol/kg had significantly higher 25-OHD concentrations at 22 and 34 wk than at 9 wk of age. Kittens given the 6.25 microg cholecalciferol/kg diet had plasma 25-OHD concentrations at 22 wk > 50 nmol/L which is considered replete for humans. An allowance of 6. 25 microg (250 IU) of cholecalciferol/kg diet is suggested to provide a margin of safety.