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Bi
Guang Tuo1, Yong Hui Yan1, Zheng Long Ge2, Gang
Wei Ou2 and Kui Zhao1
1Department
of Gastroenterology, Affiliated Hospital, Zunyi Medical College,
Zunyi 563003, Guizhou Province, China
2Department of Biochemiology, Zunyi Medical College,
Zunyi, Guizhou Province, China
Dr. Bi Guang Tuo, graduated from Beijing Medical University as a
postgraduate in 1992, associate professor of gastroenterology,
having 14 papers published.
Support by the Youth Scientific Found of Ministry of Healthy.
Correspondence to: Dr. Bi Guang Tuo, Department of
Gastroenterology, Affiliated Hospital, Zunyi Medical College, 143
Dalian Road, Zunyi 563003, Guizhou Province, China
Received:
2000-05-30
Accepted: 2000-06-23
Subject
headings: gastric mucosa; gastrins;
vitaminc; plasma; gastric
juice; Helicobacter pylori
Tuo BG, Yan YH, Ge ZL, Ou GW, Zhao K. Ascorbic acid secretion in the
human stomach and the effect of gastrin. World J Gastroentero,
2000;6(5):704-708
Abstract
AIM: To investigate the changes
of gastric mucosal ascorbic acid secretion in patients with nonulcer
dyspepsia and the effect of gastrin on
it, and to relate any observed changes to H.pylori infection
and mucosal histology.
METHODS: Ascorbic acid secretions in patients were examined
by
collecting continuously gastric juice for one hour after having
aspirated and discarded fasting gastric juice. Using the clearance
rate (mL/min) of ascorbic
acid from blood to gastric juice represented ascorbic acid secretion
in the gas
tric mucosa. Ascorbic acid concentrations in plasma and juice were
measured by ferric reduced method.
RESULTS: Gastric ascorbic acid secretions in H.pylori -posi
tive patients (1.46mL/min, range 0.27-3.78) did not significantly
differ from those in H.pylori -negative patients (1.25mL/min,
0.47-3.14) (P＞0.05).
There were no significant differences in ascorbic acid secretions
between patients with mild (1.56mL/min, 0.50-3.30), moderate
(1.34mL/min, 0.27-2.93) and severe (1.36mL/ min, 0.47-3.78) inflamm
ation (P＞0.05).
There were no significant differences in ascorbic acid
secretions between patients without activity (1.45mL/min, 0.27-3.14)
and with mild (1.32mL/min, 0.61-2.93), moderate (1.49mL/min, 0.50-3
.78) and severe (1.43mL/min, 0.51-3.26) activity of chronic
gastritis ei
ther (P＞0.05).
Ascorbic acid secretions in patients with severe atroph
y (0.56mL/min, 0.27-1.20) were markedly lower than those in patients
with
out atrophy (1.51mL/min, 0.59-3.30) and with mild (1.43mL/min, 0.53
-3.78) and moderate (1.31mL/min, 0.47-3.16) atrophy (P＜0.005).
There was a significant negative correlation between ascorbic acid
secretion and severity of atrophy (correlation coefficient=-0.43, P＜0.005).
After administration of pentagastrin, ascorbic acid secretions were
markedly elevated (from 1.39mL/min, 0.36-2.96 to 3.53mL/min,
0.84-5.91) (P＜0.001).
CONCLUSION: Ascorbic acid secretion in gastric mucosa is not
affected by H.pylori infection. Gastric ascorbic acid
secretion is markedly related to the severity of atrophy, whereas
not related to the severity of inflammation and activity. Gastrin
may stimulate gastric ascorbic acid secretion
. A decreased ascorbic acid secretion may be an important factor in
the link between atrophic gastritis and gastric carcinogenesis.
INTRODUCTION
Ascorbic acid, a powerful antioxidant, is potentially important
for the preventi
on of gastric cancer. It may be able to protect against gastric
cancer by scaven
ging nitrite and preventing the formation of carcinogenic N-nitroso
compounds w
ithin gastric juice[1-5]. In addition, it is capable of
scavenging reac
tive oxygen metabolites[6-8] that may damage gastric
mucosal DNA[
7]and play a role in the development of experimental gastric
carcinoma and p
recancerous lesions induced by N-methyl N-nitro N-nitrosoguanidine[9]
whereby it may also protect against gastric cancer. Various
epidemiological studies have clearly shown that high dietary vitamin
C intake may reduce the risk of gastric cancer[10-12]. H.pylori
infection has been associated with gastritis, peptic ulcer and
an increased risk of gastric cancer[13-17], but its
precise role in gastric carcinog
enesis is still unknown[18]. Some previous studies have
shown that asco
rbic acid is present in the gastric juice of healthy subjects in
concentrations
considerably higher than those in plasma[19-21]. This
high ratio of gas
tric juice to plasma ascorbic acid implies active secretion of
ascorbic acid by
gastric mucosa. It has been recognized recently that gastric juice
ascorbic aci
d concentrations are decreased markedly in subjects with H.pylori
infection
[22-27] and chronic gastritis[19-21,26]. This
change of gastric
juice ascorbic acid concentrations in H.pylori-infected
patients may be an
important factor in the link between H.pylori infec
tion and gastric carcinogenesis. However, these studies only
observed the change
s of ascorbic acid concentrations in gastric juice. The changes of
ascorbic acid
secretion in gastric mucosa have rarely been studied. The purpose of
this study
is, therefore, to investigate the changes of ascorbic acid secretion
in gastric
mucosa, to assess their relationships to H.pylori infection
and mucosal hi
stology, and to explore the effect of gastrin on ascorbic acid
secretion.
SUBJECTS AND METHODS
Subjects
Fifty-five consecutive cases shown nonulcer dyspepsia by
endoscopy and type
B ultrasonography were studied. None of them had undergone upper
gastrointestina
l surgery, nor had taken any drugs over the previous two weeks.
Methods
Collection of samples All patients were studied at the same
time (6：00
am) after a 10-hour overnight fast. A 2mL sample of venous bl
ood was withdraw
n into a heparinised tube for measurement of plasma ascorbic acid
concentration.
Then a nasogastric tube was inserted into the patient＇s
stomach. Gastric juice was continuously collected for one hour by a
constant suction pump after having aspirated and discarded fasting
gastric juice. One hour later, 20 consecutive patients of them were
immediately given pentagastrin (6μg/kg)intramuscularly
and followed by collecting gastric juice for one hour again. Each
gastric sample was analyzed for volume and ascorbic acid
concentration.
Ascorbic acid measurement Venous blood and gastric juice sam
ples were immediately stored at 4℃
after being collected. Ascorbic acid conce
ntrations in the plasma and gastric juice were measured by ferric
reduced method
[28]within 10 hours. This method is based on the
quantitative rapid re
duction of ferric to ferrous ion by ascorbic acid and the
colorimetric measureme
nt of the ferrous ion through its formation of a colored complex
with bathophena
nthroline. Briefly, the venous blood samples were centrifuged at
3000×g
for 20min and gastric juice for 40min before ascorbic acid assay.
Then 0.2mL aliquots of the gastric juice and the plasma supernants
were mixed
with 0.75mL of 5% tricloroacetic acid to precipitate protein, which
wer
e then removed by centrifugation at 3000g for 20min. Subsequently,
0.5mL of the further supernants were mixed with 1.0mL of acetate
buffer, 2.0mL of bathophenanthroline solution, 0.5mL of ferric ch
loride solution, and 0.2mL of phoshporic acid solution. Finally, the
con
centration was determined with a spectrophotometer at 536nm against
standards.Ascorbic acid secretion in gastric mucosa was estimated by
clearance rate of asc
orbic acid from blood to gastric juice (mL/min), which was
calculated by the f
ormula: clearance rate =GV/Bt, where V is the volume of gastric
juice col
lected over t min (mL), G the concentration of ascorbic acid in
gastric juice (μmol/L),
B the concentration of ascorbic acid in plasma(μmol/L),
t=60min.
H.pylori detection and histopathological examination
Three antral biopsies were obtained from every patient for H.pylori
detectio
n and histopathological examination. One biopsy from the lesser
curvature was used for a rapid urease test. Other two biopsies (one
from the lesser curvature
and another from the greater curvature) were used for Warthin-Starry
stain for
H.pylori and hematoxylin-eosin st
ain for histopathological examination. Patients were considered to
be H.pylori
positive if one of the two tests was positive, whereas to be H.pylori
negative if all negative. The severity and extent of gastric
inflammation, activity and atrophy were graded on a scale of mild,
moderate and severe accordi
ng to the Sydney System[29].
Statistical analysis The data in the text were expressed as
median values with ranges. Statistical analysis was carried out
using non-parametric Mann-Whitney U test. The Spearmen rank
correlation test was used to calculate correlation coefficients. A
value of P＜0.05
was considere
d to be statistically significant.
RESULTS
Among the 55 patients studied, 31 were H.pylori positive
and 24 negative.
According to the histological division of the Sydney System, 14 had
mild inflamm
ation, 17 moderate inflammation, and 24 severe inflammation; 16 had
no activity,
11 mild activity, 14 moderate activity and 14 severe activity; 17
had no atroph
y, 16 mild atrophy, 12 moderate atrophy and 10 severe atrophy.
Gastric ascorbic acid secretion and H.pylori infection
Gastric ascorbic acid secretions in H.pylori -positive
patients (1.46mL/min, 0.27-3.78) did not differ significantly from
those in H.pylori negative patients (1.25mL/min, 0.47-3.14) (P＞0.05).
Gastric ascorbic acid secretion and gastric inflammation
Gastric ascorbic acid secretions in patients with mild,
moderate and severe inflammation were respectively 1.56mL/min
(0.50-3.30), 1.34mL/min (0.27-2.93) and 1.36mL/min (0.47-3.78).
There were no significant differences between them(P＞0.05).
Gastric ascorbic acid secretion and activity of gastritis
Gastric ascorbic acid secretions in patients without
activity and with mild, moderate and severe activity were
respectively 1.45mL/min (0.27-3.14), 1.32mL/min (0.61-2.93),
1.49mL/min (0.50-3.78) and 1.43mL/min
(0.51-3.26). There were no significant differences between them
either(P＞0.05).
Gastric ascorbic acid secretion and gastric atrophy
Gastric ascorbic acid secretions in patients without atrophy
and with mild, moderate and severe atrophy were respectively 1.51mL/
min (0.59-3.30), 1.43mL/min (0.53-3.78), 1.31mL/min (0.47-3.16) and
0.56mL/mi
n (0.27-1.20). Ascorbic acid secretions in patients with severe
atrophy were significantly lower than those in patients without
atrophy and with mild and moderate atrophy (P＜0.005).
There were no significant differences between patients without
atrophy and with mild and moderate atrophy(P＞0.05).
With the progress of atrophy, ascorbic acid secretion was gradually
decreased, with a significant negative correlation (correlation
coefficient =-043, P＜0.005).
Effect of gastrin on ascorbic acid secretion
In 20 patients given pentagastrin, gastric ascorbic acid
secretions rose from 1.39mL/min (0.36-2.96) to 3.53mL/min
(0.84-5.91). There was very significant difference between them (P＜0.001).
DISCUSSION
Some previous studies have found that gastric ascorbic acid
concentrations in H.pylori -positive patients and patients
with chronic gastritis are markedly
lower than those in H.pylori -negative patients and healthy
controls[1
9-27]. However, little is known the changes of ascorbic acid
secretion in the stomach. It is also uncertain whether low gastric
juice ascorbic acid concen
trations in H.pylori -infected patients are induced by
impairing gastric mucosal ascorbic acid secretary capacity or other
causes. Some researchers speculate that lower gastric juice ascorbic
acid concentrations in H.pylori-infe
cted patients are mainly related to the impaired gastric secretary
capacity in the presence of gastritis induced by H.pylori
infection. The reason for this notion is that there is a significant
negative correlation between gastric
juice ascorbic concentration and grading of polymorphonuclear
leucocyte infiltra
tion induced by H.pylori infection[22,25].
However, some studies have shown that H.pylori can potentiate
the polymorpho
nuclear leucocyte oxidative burst[30,31], which is
accompanied by a con
siderable production of reactive oxygen metabolites. Ascorbic acid
in gastric juice may be in itself consumed in the course of
scavenging these reactive oxyge
n metabolites. In addition, some studies on gastric mucosal ascorbic
acid levels suggest that gastric mucosal ascorbic acid concentration
is not related to H.pylori infection[32,33] and
presence of inflammation[34]. In order to investigate
whether gastric ascorbic acid secretion is affected
by H.pylori infection and the changes of gastric mucosal
histology, we made an investigation on gastric ascorbic acid
secretion in patients with H.pylori infection and chronic
gastritis through collecting continuously gastric juice for one hour
after having aspirated and discarded fasting gastric
juice. We found that Gastric mucosal ascorbic acid secretion
s in H.pylori -positive patients did not significantly differ
from those in
H.pylori -negative patients. The changes of gastric ascorbic
acid secretio
n were independent of the severity and extent of gastric
inflammation and activi
ty. However, gastric ascorbic acid secretions in patients with
severe atrophy were significantly lower than those in patients
without atrophy or with mild and moderate atrophy. There was a
significant negative correlation between gastr
ic ascorbic acid secretion and severity of atrophy. The results
indicate that gastric ascorbic acid secretion is not influenced by H.pylori
infection. H.pylori infection might lower ascorbic
concentration in gastric juice through other mechanisms. A number of
reasons could be responsible for low gast
ric juice ascorbic acid concentration induced by H.pylori infection.
In addition
to potentiating polymorphoonuclear leucocyte burst described above,
one study h
as shown that the cytochrome c-like water soluble oxidant of H.pylori
may destroy ascorbic acid in the gastric juice of infected patients[35].H.pylori
can also secrete many kinds of enzymes which have higher enzyme
activity[36]. It has been shown that H.pylori
markedly influences the metabolism of certain endogenous organic
molecules[36-38]. These enzymes and the local biochemical
alterations induced by H.pylori might influence the
metabolism of ascorbic acid and lower the ascorbic acid concentra
tion in gastric juice. Ascorbic acid is a powerful antioxidant and
is potentially important for the prevention of gastric cancer. It
may protect against gastric cancer by either preventing the
formation of carcinogenic N-nitroso compounds in gastric juice[1-5]
or scavenging reactive oxygen metabolites that may damage gastric
epithelium[6-8]. Various studies have shown that ascorbic
acid levels in gastric juice are related to the inciden
ce of gastric cancer[39-41]. Blood ascorbic acid levels
in patients with gastric cancer were markedly lowered[42-44].
These studies suggest
that the decrease of ascorbic acid in gastric juice can increase the
risk of gastric carcinogenesis. Chronic atrophic gastritis is an
important precancerous
condition and has been associated with an increased risk of gastric
carcinogenes
is[45,46]. Previous studies have shown that an
environment of hypochlorhydria in atrophic gastritis favors an
overgrowth of nitrite-forming bacteria and increasing the formation
of nitrite and N-nitroso comp
ounds[47-50]. However, as ascorbic acid is a powerful
antioxidant, it may react with nitrite to form dehydroascorbic acid
and nitrous oxide and prevent the formation of carcinogenic N-nitroso
compounds. Only when the nitrite in gastric juice is in excess of
reduced capacity of ascorbic acid in gastric juice, are carcinogenic
N-nitroso compounds available. In the present study, it has been
found that gastric ascorbic acid secretions in patients with severe
atrophy are markedly decreased. There is a significant negative
correlation between gastric ascorbic acid secretion and severity of
atrophy. We speculate
that this change of gastric ascorbic acid secretions in patients
with atrophy may be an important factor in the link between atrophic
gastritis and gastric carcinogenesis. Some studies have shown that
the supplementation of ascorbic acid may elevate the ascorbic acid
concentration in gastric juice[34,51,52
], so the diet rich in vitamin C may decrease the risk of
gastric cancer in patients with gastric atrophy.
The
mechanism whereby gastric mucosa secretes ascorbic acid is unclear.
Some
studies on the rats have shown that gastric ascorbic acid secretion
is physiolog
ically regulated not only by muscarinic receptor-associated
cholinergic stimul
ation[53] but also by CCK receptor-associated humoral
stimulation[
54]. Our study found that gastric ascorbic acid secretion was
markedly elevated after given pentagastrin. The result indicates
that gastrin may also stimulate gastric ascorbic acid secretion. In
the present study, it was observed
that the changes of gastric ascorbic acid secretion were related to
the severit
y of atrophy, whereas not related to the severity of inflammation
and activity.
As the histologic alteration of atrophy is the loss of specialized
gland, we speculate that gastric glands may participate in the
secretion of ascorbic acid.
However, the detailed mechanism about gastric ascorbic acid
secretion will be further investigated.
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