National Academy of Sciences
References
41. Carcinogenesis 1996
Mar;17(3):559-62
Ascorbic acid may protect against human gastric cancer by
scavenging mucosal
oxygen radicals.
Drake IM, Davies MJ, Mapstone NP, Dixon MF, Schorah CJ,
White KL, Chalmers DM,
Axon AT
The Centre for Digestive Diseases, The General Infirmary at
Leeds, UK.
High dietary ascorbic acid intake appears to protect
against gastric cancer.
This may be due to its action as a scavenger of reactive
radical species formed
in the gastric mucosa, resulting in a reduced level of
radical-mediated DNA
damage. We have studied 82 patients, of whom 37 had
Helicobacter
pylori-associated gastritis, a condition which predisposes
to gastric cancer.
Using electron paramagnetic resonance (EPR) spectroscopy we
have demonstrated,
for the first time, that ascorbyl radicals are generated in
human gastric
mucosa, presumably as a result of scavenging of free
radicals by ascorbic acid.
Quantification of ascorbyl radicals demonstrates that there
is a higher
concentration in those patients with H.pylori gastritis
compared with subjects
with normal histology (P < 0.01). We also found gastric
mucosal luminol-enhanced
chemiluminescence and malondialdehyde concentrations (which
are believed to be
markers of radical generation and tissue damage) to be
higher in patients with
H.pylori gastritis compared with those with normal histology
(P < 0.001 and P <
0.01 respectively). The observed concentrations of the
ascorbyl radical
correlate with the level of luminol-enhanced
chemiluminescence (r = 0.41, P <
0.001), but not with malondialdehyde concentrations (r =
0.08, P = 0.47).
Mucosal ascorbic acid and total vitamin C concentrations did
not vary between
histological groups, nor did they correlate with mucosal
levels of the ascorbyl
radical, chemiluminescence or malondialdehyde. These data
suggest that ascorbic
acid is acting as a scavenger of free radicals generated in
human gastric
mucosa. The experiments therefore provide direct supportive
evidence for the
hypothesis that ascorbic acid protects against gastric
cancer by scavenging
reactive radical species which would otherwise react with
DNA, with resultant
genetic damage.
42. Biochim Biophys Acta 1995 Aug
3;1257(3):279-87
Vitamin C prevents metal ion-dependent initiation and
propagation of lipid
peroxidation in human low-density lipoprotein.
Retsky KL, Frei B
Whitaker Cardiovascular Institute, Boston University School
of Medicine, MA,
USA.
Lipid peroxidation and oxidative modification of
low-density lipoprotein (LDL)
have been implicated as causal factors in the pathogenesis
of atherosclerosis,
and prevention of LDL oxidation by antioxidants may be an
effective strategy to
inhibit the progression of the disease. We investigated the
effects of the
reduced form of vitamin C (L-ascorbic acid, AA) and its
two-electron oxidation
product (dehydro-L-ascorbic acid, DHA) upon metal
ion-dependent oxidative
modification of human LDL. We found that low micromolar
concentrations of both
AA and DHA protect LDL against oxidation induced by Cu2+ or
by hemin and
hydrogen peroxide. In a dose-dependent manner, AA and DHA
prevented the
initiation of lipid peroxidation in LDL, as determined by a
sensitive and
selective assay for lipid hydroperoxides utilizing HPLC with
chemiluminescence
detection. AA and DHA also preserved the LDL-associated
antioxidants
alpha-tocopherol, beta-carotene, and lycopene, but not
ubiquinol-10.
Furthermore, AA was able to stop propagation of lipid
peroxidation in LDL,
whereas DHA lacked this ability. The addition of 60 microM
AA to LDL containing
up to 38 nmol/mg protein of pre-formed lipid hydroperoxides
led to their rapid
disappearance; this activity of AA was dependent on the
presence of redox-active
copper, but did not lead to the formation of lipid
hydroxides, the reduced form
of lipid hydroperoxides. Our data show that in
Cu(2+)-exposed LDL (i) vitamin C
primarily spares, rather than regenerates, alpha-tocopherol
and other endogenous
antioxidants, except for AA and DHA prevent initiation of
lipid peroxidation in
LDL; and (iii) AA can terminate lipid peroxidation, thereby
protecting partially
oxidized LDL against further oxidative modification.
43. J Lipid Res 1994
Jun;35(6):1085-92
A critical assessment of the effects of aminoguanidine and
ascorbate on the
oxidative modification of LDL: evidence for interference
with some assays of
lipoprotein oxidation by aminoguanidine.
Scaccini C, Chiesa G, Jialal I
Center for Human Nutrition, University of Texas,
Southwestern Medical Center at
Dallas 75235.
Several lines of evidence support a role for oxidized low
density lipoprotein
(LDL) in the genesis of the atherosclerotic lesion. Hence,
the effect of
compounds with antioxidant properties on LDL oxidation
assumes great
significance. Ascorbate, a potent water-soluble
chain-breaking antioxidant, has
been shown to inhibit LDL oxidation. Aminoguanidine (AMG) is
a pharmacological
inhibitor of advanced non-enzymatic glycosylation. Recently
it has been
suggested that aminoguanidine might have an inhibitory
effect on LDL oxidation,
but total lipid peroxidation assayed by conjugated diene
formation was not
inhibited. Thus, in this study, we compared the effect of
aminoguanidine with
ascorbate to obtain a better appreciation of the effect of
AMG on
Cu(2+)-catalyzed LDL oxidation. Oxidative modification of
LDL was monitored by
assaying intermediates and end products of lipid
peroxidation, conjugated dienes
(CD), lipid peroxides (LPO), and relative electrophoretic
mobility (REM).
Apolipoprotein B-100 modification (increased fluorescence,
fragmentation on
SDS-PAGE, and 125I-labeled LDL degradation by human
macrophages) was also
measured. Ascorbate (100 microM) inhibited LDL oxidation by
> 95%, as evidenced
by all of the selected indices. Aminoguanidine (20 mM)
substantially decreased
thiobarbituric acid-reactive substances (TBARS) activity and
lipid peroxide
formation, but only partially prevented the increase of REM
(-55%), apoB
fluorescence (-39%), and degradation by macrophages (-54%).
Unlike ascorbate,
AMG failed to preserve alpha-tocopherol in LDL, prevent
apoB-100 fragmentation,
or inhibit conjugated diene formation during LDL oxidation.
Furthermore,
incubation of AMG with already oxidized LDL resulted in a
significant decrease
in TBARS activity and LPO, and 26.9% decrease in the REM of
LDL.
44. J Lipid Res 1994
Jun;35(6):1085-92
A critical assessment of the effects of aminoguanidine and
ascorbate on the
oxidative modification of LDL: evidence for interference
with some assays of
lipoprotein oxidation by aminoguanidine.
Scaccini C, Chiesa G, Jialal I
Center for Human Nutrition, University of Texas,
Southwestern Medical Center at
Dallas 75235.
Several lines of evidence support a role for oxidized low
density lipoprotein
(LDL) in the genesis of the atherosclerotic lesion. Hence,
the effect of
compounds with antioxidant properties on LDL oxidation
assumes great
significance. Ascorbate, a potent water-soluble
chain-breaking antioxidant, has
been shown to inhibit LDL oxidation. Aminoguanidine (AMG) is
a pharmacological
inhibitor of advanced non-enzymatic glycosylation. Recently
it has been
suggested that aminoguanidine might have an inhibitory
effect on LDL oxidation,
but total lipid peroxidation assayed by conjugated diene
formation was not
inhibited. Thus, in this study, we compared the effect of
aminoguanidine with
ascorbate to obtain a better appreciation of the effect of
AMG on
Cu(2+)-catalyzed LDL oxidation. Oxidative modification of
LDL was monitored by
assaying intermediates and end products of lipid
peroxidation, conjugated dienes
(CD), lipid peroxides (LPO), and relative electrophoretic
mobility (REM).
Apolipoprotein B-100 modification (increased fluorescence,
fragmentation on
SDS-PAGE, and 125I-labeled LDL degradation by human
macrophages) was also
measured. Ascorbate (100 microM) inhibited LDL oxidation by
> 95%, as evidenced
by all of the selected indices. Aminoguanidine (20 mM)
substantially decreased
thiobarbituric acid-reactive substances (TBARS) activity and
lipid peroxide
formation, but only partially prevented the increase of REM
(-55%), apoB
fluorescence (-39%), and degradation by macrophages (-54%).
Unlike ascorbate,
AMG failed to preserve alpha-tocopherol in LDL, prevent
apoB-100 fragmentation,
or inhibit conjugated diene formation during LDL oxidation.
Furthermore,
incubation of AMG with already oxidized LDL resulted in a
significant decrease
in TBARS activity and LPO, and 26.9% decrease in the REM of
LDL.
45. Int J Infect Dis
2000;4(1):46-50
Generation of reactive oxygen species and formation and
membrane lipid peroxides
in cells infected with Chlamydia trachomatis.
Azenabor AA, Mahony JB
Department of Pathology and Regional Virology, and
Chlamydiology Laboratory,
McMaster University, Hamilton, Ontario, Canada.
OBJECTIVES: Chlamydiae are obligate intracellular
pathogens that cause many
diseases for which the pathogenic mechanisms are largely
unknown. Because
reactive oxygen species (ROS) have been implicated in
pathogenesis of many viral
and bacterial infections, the authors assessed the release
of ROS in selected
host cells (monocytes, Sup-T1 cells, and Hep-2 cells)
infected with Chlamydia
trachomatis. METHODS: Infected cell cultures demonstrated a
dramatic depletion
of uric acid from culture media that was not seen in
uninfected cultures.
Reactive oxygen species generated in infected cultures were
associated with the
formation of lipid peroxides in host cell membrane. RESULTS:
There was a
significant increase in lipid peroxide levels in infected
cells compared to
uninfected controls. Ascorbic acid treatment of infected
cell cultures reduced
the formation of membrane lipid peroxides. CONCLUSIONS:
These results suggest
that ROS produced during chlamydial replication cause
membrane lipid
peroxidation. The role of ROS-induced membrane damage in
chlamydial pathogenesis
is discussed.
46. Am J Clin Nutr 1977
Jul;30(7):1077-81
Effect of mega doses of vitamin C on bactericidal ativity of
leukocytes.
Shilotri PG, Bhat KS
Effect of ingesting mega doses of ascorbic acid was
studied on the leukocyte
function in five normal human subjects. During the first 15
days the subjects
received daily supplements of 200 mg of ascorbic acid, and
during the next 2
weeks they were given 2 g of vitamin C per day.
Supplementation of 200 mg as
well as 2 g of ascorbic acid stimulated hexose monophosphate
shunt activity of
resting leukocytes indicating an increase in resting
metabolism. Intakes of 200
mg of ascorbic acid per day did not affect bacterial killing
by leukocytes. On
the other hand, daily intakes of 2 g of ascorbic acid for 2
weeks significantly
impaired bactericidal activity. Four weeks after withdrawal
of the viatmin
supplementation, bactericidal activity returned to
normal.
47. Int J Vitam Nutr Res Suppl
1982;23:23-34
Effects of ascorbate on normal and abnormal leucocyte
functions.
Anderson R
The stimulatory effects of ascorbate on neutrophil
motility in vitro and in vivo
and lymphocyte transformation to mitogens following
ingestion or intravenous
injection of ascorbate have been found to be related
entirely to inhibition of
the autooxidative effect of the myeloperoxidase/hydrogen
peroxide/halide system
(MPO/H2O2/halide system). Stimulation of neutrophil
migration and lymphocyte
transformation following a single intravenous injection of 1
g of ascorbate was
associated with inhibition of the MPO/H2O2/halide system.
The immunostimulatory
activity and peroxidase inhibitory activity was related
entirely to the serum
ascorbate level. The relationship between inhibition of
the
peroxidase/h2O2/halide system and stimulation of neutrophil
motility and
lymphocyte mitogen-induced transformation was further
established by using the
horseradish peroxidase (HRP)/H2O2/halide system in vitro.
Neutrophils and
lymphocytes, exposed to this system, manifested markedly
impaired chemotactic
responsiveness and mitogen-induced transformation,
respectively. However
inclusion of ascorbate with the peroxidative system
protected the neutrophils
and lymphocytes from these inhibitory effects. Further
studies in 3 patients
with chronic granulomatous disease (CGD) and 10 patients
with bronchial asthma
suggested that ascorbate may be of value to improve the
primary immunological
abnormalities (neutrophil motility and antimicrobial
activity) in CGD and the
secondary abnormalities (neutrophil motility and lymphocyte
transformation)
found in some individuals with bronchial asthma.
48. Arch Otolaryngol 1982
Feb;108(2):122-4
Malignant external otitis and polymorphonuclear leukocyte
migration impairment.
Improvement with ascorbic acid.
Corberand J, Nguyen F, Fraysse B, Enjalbert L
Malignant external otitis (MEO) is a rare disease due to a
Pseudomonas infection
of the external ear occurring in an elderly patient with
uncontrolled diabetes
mellitus. Its high mortality raises the question of an
alteration of the defense
mechanisms of the body. A 58-year-old man was affected with
MEO, and after
several months of unsuccessful treatment, a study of the
function of his
polymorphonuclear neutrophil leukocytes (PMNs) revealed a
defect of the
migration capability. Ascorbic acid (vitamin C) was proved
in vitro to be able
to improve the results of the migration test. The patient
was treated for one
month with ascorbic acid and, parallel to the normalization
of the chemotaxis
test results, the ear lesions healed. The mechanism of such
an alteration of the
PMN function, implying several factors (the active
infection, old age, and
diabetes mellitus), is still unclear. Nevertheless, it is
certainly important to
test the PMN function in patients with MEO and treat them
with immunomodulators.
49. S Afr Med J 1979 Sep
8;56(11):429-33
Effects of ascorbate on leucocytes: Part III. In vitro and
in vivo stimulation
of abnormal neutrophil motility by ascorbate.
Anderson R, Theron A
Abnormal in vitro neutrophil motility was found in 10
patients with recurrent
bacterial infection. The defect appeared to be primary in 3
patients, secondary
to hyperimmunoglobulinaemia E in 2 patients and secondary to
bacterial infection
in 5 patients. In 7 patients impaired polymorphonuclear
leucocyte (PMN) motility
was the only detectable abnormality; defective lymphocyte
function was found in
2 patients and 1 had a total IgA deficiency. Increased
random motility and
migration to endotoxin-activated serum (EAS) and partially
purified C5a was
observed when patients' neutrophils were incubated with 5 x
10(-2)M calcium
ascorbate or 10(-1)M sodium ascorbate in the presence of 5%
autologous serum in
vitro. Six of the patients, 4 children and 2 adults, were
given oral ascorbate,
1 g daily for children and 3 g daily for adults, and tests
of neutrophil
migration were performed at monthly intervals thereafter.
Improved neutrophil
motility was observed in all patients and this correlated
with clinical
improvement in 5 of the 6.
50. Immunopharmacol Immunotoxicol
1989;11(1):119-29
Monocyte locomotion in anergic chronic brucellosis patients:
the in vivo effect
of ascorbic acid.
Boura P, Tsapas G, Papadopoulou A, Magoula I, Kountouras
G
2nd Medical Department, Aristotelian University,
Thessaloniki, Greece.
In 14 patients suffering from relapsing chronic
brucellosis who were anergic to
brucella antigens, we have studied peripheral blood monocyte
random migration
and chemotaxis against non-specific and specific
leukoattractants, as well as
plasma and monocyte ascorbic acid levels. We found that all
parameters studied,
were significantly beneath normal, when compared to normal
subjects. After the
oral administration of ascorbic acid at a daily dose of 1gr
for 15 consequetive
days, random and directed migration against a non-specific
stimulus (casein)
returned to normal. Directed migration against disease
associated
leukoattractants (brucella melitensis and brucella abortus)
antigens improved
significantly, without reaching normal values. We concluded
that ascorbic acid
supplementation might partially restore peripheral, monocyte
function and help
the monocyte-macrophage system to mount an effective immune
response against
chronicity of brucella infection.