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PubMed1983

Studies on the mutagenic activity of ascorbic acid in vitro and in vivo.

In vitro data are presented to show that ascorbic acid does not have intrinsic mutagenicity towards strain TA100 of S. typhimurium if deionized water is used to prepare the incubation medium. The addition of Cu2+ ions to the bacterial medium that contains ascorbic acid, or the use of tap water and ascorbic acid alone, causes a mutagenic and cytotoxic response that is blocked by EDTA. Additional in vitro data demonstrate that hydrogen peroxide is mutagenic to S. typhimurium strain TA100 and it is suggested that ascorbic acid may be mutagenic and cytotoxic through the generation of hydrogen peroxide. In vivo studies using a sensitive intrahepatic host-mediated mutagenicity assay indicate that ascorbic acid is not genotoxic in guinea pigs even when the dietary intake of vitamin C is above the level required for tissue saturation (5000 mg/kg body weight/day).

Animals↗

PubMed1989

Ascorbic acid inhibits polymorphonuclear leukocytes influx to the place of inflammation--possible protection of lung from phagocyte-mediated injury.

Ascorbic acid as a scavenger of oxidants derived from human polymorphonuclear leukocytes (PMNL) may have clinical significance in antioxidant prevention of emphysema. However, there is a risk relevant to its administration because this drug was reported to enhance PMNL chemotactic response and thus could create protease burden in the lower airways. In this study we have investigated the effect of ascorbic acid on the PMNL influx to the place of inflammation developed in the mouse pleural cavity after injection of zymosan-activated serum (ZAS). We also evaluated the influence of ascorbic acid on human PMNL spontaneous migration, chemotaxis to ZAS and n-formyl-methionyl-leucyl-phenylalanine (FMLP) under agarose. The previous ascorbic acid intraperitoneal administration (single dose 10 mg per day for 3 following days) inhibited leukocyte influx. Total number of cells found in the cavity, number of PMNL and lymphocytes was 2.4, 3.5, 1.7-fold lower than in animals without ascorbic acid, respectively. In vitro ascorbic acid (concentrations of 1 to 10 mg/dl) enhanced PMNL spontaneous migration, concentrations 10 mg/dl and higher inhibited PMNL chemotaxis to ZAS and had no influence on migration of the cells toward FMLP. These results suggest that ascorbic acid may be useful for prevention of lung oxidant injury not only as oxidant scavenger but also as an inhibitor of PMNL influx to the pulmonary tissue.

Animals↗

PubMed1992

Chromium (VI) reducing capacity of ascorbic acid and of human plasma in vitro.

In the metabolism of chromium(VI) its reduction in human plasma is of importance; an extracellular reduction of Cr(VI) is regarded as a detoxification step. Ascorbic acid has been suggested to represent the majority of the Cr(VI)-reducing capacity of human plasma. Therefore the kinetics of the reaction of Cr(VI) with ascorbic acid, at biologically realistic concentrations were studied. Ascorbic acid, in 0.2 M HEPES buffer and at concentrations ranging from 14.2 to 113.6 nmol ml-1 (2.5-20.0 microgram ml-1), was mixed with Cr(VI) (0.4-1.5 nmol ml-1) and incubated at pH 7.4 and 37 degrees C. In addition, chromate solutions at different concentrations [1.5-100 nmol ml-1 Cr(VI)], were incubated at 37 degrees C with freshly drawn blood. From these incubates, ascorbic acid and its oxidized form, dehydroascorbic acid, were simultaneously analyzed by HPLC and post-column derivatization. Chromate was determined by flow injection analysis. The reaction kinetics of ascorbic acid in HEPES buffer with Cr(VI) is of pseudo-first order at higher concentrations, whilst apparently at lower concentrations kinetics are consistent with an autocatalyzed reaction. Results obtained after spiking human plasma are similar. However, when Cr(VI) was reacted with human plasma, no changes in the intrinsic contents of ascorbic acid of the plasma samples occurred. Also, comparing different plasma samples the intrinsic plasma contents of ascorbic acid and the reduction capacities for Cr(VI) [ranging between 0.48 and 0.63 nmol ml-1 Cr(VI) to be reduced] did not correlate. This shows that the reduction of Cr(VI) in native human plasma is complex and is not only determined by the plasma ascorbic acid levels. This is in contrast to the situation in lung lavage fluids (Suzuki 1988; Suzuki and Fukuda 1990) where the concentrations of ascorbic acid are much higher than in blood.

Ascorbic Acid↗

PubMed1985

Ascorbic acid and catecholamine release from digitonin-treated chromaffin cells.

The subcellular localization of catecholamines and ascorbic acid in cultured bovine adrenal chromaffin cells was studied by permeabilizing the cells with digitonin, a steroid glycoside. Catecholamine release from permeabilized chromaffin cells was dependent on the free calcium concentration and the temperature of the incubation mixture. By contrast, [14C]ascorbic acid, preloaded into the cells, was released by digitonin treatment in a manner independent of the concentration of free calcium and with only moderate regard to the incubation temperature. The sensitivity of ascorbic acid release to digitonin treatment was identical to that of calcium-dependent catecholamine release. These results thus suggest that ascorbic acid preloaded into the cells may directly efflux from the cell cytoplasm as a result of the permeabilization of the plasma membrane. Dimethylepinephrine, a permanently positively charged catecholamine analog which is known to be excluded from vesicular fractions, was also released by digitonin treatment in a manner independent of calcium. The time course of dimethylepinephrine release was very similar to that of ascorbic acid release. Thus, newly accumulated ascorbic acid in chromaffin cells may be localized to a free pool in the cell cytoplasm rather than in a vesicular compartment.

Adrenal Medulla↗

PubMed1968

The effect of molybdenum on ascorbic acid metabolism in rats.

1. The effect of dietary molybdenum on the growth rate and also on ascorbic acid metabolism in rats was studied. An excess of dietary molybdenum resulted in growth retardation and loss of weight. Tolerance to molybdenum was affected by the nature of the molybdenum salt administered. 2. Molybdenum ingestion altered certain aspects of ascorbic acid metabolism in rats. The conversion of d-glucuronolactone into l-ascorbic acid in vitro and the oxidative breakdown of l-ascorbic acid by liver enzymes decreased with high molybdenum intakes. The activity of liver uronolactonase was slightly inhibited. The activities of l-gulonate dehydrogenase and l-gulonate decarboxylase were not affected appreciably. 3. Molybdenum supplementation of the control diet resulted in an increase in ascorbic acid content of spleen and adrenal gland, and in a marked decrease in the urinary excretion of ascorbic acid and glucuronic acid. The implications of these findings are discussed.

Adrenal Glands↗

PubMed2000

Determination of ascorbic acid and dehydroascorbic acid in biological samples by high-performance liquid chromatography using subtraction methods: reliable reduction with tris[2-carboxyethyl]phosphine hydrochloride.

Determination of dehydroascorbic acid in biological samples most commonly involves indirect measurement. The concentration is calculated by subtraction of the measured ascorbic acid concentration from that of total ascorbic acid analyzed after reduction of the dehydroascorbic acid present; a methodology also referred to as subtraction methods. Consequently, successful determination of dehydroascorbic acid is dependent on proper sample handling, quantitative reduction of the compound, and accurate quantification of both ascorbic acid and total ascorbic acid. In this paper, the recently introduced reductant tris[2-carboxyethyl]phosphine (TCEP) is evaluated as a reliable alternative to the commonly used reducing agent dithiothreitol (DTT). The results show that TCEP offers a more efficient reduction of dehydroascorbic acid at low pH compared to that of DTT. Moreover, while DTT maintains a reducing sample environment for less than 24 h, TCEP show complete protection from oxidation of ascorbic acid for at least 96 h following sample preparation. Removal of TCEP prior to analysis is unnecessary. A revised HPLC-EC method incorporating TCEP as reductant as well as the coanalysis of isoascorbic acid and uric acid is presented. The within- and between-day coefficients of variation for the complete assay are less than 1.5 and 3.5% for all analytes. As a whole, the method presented here is simpler and more reliable than existing methods.

Ascorbic Acid↗

PubMed1994

Effects of ascorbic acid on collagen matrix formation and osteoblast differentiation in murine MC3T3-E1 cells.

Treatment of mouse MC3T3-E1 cells with ascorbic acid initiates the formation of a collagenous extracellular matrix and synthesis of several osteoblast-related proteins. We recently showed that ascorbic acid dramatically increases alkaline phosphatase and osteocalcin mRNAs and that this induction is blocked by inhibitors of collagen triple-helix formation (Franceschi and Iyer, J Bone Miner Res 7:235). In the present study, the relationship between collagen matrix formation and osteoblast-specific gene expression is explored in greater detail. Kinetic studies revealed that ascorbic acid increased proline hydroxylation in the intracellular procollagen pool within 1 h and stimulated the cleavage of type I collagen propeptides beginning at 2.5 h. Mature alpha 1(I) and alpha 2(I) collagen components were first detected at 10 h and continued to increase in both cell layer and culture medium for up to 72 h. Ascorbic acid also increased the rate of procollagen secretion from cell layers to culture medium. The secretion of another matrix protein, fibronectin, was only slightly affected. Alkaline phosphatase or its mRNA was first detected 2-3 days after ascorbic acid addition, but osteocalcin mRNA was not seen until day 6. Two inhibitors of collagen triple-helix formation, ethyl-3,4-dihydroxybenzoate and 3,4-dehydroproline, inhibited procollagen hydroxylation and alkaline phosphatase induction. 3,4-Dehydroproline also inhibited the induction of alkaline phosphatase and osteocalcin mRNAs. Surprisingly, induction was not blocked if cells were exposed to ascorbic acid before inhibitor addition. Alkaline phosphatase was also partially inhibited if cells were grown in the presence of purified bacterial collagenase. These results indicate that the induction of osteoblast markers by ascorbic acid does not require the continuous hydroxylation and processing of procollagens and suggest that a stable, possibly matrix-associated signal is generated at early times after ascorbic acid addition that allows subsequent induction of osteoblast-related genes.

3T3 Cells↗

PubMedDate not supplied

The role of ascorbic acid in the regulation of cholesterol metabolism and in the pathogenesis of artherosclerosis.

Strong clinical and experimental evidence suggests that chronic latent vitamin C deficiency leads to hypercholesterolaemia and the accumulation of cholesterol in certain tissues. Ascorbic acid supplementation of the diet of hypercholesterolaemic humans and animals generally results in a significant reduction in plasma cholesterol concentration. While most studies relating ascorbic acid to atherosclerosis have used the rabbit as a model, those concerned with elucidating the role of ascorbic acid in the regulation of cholesterol metabolism have generally used the guinea pig. Comparatively little use has been made of the non-human primates. A significant advance in recent years has been the development of a model of chronic latent scurvy in the guinea pig. Chronic dietary inadequacy of vitamin C may influence the pathogenesis of atherosclerosis as it affects not only plasma cholesterol and triglyceride concentrations but also the integrity of the vascular wall. Ascorbic acid is involved in the regulation of cholesterol metabolism in several ways. Dietary inadequacy of vitamin C is associated indirectly with a lowering of cholesterol absorption, this effect resulting from a reduction in the availability of bile acids, monoglycerides and fatty acids. The excretion of cholesterol as neutral steroids, however, appears not to be affected by ascorbic acid. Although much of the evidence for the involvement of ascorbic acid in cholesterol synthesis is equivocal, it seems likely that cholesterol synthesis is decreased in vitamin C deficiency. A series of studies using guinea pigs with chronic latent vitamin C deficiency has provided clear evidence that bile acid synthesis is reduced in this condition. Indirect evidence strongly suggests that this results from a decrease in the activity of the microsomal enzyme cholesterol 7 alpha-hydroxylase. However, some evidence suggests that the mitochondrial reactions of bile acid synthesis require ascorbic acid. The role of ascorbic acid in the regulation of steroidogenesis appears to involve selective inhibitory and stimulatory effects on the desmolase, hydroxylase and dehydrogenase reactions which lead to the formation of pregnenolone and its subsequent conversion to steroid hormones.

Absorption↗

PubMed1978

Intestinal absorpiton of ascorbic acid and its passage through the lipoid membrane of guinea pigs.

Diffusion of ascorbic acid takes place through intestinal lipoid membrane of guinea-pigs. In consequence, plasma and leucocyte concentrations of ascorbic acid increase. Intestinal absorpiton of ascorbic acid in scorbutic guinea-pigs is impaired in contrast to that in normal and saturated guinea-pigs as shown by the accumulation of ascorbic acid in the intestinal mucosal cells of guinea-pigs.

Animals↗

PubMed1994

[The Ascorbic Acid Reference Standard (Control 931) of the National Institute of Health Sciences].

Raw ascorbic acid material was tested for preparation of the "Ascorbic Acid Reference Standard (Control 931)". Analytical data obtained were as follows: infrared spectrum, the same as that of the JP Ascorbic Acid Reference Standard; optical rotation -alpha-20D, + 21.4 degrees; melting point, 190.3 degrees C (decomposition); loss on drying, 0.02%; assay result, 100.1% by iodometry. Based on the above findings, the raw material was authorized as the JP Ascorbic Acid Reference Standard (Control 931).

Ascorbic Acid↗

PubMed1998

Modulation of humoral immune response by ascorbic acid in Oreochromis mossambicus (Peters).

Fish were treated with sublethal doses of ascorbic acid before being immunised with different physical forms of bovine serum albumin (BSA). Ascorbic acid elevates the antibody response to all the physical forms of BSA tested. Generally, there was an inverse relationship between the dose of ascorbic acid and antibody response. In fish administered with multiple doses of ascorbic acid, no significant enhancement of antibody response was observed.

Adjuvants, Immunologic↗

PubMed2003

Effects of ascorbic acid on lead induced alterations of synaptic transmission and contractile features in murine dorsiflexor muscle.

Lead is a common environmental toxin that affects neuromuscular junction and potentially might cause muscle weakness. Antioxidants like ascorbic acid may protect against lead induced myopathy. The present study measured isometric twitch tensions (evoked either directly by muscle stimulation or indirectly by nerve stimulation) to study effects of ascorbic acid on lead induced alterations at murine dorsiflexor skeletal muscle. Resting membrane potentials (RMPs), endplate potentials (EPPs) and miniature endplate potentials (MEPPs) were also recorded. Forty animals were divided into four groups of n = 10 each. (10 control, 10 lead alone, 10 ascorbic acid alone, 10 lead treated plus ascorbic acid). Lead (1 mg/kg) i.p, was administered daily for 2 weeks before the recording day and ascorbic acid (200 mg/kg, i.p) was given daily for 3 weeks prior to the experiment day. Lead treatment reduced twitch tension significantly (from 4.3 +/- 0.5 g to 2.7 +/- 0.2 g) and delayed half time of decay compared to the control. Similarly MEPPs frequencies were reduced following lead treatment. Application of ascorbic acid prevented twitch tension reduction in lead treated mice (3.3 +/- 0.3 g) and reversed lead induced delay in half time of decay. The negative actions of lead treatment on MEPPs frequencies were also modified with ascorbic acid. It appears that ascorbic acid exerts a protective role against lead induced peripheral nerve and muscle dysfunction. This effect of ascorbic acid on lead induced neuromyopathy is probably mediated via a free radical scavenging mechanism or modification of Ca(2+) homeostasis.

Animals↗

PubMed1989

Radiation-induced neoplastic transformation of C3H10T1/2 cells is suppressed by ascorbic acid.

X-ray induced transformation of C3H10T1/2 cells was suppressed in a concentration-dependent manner by administration of ascorbic acid after irradiation (0.1-20 micrograms/ml for the first week) in the culture medium. The dose-response curve was shifted about 60% downward and was slightly steeper in the presence of ascorbic acid (5 micrograms/ml for the first week) than in its absence. The 1-week treatment procedure revealed that cells initiated by radiation remained susceptible to ascorbic acid until the time of morphological phenotype expression. The neoplastically transformed phenotype expressed after incubation for 8 weeks could no longer be suppressed by ascorbic acid even after culture transfer. Similarly, the neoplastically transformed phenotype suppressed for 8 weeks by ascorbic acid treatment was not subsequently expressed in the absence of ascorbic acid. On the basis of the oxygen-detoxifying nature of ascorbic acid, we postulated that expression of the neoplastically transformed phenotype is promoted by reactive oxygen species and peroxy radicals generated in cells during the whole assay period. The data may be useful as a guide for chemopreventive efforts against radiation carcinogenesis.

Animals↗

PubMedDate not supplied

Ascorbic acid clearance in diabetic nephropathy.

The incidence of cardiovascular disease is increased in diabetic nephropathy. Increased oxidative stress in diabetes is believed to play an important role in the pathogenesis of atherosclerosis in diabetes. Since antioxidant vitamins, such as ascorbic acid, often are reduced in diabetes, we hypothesized that the renal clearance of ascorbic acid is increased in patients with diabetic nephropathy. Thirty-seven subjects with diabetic nephropathy were studies: 18 had microalbuminuria (30-300 mg/day albuminuria); the remainder had clinical nephropathy (> 300 mg/day albuminuria). Indices of glycemic control (glucose, hemoglobin A1C) and renal function (albuminuria and creatinine clearance) were measured in addition to serum and urinary ascorbic acid levels. Results showed that subjects with clinical nephropathy had lower mean plasma ascorbic acid (p=0.0009) and higher renal clearance of ascorbic acid (p=0.005) than those with microalbuminuria. Bivariate analysis revealed an inverse correlation between creatinine clearance and AA clearance (r=-0.42, p=0.009). There was a significant linear association between the quantity of albuminuria and ascorbic acid clearance (r=0.49, p=0.002). Thus, patients with diabetic nephropathy have reduced ascorbic acid levels due to increased ascorbic acid clearance. The decrease in antioxidant defense that arises from the low levels of vitamin C may contribute to the increased cardiovascular morbidity and mortality observed in this population.

Adult↗

PubMed1975

Metabolic Conversion of l-Ascorbic Acid to Oxalic Acid in Oxalate-accumulating Plants.

l-Ascorbic acid-1-(14)C and its oxidation product, dehydro-l-ascorbic acid, produced labeled oxalic acid in oxalate-accumulating plants such as spinach seedlings (Spinacia oleracea) and the detached leaves of woodsorrel (Oxalis stricta and O. oregana), shamrock (Oxalis adenopylla), and begonia (Begonia evansiana). In O. oregana, conversion occurred equally well in the presence or absence of light. This relationship between l-ascorbic acid metabolism and oxalic acid formation must be given careful consideration in attempts to explain oxalic accumulation in plants.

Journal Article↗

PubMed1990

Ascorbic acid safety: analysis of factors affecting iron absorption.

The potential for excessive iron absorption by subjects ingesting ascorbic acid doses above the recommended dietary allowance (60 mg) was evaluated by examining published literature (24 studies, 1412 subjects) in which ascorbic acid was part of a test meal given to determine effects on iron absorption. Three parameters associated with iron absorption were identified: (1) a relatively shallow slope for the dose-response curve relating ascorbic acid dosage (1-1000 mg) and percent iron absorption; (2) no significant effect of ascorbic acid on the absorption of high (60 mg) iron doses; and (3) an inverse relationship between iron absorption and plasma transferrin saturation. Ascorbic acid did not increase the incidence of 'high' iron absorbers (greater than 2 SD from population mean) above control levels; limited data for ascorbic acid doses greater than 100 mg/d indicated no change in the distribution of iron absorption values.

Adult↗

PubMed1997

Pharmacokinetic model of ascorbic acid in healthy male volunteers during depletion and repletion.

PURPOSE: To develop a new pharmacokinetic model for ascorbic acid (vitamin C) since no previously published model describes ascorbic acid absorption and disposition over a broad physiologic range of doses and plasma concentrations. METHODS: A new model was developed through exploratory simulations. The model was fitted to pharmacokinetic data obtained from seven healthy volunteers who underwent ascorbic acid depletion then gradual repletion. Concentrations of ascorbic acid were measured in plasma and urine. Final pharmacokinetic model parameter estimates were obtained using nonlinear regression analysis. RESULTS: The new model included saturable absorption, distribution and renal tubular reabsorption parameters. The model described ascorbic acid concentrations in plasma, cells, and urine during depletion and gradual repletion phases with a residual error less than 15%. CONCLUSIONS: The model was useful for obtaining a new understanding of the likely causes for the complex concentration-time profile observed during gradual repletion. At doses of 200 to 2500 mg per day, the plateau in pre-dose concentrations is largely due to apparent saturation of tissue uptake and less a function of oral bioavailability and renal excretion than previously thought.

Adult↗

PubMed2005

Mechanism of enhanced bioavailability and diuretic effect of azosemide by ascorbic acid in rats.

To increase the extent of comparative oral bioavailability (F) value and the diuretic and natriuretic effects of orally administered azosemide, ascorbic acid was coadministered to rats. The rationales for this study are that ascorbic acid might inhibit intestinal first-pass effect of azosemide and might increase the unionized fraction of azosemide at the receptor sites. After oral administration of azosemide (20 mg/kg) with 100 mg of ascorbic acid, the F value (138% vs. 100%), 8-h urinary excretion of azosemide (5.18% vs. 1.32% of oral dose), 8-h urine output (41.3 vs. 23.0 ml), and 8-h urinary excretion of sodium (24.6 vs. 15.3 mmol/kg) were greater than controls (without ascorbic acid). The amount of spiked azosemide remaining after 30 min incubation of 50 mug of azosemide with the 9000 g supernatant fraction of rat small intestine was significantly greater by 100 microg of ascorbic acid (45.3 vs. 40.9 microg) than controls (without ascorbic acid). After oral administration of azosemide with NH4Cl, the urine pH decreased by 0.5 U, and 8-h urine output (25.8 vs. 11.0 ml) and 8-h urinary excretion of sodium (13.3 vs. 6.89 mmol/kg) were significantly greater than controls (without NH4Cl). The increase in F value and diuretic and natriuretic effects of azosemide with coadministration of ascorbic acid seemed to be due to reduced intestinal first-pass metabolism of azosemide, increased urinary excretion of azosemide, and increased unionized fraction of azosemide at the renal tubular receptor sites.

Ammonium Chloride↗