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May 9, 2000

National Academy of Sciences References

31. Mutat Res 1995 Jun;329(1):37-47The effect of antioxidants on bleomycin treatment in in vitro and in vivogenotoxicity assays.Anderson D, Basaran N, Blowers SD, Edwards AJBIBRA International, Carshalton, Surrey, UK.

Antioxidants are thought to be important in protecting against damage fromactive oxygen species. The effects of the antioxidant nutrients vitamins C and Ehave been investigated after bleomycin treatment in the Salmonella typhimuriumbacterial mutation assay, in the human peripheral lymphocyte chromosomeaberration assay, and in the mouse micronucleus assay in peripheral blood andbone marrow cells. There were no protective effects from vitamins C and E in thebacterial mutation assay, but vitamin C and not vitamin E abolished chromosomedamaging responses in human peripheral lymphocytes, and both vitamins reducedresponses in micronuclei from peripheral blood cells in mice. This would suggestthat in human cells in vitro and mouse cells in vivo these vitamins could have aprotective role.

32. Cancer Epidemiol Biomarkers Prev 1995 Oct-Nov;4(7):751-8Cigarette smoking, intracellular vitamin deficiency, and occurrence ofmicronuclei in epithelial cells of the buccal mucosa.Piyathilake CJ, Macaluso M, Hine RJ, Vinter DW, Richards EW, Krumdieck CLDepartment of Nutrition Sciences, University of Alabama at Birmingham 35294,USA.

The study focuses on the assessment of chromosomal damage associated with folateand vitamin B12 deficiency, and with cigarette smoking in a tissue directlyexposed to cigarette smoke (buccal mucosa) while controlling for potentialconfounding factors. A cross-sectional study was carried out among 39 currentsmokers (CSs) and 60 noncurrent smokers (NCSs). Buccal mucosal cells, saliva,and blood samples were collected from each subject. The Health Habits andHistory Questionnaire (Block et al., 1986) was modified to obtain dietary andother relevant information. Methods used to measure folate, vitamin B12 levels,and the frequency of micronucleated cells in buccal mucosal cells gavereproducible results. The study results suggest that CSs have buccal mucosalfolate and vitamin B12 levels that are lower than those among NCSs. CSs werethree times more likely to have micronucleated buccal mucosal cells compared toNCSs. There appeared to be no association between low buccal folate and vitaminB12 levels chromosomal damage. The salivary vitamin B12 concentrations andplasma vitamin C and E concentrations, however, seem to be marginally protectiveagainst the occurrence of buccal mucosal micronuclei, whereas plasmabeta-carotene seems to increase the occurrence of micronuclei. Overall, theresults do not support the concept that localized folate and vitamin B12deficiencies in the buccal mucosal cells of smokers are associated withchromosomal damage in those cells. The presence of vitamin B12 deficiencies inthe buccal mucosal cells of smokers are associated with chromosomal damage inthose cells. The presence of vitamin B12 in the immediate environment (saliva)and vitamin C and E in the plasma, however, appear to be marginally protectiveagainst chromosomal damage in buccal mucosal cells.

33. Cytobios 1995;81(326):171-4Cumulative effect of T-2 toxin and vitamin C on chromosomal abnormalities in thebone marrow cells of mice (Mus musculus).Bilgrami KS, Masood A, Rahman MFDepartment of Botany, Bhagalpur University, India.

A regular dose of 10 mg/kg body wt/day of vitamin C as a part of the daily dietmarkedly reduced T-2 toxin-induced abnormalities in the chromosomal cells inmice (Mus musculus). The preventive effect on individual types of change inchromosomes such as breakages, chromatid gaps, ring formations and widespreadfragmentation, was increased.

34. Teratog Carcinog Mutagen 1999;19(1):53-9Protection and induction of chromosomal damage by vitamin C in human lymphocytecultures.Antunes LM, Takahashi CSDepartamento de Genetica, Fac. Med. de Ribeirao Preto-USP, SP,

Some chemotherapeutic approaches have proposed the use of antioxidants such asvitamin C (VC) to minimize the cytotoxicity and damage induced in normal tissueby antitumor agents that produce free radicals. Nevertheless, VC can also becytotoxic, genotoxic, and harmful when combined with antitumor agents in humancells in vitro. The present study was undertaken to investigate the effects ofVC (100, 200, 500, and 1,000 microg/ml) on human peripheral blood lymphocytes invitro and its anticlastogenic effect on chromosomal aberrations induced bydoxorubicin (DXR). VC did not show a clastogenic effect by itself, except at1,000 microg/ml. At the concentration of 100 or 200 microg/ml of VC,administered in pre-, post-, or simultaneous treatment, there was a significantreduction in both chromosome aberrations and number of abnormal metaphasesinduced by DXR. At the doses of 500 or 1,000 microg/ml, VC did not present thesame protective effect and was cytotoxic. Under the present experimentalconditions, the efficiency of VC in protecting against chromosome damage wasdependent on the doses used.

35. J Physiol Pharmacol 1999 Dec;50(5):695-710Helicobacter pylori associated gastric pathology.Konturek PC, Bielanski W, Konturek SJ, Hahn EGMedizinische Klinik I, Universitat Erlangen-Nurnberg, Erlangen, Germany.

Helicobacter pylori (HP), undoubtedly, the most common world-wide infectionplays an important role in pathogenesis of peptic ulcer. Proof for a causal rolefor HP in peptic ulcer rests in two major points; 1) the majority of ulcerpatients are HP infected and the prevalence of this infection for both gastriculcer (GU) and duodenal ulcer (DU) is much higher than for gender- andage-adjusted controls and 2) the cure of HP infection dramatically reduces ulcerrecurrence. Conclusions regarding the mechanisms by which HP induces pepticulcer are restricted mainly to studies observing the consequences of itseradication by antibiotics combined with gastric inhibitors or bismuth agents.Several specific virulence factors such as cytotoxin-associated gene A (CagA)and vacuolating cytotoxin A (VacA) as well as other noxious substances includingammonia, lipopolysaccharide (endotoxin), platelet activating factor (PAF),nitric oxide (NO) and others have been implicated in gastritis and were found tobe significantly more frequent in gastric cancer than in gender- and age-matchedcontrols, especially in younger generation. Chronic inflammation, atrophicgastritis, intestinal metaplasia, impaired defense mechanisms combined withhypergastrinemia, deficiency of vitamin C in the stomach , excessive oxygenmetabolites and epithelial cell proliferation have been associated with gastriccancer. This multi-step pathway originally proposed by Correa and hiscolleagues, long before the HP was discovered in the stomach, leads to cancerbut may be reversed by eradication of HP. This is, however, a controversialissue because gastric atrophy and intestinal metaplasia may be also caused byother factors such as bile reflux, dietary irritants, and autoimmunity. Theimplication of HP in MALT-lymphoma is based on the observations that eradicationof HP in early stage of low-grade of this tumor leads to complete remission. Thesignificance of HP in non-ulcer dyspepsia remains questionable and requiresfurther studies.

36. Immunol Lett 1999 Dec 1;70(3):185-9Treatment of H. pylori infected mice with antioxidant astaxanthin reducesgastric inflammation, bacterial load and modulates cytokine release bysplenocytes.Bennedsen M, Wang X, Willen R, Wadstrom T, Andersen LPDepartment of Clinical Microbiology, Rigshospitalet, Copenhagen,

Helicobacter pylori is a gram-negative bacterium affecting about half of theworld population, causing chronic gastritis type B dominated by activatedphagocytes. In some patients the disease evolves into gastric ulcer, duodenalulcer, gastric cancer or MALT lymphoma. The pathogenesis is in part caused bythe immunological response. In mouse models and in human disease, the mucosalimmune response is characterized by activated phagocytes. Mucosal T-lymphocytesare producing IFN-gamma thus increasing mucosal inflammation and mucosal damage.A low dietary intake of antioxidants such as carotenoids and vitamin C may be animportant factor for acquisition of H. pylori by humans. Dietary antioxidantsmay also affect both acquisition of the infection and the bacterial load of H.pylori infected mice. Antioxidants, including carotenoids, haveanti-inflammatory effects. The aim of the present study was to investigatewhether dietary antoxidant induced modulation of H. pylori in mice affected thecytokines produced by H. pylori specific T-cells. We found that treatment of H.pylori infected mice with an algal cell extract containing the antioxidantastaxanthin reduces bacterial load and gastric inflammation. These changes areassociated with a shift of the T-lymphocyte response from a predominantTh1-response dominated by IFN-gamma to a Th1/Th2-response with IFN-gamma andIL-4. To our knowledge, a switch from a Th1-response to a mixed Th1/Th2-responseduring an ongoing infection has not been reported previously.

37. J Gastroenterol Hepatol 1999 Nov;14(11):1070-3Gastric juice ascorbic acid is related to Helicobacter pylori infection but notethnicity.Fraser AG, Woollard GADepartment of Medicine, University of Auckland, New

BACKGROUND: Maori and Pacific Island ethnic groups in New Zealand have a highrisk for gastric cancer. Low levels of gastric juice ascorbic acid (vitamin C)have been suggested to be a risk factor for gastric cancer. Previous studieshave shown that gastric juice ascorbic acid may be independently associated withboth ethnicity and Helicobacter pylori infection. This study aimed to examinethe interrelationship between H. pylori and ethnicity in New Zealand. METHODS:Gastric juice was collected into 70% perchloric acid preservative and stored at-80 degrees C. Ascorbic acid was analysed by high-performance liquidchromatography using ion-pair chromatography and electrochemical detection.Inflammation and atrophy was graded from biopsies from multiple sites in theantrum and body. Gastric juice was collected from 89 patients during routineendoscopy. RESULTS: There was a wide range of measured gastric juice ascorbicacid from 0.001 to 410 microg/mL. The median concentration of ascorbic acid forH. pylori-negative patients was 1.78 microg/mL (n = 57) and 0.12 microg/mL (n =32) for H. pylori-positive patients (P = 0.001). Gastric juice ascorbic acidconcentration was not associated with age, endoscopic diagnosis or intestinalmetaplasia, but was significantly associated with the degree of acuteinflammation (P = 0.01) and the presence of atrophy (P = 0.04).The medianascorbic acid concentration for European patients was 0.92 microg/mL (n = 44)and 0.09 microg/mL (n = 38) for Maori and Pacific Island ethnic groups combined(P = 0.1). Multiple step-wise regression analysis showed that only H. pyloriinfection was a significant factor for predicting ascorbic acid concentrations(r2 = 0.12). CONCLUSIONS: This study has confirmed that gastric juice ascorbicacid concentration is lower in the presence of H. pylori infection.

38. Eur J Clin Invest 1999 Jan;29(1):56-62Relationship of Helicobacter pylori CagA(+) status to gastric juice vitamin Clevels.Rokkas T, Liatsos C, Petridou E, Papatheodorou G, Karameris A, Ladas SD, RaptisSAGastroenterology Unit, Army General Hospital, Athens,

BACKGROUND: To date it is not known whether gastric juice vitamin C levels areinfluenced by Helicobacter pylori CagA(+) strains. The aim of the present study,therefore, was to study the impact of H. pylori CagA status on gastric juicevitamin C levels. MATERIALS AND METHODS: We studied 30 H. pylori(+) patients,and the results were compared with 10 endoscopically and histologically normalH. pylori(-) subjects (control group) who were similar to the H. pylori(+) groupin terms of age and sex. In all patients, gastric juice vitamin C levels weredetermined and the severity of gastritis was graded on a scale of 0 (absent) to3 (severe). CagA was determined by immunoblotting the sera from patients againstH. pylori antigens. RESULTS: Among 30 H. pylori(+) patients, 20 were CagA(+) and10 CagA(-). In the entire group of H. pylori(+) patients, the median gastricjuice vitamin C levels (mg L-1) were 16.35 (range 3.5-33.6) and weresignificantly lower (P < 0.001) than in the control group of H. pylori(-)patients [35.5 (23.1-50.2)]. In addition, in the entire group of H. pylori(+)patients there was a highly significant (P < 0.0001) inverse correlation betweenthe gastritis activity score and the gastric juice vitamin C levels. In thegroup of H. pylori CagA(+) patients, the median levels of gastric juice vitaminC were 13.8 (3.5-31.2) and were significantly lower than the correspondinglevels in both the H. pylori CagA(-) group [24.8 (22-33.6), P < 0.01] and the H.pylori(-) control group [35.5 (23.1-50.2), P < 0.001], the last groups beingsimilar. Furthermore, the gastritis activity median score in the H. pyloriCagA(+) group [2 (1-3)] was significantly higher (P < 0.05) than in the H.pylori CagA(-) group [1 (1-2)]. CONCLUSION: These data indicate that infectionwith CagA(+) H. pylori strains significantly lowers the gastric juice vitamin Clevels in comparison with CagA(-) H. pylori strains, which might have asignificant impact on gastric carcinogenesis.

39. Eur J Cancer Prev 1998 Dec;7(6):449-54Effects of high dose vitamin C treatment on Helicobacter pylori infection andtotal vitamin C concentration in gastric juice.Jarosz M, Dzieniszewski J, Dabrowska-Ufniarz E, Wartanowicz M, Ziemlanski S,Reed PIDepartment of Metabolic Diseases and Gastroenterology, National Food andNutrition Institute (WHO Collaborating Centre for Nutrition), Warsaw, Poland.

Low gastric juice total vitamin C concentration in the presence of Helicobacterpylori (H. pylori) infection probably plays a role in gastric carcinogenesis. Invitro vitamin C has been shown to inhibit the growth of H. pylori. The aims ofthis study were to determine the effect of high dose vitamin C administration onH. pylori infection and on gastric juice total vitamin C concentration inpatients with H. pylori related chronic gastritis. Sixty patients with dyspepticsymptoms and proven chronic gastritis and H. pylori infection, who wereundergoing routine endoscopy, entered the study after giving informed consent.They were randomly coded into two treatment groups. Group 1 (controls, n = 28)were treated with antacids for 4 weeks and Group 2 (n = 32) received vitamin C5g daily also for 4 weeks. Nine patients did not complete the study and wereexcluded. Plasma and gastric juice total vitamin C levels were measured atbaseline, at the end of 4 weeks treatment and again 4 weeks after treatmentcessation. In the control group H. pylori infection remained unchanged in all 24patients throughout as did the mean gastric juice total vitamin C concentration.However, in the vitamin C treated group eight of 27 patients (30%) who completedthe treatment course the H. pylori infection was eradicated (P = 0.01). In thesepatients the mean gastric juice total vitamin C concentration rose significantlyfrom 7.2 1.6 micrograms/ml after 4 weeks treatment (P < M 0.001) and 19.8micrograms/ml 4 weeks after treatment was discontinued (P < 0.001). In theremaining 19 patients with persistent H. pylori infection, the mean gastricjuice total vitamin C concentration rose less than in those with successful H.pylori eradication; 6.3 1.7 micrograms/ml before treatment, 10.8 1.5micrograms/ml after 4 weeks treatment (P < 0.05) and a return to pre-treatmentlevels (7.1 2.7 micrograms/ml) 4 weeks after vitamin C intake stopped. Therewere no side effects of vitamin C treatment. This study has shown that 4 weeksdaily high dose vitamin C treatment in H. pylori infected patients with chronicgastritis resulted in apparent H. pylori eradication in 30% of those treated. Inthose patients there was also a highly significant rise in gastric juice totalvitamin C concentration which persisted for at least 4 weeks after the treatmentceased. A significant, though less marked, gastric juice total vitamin Cconcentration increase was observed during vitamin C treatment even in subjectswith persistent H. pylori infection, though this was not maintained aftertreatment ended. The mechanism whereby vitamin C treatment appeared to result inH. pylori eradication is unclear. Further confirmatory studies are indicated.

40. Gut 1998 Sep;43(3):322-6The relation between gastric vitamin C concentrations, mucosal histology, andCagA seropositivity in the human stomach.Zhang ZW, Patchett SE, Perrett D, Katelaris PH, Domizio P, Farthing MJDigestive Diseases Research Centre, St Bartholomew's, London, UK.

BACKGROUND: Vitamin C may be protective against gastric cancer though infectionwith Helicobacter pylori is associated with a reduction in intragastricconcentrations of vitamin C. AIMS: To examine the effects of H pylori infection,gastric juice pH, the severity and extent of gastric inflammation, and CagAantibody status of the individual on gastric juice and mucosal vitamin Cconcentrations. PATIENTS: One hundred and fifteen patients undergoing routinegastroscopy for investigation of dyspepsia. METHODS: High performance liquidchromatography was used to determine vitamin C concentrations. CagA antibody wasdetected by western blot analysis. RESULTS: Gastric juice ascorbic acidconcentration was significantly lower in patients infected with H pyloricompared with those uninfected (19.3 mumol/l (interquartile range (IQR)10.7-44.5) versus 66.9 mumol/l (IQR 24.4-94.2), p = 0.003). The reduction ingastric juice ascorbic acid concentration was inversely related to the severityof gastritis (p = 0.01). CagA positive patients had significantly lower gastricjuice ascorbic acid concentrations than CagA negative ones (14.8 mumol/1 (IQR7.9-52.2) versus 39 mumol/l (IQR 19.9-142.2), p = 0.05). Decreased gastric juicedehydroascorbic acid concentrations were observed in patients with gastricatrophy and intestinal metaplasia. Mucosal ascorbic acid concentrations werealso significantly lower in infected patients than uninfected patients (p =0.04). CONCLUSIONS: The reduction in gastric vitamin C concentrations is relatedto gastric juice pH, the severity and extent of gastritis, the presence of Hpylori, and the CagA antibody status of the individual. These findings may haveimplications in H pylori associated carcinogenesis.