Acetaldehyde and gastric cancer

Transcription

1 Journal of Digestive Diseases 2011; 12; doi: /j x Leading article Acetaldehyde and gastric cancer Mikko SALASPURO Research Unit on Acetaldehyde and Cancer, University of Helsinki, Helsinki, Finland Aldehyde dehydrogenase (ALDH2) and alcohol dehydrogenase (ADH) gene polymorphisms associating with enhanced acetaldehyde exposure and markedly increased cancer risk in alcohol drinkers provide undisputable evidence for acetaldehyde being a local carcinogen not only in esophageal but also in gastric cancer. Accordingly, acetaldehyde associated with alcoholic beverages has recently been classified as a Group 1 carcinogen to humans. Microbes are responsible for the bulk of acetaldehyde production from ethanol both in saliva and Helicobacter pylori-infected and achlorhydric stomach. Acetaldehyde is the most abundant carcinogen in tobacco smoke and it readily dissolves into saliva during smoking. Many foodstuffs and non-alcoholic beverages are important but unrecognized sources of local acetaldehyde exposure. The cumulative cancer risk associated with increasing acetaldehyde exposure suggests the need for worldwide screening of the acetaldehyde levels of alcoholic beverages and as well of the ethanol and acetaldehyde of food produced by fermentation. The generally regarded as safe status of acetaldehyde should be re-evaluated. The as low as reasonably achievable principle should be applied to the acetaldehyde of alcoholic and non-alcoholic beverages and food. Risk groups with ADH-and ALDH2 gene polymorphisms, H. pylori infection or achlorhydric atrophic gastritis, or both, should be screened and educated in this health issue. L-cysteine formulations binding carcinogenic acetaldehyde locally in the stomach provide new means for intervention studies. KEY WORDS: acetaldehyde, alcohol, cancer, gene polymorphism, microbe. INTRODUCTION The key issue in cancer prevention is the identification of specific etiologic factors. Acetaldehyde is the first metabolite of ethanol oxidation and the most abundant carcinogenic compound of tobacco smoke. In October 2009, the International Agency for Research Correspondence to: Mikko SALASPURO, Research Unit on Acetaldehyde and Cancer, Faculty of Medicine, P.O. Box 63 (BIOMEDICUM), Fin University of Helsinki, Finland. mikko.salaspuro@helsinki.fi Conflict of interest: Board member of Biohit Oyj, Finland. Journal of Digestive Diseases 2011 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Blackwell Publishing Asia Pty Ltd. on Cancer (IARC), World Health Organization concluded that acetaldehyde derived from the alcoholic beverage itself and formed from ethanol endogenously is a Group 1 carcinogen to humans. 1 This conclusion is based on the uniform epidemiological, genetic, biochemical and microbiological evidence derived from alcohol-consuming individuals carrying alcohol (ADH) and aldehyde (ALDH2) dehydrogenase gene mutations. In the presence of ethanol these mutations result in an increased exposure of the upper digestive tract mucosa to acetaldehyde. 2,3 The scientific evidence strongly supports the role of acetaldehyde as a cumulative and local carcinogen especially in the oral cavity and the esophagus. 3 However, there is increasing evidence suggesting that microbial acetaldehyde formation also plays an essential role in the pathogenesis of stomach cancer. By and large, all 51

2 52 M Salaspuro Journal of Digestive Diseases 2011; 12; known environmental and genetic risk factors of upper digestive tract cancer are associated with the enhanced exposure of the gastric mucosa to carcinogenic acetaldehyde. Environmental risk factors for stomach cancer The two main risk factors of stomach cancer are Helicobacter pylori (H. pylori) and atrophic gastritis. 4,5 H. pylori infection has been classified as a Class 1 carcinogen to humans but the mechanism by which H. pylori causes gastric cancer has remained obscure. 6 Regarding atrophic gastritis, Correa s hypothesis, which proposes that gastric bacterial colonization leads to the reduction of nitrates to nitrites and the formation of potentially carcinogenic N-nitroso compounds, has also remained controversial. 7 Tobacco smoking is another independent risk factor for stomach cancer both in the USA and Europe. 8,9 In a prospective European study including 10 European countries and individuals the hazard ratio for ever smokers was 1.45, and for current smokers 1.73 in men and 1.87 in women. 9 The risk of stomach cancer increases with the duration and intensity of smoking cigarettes. Approximately 18% of gastric cancers have been estimated to be attributable to tobacco smoking. 10 A combined high use of cigarettes (>20/day) and alcohol (>5 occasions/14 days) appears to increase the risk of non-cardia gastric cancer nearly fivefold compared to nonusers. 10 Cigarette smoking is associated with an increased risk for both esophageal squamous cell and adenocarcinomas and as well for gastric cardia and non-cardia cancers. 11 In a prospective follow-up study from Japan the risk for stomach cancer was 1.0 among H. pylori-negative non-smokers, 11.4 among H. pylori-positive smokers, 5.8 among H. pylori-negative smokers and 6.9 among H. pylori-positive non-smokers. 12 It is generally agreed that tobacco and alcohol are independent and multiplicative risk factors for oral, pharyngeal, laryngeal and esophageal cancers 13,14 whereas the epidemiological evidence for the possible association between alcohol consumption and stomach cancer is controversial. In a meta-analysis of alcohol-related cancers (235 studies and over cases) the relative risk for gastric cancer was 1.32/ 100 g alcohol daily. 15 However, this number may be biased by the unrecorded alcohol and acetaldehyde present in foodstuffs and in so-called non-alcoholic beverages, as will be discussed in the following sections. Indeed, there is increasing evidence supporting the role of acetaldehyde as a plausible explanation for the increased gastric cancer risk in patients with H. pylori infection or atrophic gastritis, or both, especially among heavy drinkers and smokers. Microbes and tobacco as major sources of local acetaldehyde exposure Many microbes representing normal oral or intestinal flora possess ADH activity and are able to produce acetaldehyde from ethanol by oxidation. 16 However, their ability to detoxify acetaldehyde is limited, which results during alcohol challenge in the accumulation of acetaldehyde in the saliva. 17 After about three doses (0.5 g/kg) of alcohol peak salivary acetaldehyde concentrations range from 19 to 144 mmol/l and decrease slowly with decreasing salivary ethanol concentrations during the subsequent 4 h. 17 There is considerable inter-individual variation in the capacity of oral microbes to produce acetaldehyde. Rinsing the mouth for 3 days with a chlorhexidine mouthwash decreases microbial acetaldehyde production by about 40% and this is associated with a significant decrease in the counts of both aerobic and anaerobic oral bacteria. 17 Acetaldehyde produced in the oral cavity is transported via swallowing to the esophagus and stomach. In higher salivary ethanol concentrations the acetaldehyde levels of saliva are also higher. 17 This can be explained by the fact that some microbial ADH enzymes are not saturated with ethanol and thus they produce more acetaldehyde at higher ethanol concentrations. Heavy drinking, chronic smoking and poor oral hygiene are well-known risk factors for upper digestive tract cancer. Same factors modify oral flora to produce more acetaldehyde from ethanol in the saliva. 18 The normal acidic human stomach is free of microbes. However, bacteria and yeasts can survive and even proliferate in the gastric contents of patients with achlorhydric atrophic gastritis. 19 In these patients bacterial overgrowth results in the local formation of endogenous ethanol and acetaldehyde from glucose. 20 The intragastric acetaldehyde production is enhanced 6.5-fold in these patients after a dose of alcohol. 20 Hypochlorhydria induced by acid secretor inhibitors also leads to the marked overgrowth of aerobic bacteria in the stomach and this is associated with the intragastric formation of both ethanol and acetaldehyde. 21,22 It should be noted that not only oral microbes but also many H. pylori strains possess significant ADH activity and are able to produce acetaldehyde from ethanol under microaerobic conditions. 23,24

3 Journal of Digestive Diseases 2011; 12; Acetaldehyde and gastric cancer 53 In tobacco smoke there are 11 known and seven probable human carcinogens. However, the concentration of acetaldehyde in cigarette smoke is over 1000-fold compared with other carcinogens, for example, polycyclic aromatic hydrocarbons and tobacco-specific nitrosamines. 25 As a water soluble agent, the acetaldehyde of tobacco smoke dissolves readily in the saliva during active smoking resulting in mean 260 mmol/l acetaldehyde concentration in saliva. 26 Because chronic smoking modifies oral flora to produce more acetaldehyde from ethanol, concomitant smoking and drinking have a synergistic, sevenfold effect on the exposure of the upper digestive tract to acetaldehyde. 26 Beverages and food as a source of acetaldehyde exposure Drinking Calvados has been shown to be associated with abnormally high esophageal cancer risk in Normandy and indeed, home-made Calvados may contain up to 4000 mmol/l of acetaldehyde. 27 Furthermore, the lifetime cancer risks for acetaldehyde from alcoholic beverages has been shown to greatly exceed the usual limits for cancer from the environment and thus to be a major health problem requiring intervention. 28 Microbes capable of alcoholic fermentation have been used for centuries in beverage and food fermentation technology. 29 Depending on the individual microbes and technology used, the acetaldehyde concentration of official alcoholic beverages may vary from 0 to over mmol/l (mutagenic concentration = 100 mmol/l). Remarkably high acetaldehyde levels are found in fortified wines, for example, in sherries, port wines and madeira. 30 In some strong fruit-based Chinese spirits sold in Germany the acetaldehyde concentration may be over mmol/l. 30 High acetaldehyde concentrations are also found in some sakes and whiskies. 31 The lowest acetaldehyde levels in general are found in vodkas and beer. 30 Only beverages containing over 2.8% ethyl alcohol are classified as official alcoholic beverages. Foodstuffs and so-called non-alcoholic beverages containing % ethyl alcohol and mutagenic concentrations of acetaldehyde, however, expose the mucosa of the upper digestive tract by and large same mechanisms to acetaldehyde as the official alcoholic beverages do. Microbial acetaldehyde formation from ethanol starts in the oral cavity in seconds and continues 5 10 min after each sip of the alcohol-containing beverage and as well during mastication of alcohol-containing food (unpublished observation). Thus, so-called nonalcoholic beverages and foodstuffs containing less than 2.8% ethyl alcohol may expose the oral cavity and esophagus to acetaldehyde for tens of minutes daily. Depending on the gastric emptying rate, the mucosa of H. pylori-infected or achlorhydric stomachs may be exposed by this same mechanism to acetaldehyde daily for hours. This causes a major confounder and bias in cancer epidemiology. Only the consumption of official alcoholic beverages has been systematically followed and recorded. Widely used foodstuffs and beverages containing acetaldehyde or ethanol or both are, for example, kefir, yogurt, soya products, vinegar, home-brewed beers and meads, tofu, kimchi and pickled vegetables. 29,31,32 Acetaldehyde is also widely used as a food additive and aroma agent. 33 The low ethanol concentrations of foodstuffs and so-called nonalcoholic beverages in general is not reported to consumers by the manufacturers. The acetaldehyde concentration of beverages and foodstuffs is not known either, since acetaldehyde still is generally regarded as safe (GRAS). 34 The GRAS status of acetaldehyde allows it to be used as a food additive and aroma agent. The GRAS status of acetaldehyde strongly contradicts IARC s classification of acetaldehyde as a Class 1 carcinogen to humans and creates an obvious bias in cancer epidemiology. The consumption of acetaldehyde present in food and beverages or formed endogenously by digestive tract microbes from the ethanol present in alcohol-containing foodstuffs has been neither measured nor used in epidemiological studies. There is some evidence suggesting that high dietary salt intake might increase the risk of gastric cancer, at least in Asia. 35,36 However, in a prospective population-based study from Norway, a high intake of dietary salt did not appear to increase the risk of gastric adenocarcinomas. 37 These controversial findings can be explained by the high consumption of some other potential carcinogen associated with a high salt intake, for example, acetaldehyde. In some early studies the increasing use of refrigerators for food storage has been found to be in a negative correlation with the incidence of gastric cancer. 38,39 Indeed, before the time of refrigerators, fermentation technology was the most widespread method for food preservation and this is still the case in many undeveloped countries. Alcoholic fermentation, which is commonly associated with many fermentation processes, results under anaerobic conditions in the formation of acetal-

4 54 M Salaspuro Journal of Digestive Diseases 2011; 12; dehyde. 29 On the other hand, some other microbes present in food or beverages may oxidize ethanol to acetaldehyde. 29 The acetaldehyde hypothesis is supported by some epidemiological findings. Kimchi, soybean pastes and fermented soy food have been shown to be risk factors for stomach cancer. 40,41 Furthermore, there is evidence that non-fermented soy food may be protective. 42 Genetic cancer risk factors and acetaldehyde exposure A single point mutation in the ALDH2 gene results in an enzyme with a markedly deficient ability to detoxify acetaldehyde. 43 The mutation provides a unique human model for long-term acetaldehyde exposure and consequently offers strong evidence for the causal role of local acetaldehyde in the pathogenesis of upper digestive tract cancers. The mutant allele is particularly prevalent among East Asian populations. The origin of the mutation has been traced back to ancient Pai-Yuei tribe in South China. 44 Several epidemiological studies uniformly confirm that the risk of upper digestive tract cancer, especially that of squamous cell esophageal cancer, is markedly increased among ALDH2-deficient alcohol users compared with those with the normal enzyme These epidemiological associations can be explained by the enhanced exposure of the upper digestive tract mucosa to carcinogenic acetaldehyde via saliva during an alcohol challenge. After a moderate dose of alcohol, ALDH2-deficient individuals have a twofold to threefold higher acetaldehyde level in their saliva than those with the normal genotype, as long as they have measurable levels of ethanol in their saliva Subsequent studies revealed that the deficient capacity of the parotid glands to remove acetaldehyde produced from ethanol by their own ADH enzyme is the most probable source of additional acetaldehyde in the saliva of ALDH2-deficient participants. 52,53 Thus after drinking alcohol ALDH2-deficient individuals are exposed not only microbially from ethanol-derived acetaldehyde but also to the acetaldehyde produced by their own salivary glands and perhaps also mucosal cells. There are only a few studies on the possible association between ALDH2 deficiency and stomach cancer. A relative risk of 3.5 of stomach cancer in ALDH2- deficient heavy drinkers has been reported. 45 In a more recent Japanese study it was found that the gastric cancer risk is remarkably increased among ALDH2- deficient alcoholics with severe atrophic gastritis (CAG). 55 The study included 45 alcoholics with gastric cancer and 281 controls. The odds ratio for those with CAG in combination with ALDH2 deficiency was 39.2 as compared to 17.6 for those with CAG alone and 9.7 for those with ALDH2 deficiency alone. The Asian-type ALDH2 mutation is almost nonexistent in Europe. Some other ALDH2 gene mutations may, however, be associated with increased acetaldehyde exposure and cancer risk among Caucasians. In a European multicenter case-control study including 811 patients and 1083 controls an ALDH2 variant with a deficient ability to detoxify acetaldehyde was found to be associated with a 1.76-fold risk of upper aero-digestive tract cancers among moderate drinkers. 56 The OR was 5.79 among heavy drinkers. In a study from Poland the same ALDH2 variant was found to be associated with a 2.3-fold risk of stomach cancer among daily drinkers and a threefold risk was reported among those with 40 or more drink-years. 57 The low active ADH1B among East Asians is also associated with a markedly increased risk of upper digestive tract cancer in heavy drinkers ,51,52 This gene polymorphism results in the decreased elimination of ethanol from blood and saliva and thus in the prolonged exposure of the upper digestive tract to microbially derived acetaldehyde. 58 The high active ADH 1C*1 allele among Caucasians has been shown to be associated with a significantly increased risk of head and neck cancer and as well with an enhanced exposure of the upper digestive tract mucosa to acetaldehyde via saliva during an alcohol challenge. 59,60 Acetaldehyde as a local and cumulative carcinogen According to the IARC the use of alcoholic beverages is carcinogenic to humans but there is no evidence that the ethanol molecule itself has any carcinogenic potential. However, acetaldehyde has been shown to be carcinogenic to experimental animals. 61 In 2007 the IARC agreed that there was substantial evidence in humans with deficient ALDH2 that indicated that acetaldehyde derived from the metabolism of ethanol in alcoholic beverages contributes towards causing malignant esophageal tumors. 62 Finally, in 2009, acetaldehyde associated with alcoholic beverages was classified as a Class 1 carcinogen to humans. 1 Acetaldehyde is mutagenic and carcinogenic. It causes DNA damage and it has several cancer-promoting effects. 3,63 Acetaldehyde is converted to crotonaldehyde by polyamines in dividing cells and forms

5 Journal of Digestive Diseases 2011; 12; Acetaldehyde and gastric cancer 55 Table 1. Acetaldehyde exposure from environmental and genetic sources is cumulative and includes by and large all known risk factors for upper digestive tract cancer 2,65 Cancer risk factor Acetaldehyde exposure through saliva Alcoholic beverages After about three doses (0.5 g/kg) of alcohol peak salivary acetaldehyde concentrations range from 19 to 144 mmol/l and decrease slowly with decreasing salivary ethanol concentrations during the subsequent 4 h. 17 Rinsing the mouth with chlorhexidine results in decreased acetaldehyde levels in saliva. 17 Acetaldehyde as a congener High levels of acetaldehyde (up to 26 mmol/l) in strong fruit beverages, sherries and Calvados and as well in some sake 27,30,31 results in enhanced local acetaldehyde exposure lasting for 1 2 min after each sip (unpublished observation). Smoking Mean acetaldehyde concentration in saliva during active smoking is 260 mmol/l and lasts for about 5 min. 26 Thus, daily acetaldehyde exposure depends on the number of cigarettes smoked. Heavy drinking, chronic smoking Modify oral flora to produce more acetaldehyde from ethanol. The increase in and poor oral hygiene acetaldehyde exposure through saliva after a dose of alcohol is 60% 75% in vitro and 100% in vivo. 18,26 Smoking and drinking Have a synergistic (sevenfold) effect on acetaldehyde exposure through saliva. 26 ALDH2-deficiency A twofold to threefold increase in salivary acetaldehyde after a dose of alcohol Low active ADH1B Decreased elimination rate of ethanol associating with prolonged exposure to microbially derived acetaldehyde. 58 High active ADH1C Increased acetaldehyde exposure through saliva after a dose of alcohol. 59 Atrophic gastritis, acid secretor Achlorhydric stomach is colonized by oral microbes, which produce acetaldehyde inhibitors and Helicobacter both from ethanol and glucose. 20,22 Many H. pylori strains also possess ADH and pylori (H. pylori) are able to produce acetaldehyde. 23,24 Non-alcoholic beverages Official alcoholic beverages contain 2.8% or more ethyl alcohol. However, many and foodstuffs so-called non-alcoholic beverages and foodstuffs produced by fermentation contain % ethanol and mutagenic (up to 3000 mmol/l) levels of acetaldehyde. This results in local acetaldehyde exposure especially in an achlorhydric and H. pylori-infected stomach and forms a major confounder and bias in gastric cancer epidemiology. DNA adducts and mutagenicity increases exponentially from 25 mmol/l to 500 mmol/l acetaldehyde concentrations. 64 mutagenic 1,N 2 -propanodeoxyguanosine adducts. 64 These adducts are already significantly elevated at a 25 mmol/l acetaldehyde concentration and their levels increase exponentially with increasing acetaldehyde concentrations. 64 Associated mutagenic DNA changes increase exponentially from a 100 mmol/l to a 500 mmol/l acetaldehyde concentration. 64 Most importantly, equal acetaldehyde levels are measured in human saliva during and after drinking alcohol and as well during active smoking (Table 1). Exposure to acetaldehyde may vary greatly in different populations and geographical areas, since it is individual, cumulative and dependent on both environmental and genetic factors (Table 1). 2,65 Tobacco and alcohol, two major risk factors of upper digestive tract cancer, synergistically increase acetaldehyde exposure and the risk of oral and esophageal cancers. Genetic cancer risk factors, ALDH2-deficiency among East Asians and highly active ADH among Caucasians are associated during alcohol challenge with the enhanced exposure of the upper digestive tract mucosa via saliva to carcinogenic acetaldehyde. Another cancer risk factor, the low active ADH1B genotype among East Asians results in a decreased elimination rate of ethanol and thus in prolonged exposure to microbially derived carcinogenic acetaldehyde. In conclusion, acetaldehyde exposure from environmental and genetic sources appears to be cumulative and includes by and large all known risk factors for upper digestive tract cancer, as demonstrated in Table 1. 2,65 Local acetaldehyde production presumably also plays a significant role in the pathogenesis of stomach cancer, since gastric cancer risk is highest among ALDH2-deficient East Asian heavy drinkers with atrophic gastritis. 55 So far, the role of gene polymorphisms in the regulation of acetaldehyde levels in an achlorhydric or H. pylori-infected stomach is not known. The quantitative role of non-alcoholic beverages and

6 56 M Salaspuro Journal of Digestive Diseases 2011; 12; foodstuffs containing less than 2.8% of ethyl alcohol and mutagenic concentrations of acetaldehyde in the pathogenesis of upper digestive tract cancers remains to be resolved. There is, however, increasing evidence that these factors may play a significant role in the wide geographical distribution and periodical changes in the incidence of upper digestive tract cancers demonstrated worldwide during the 19 th century 67. Cancer prevention: early screening and reduction of acetaldehyde exposure In 2008 the worldwide incidence of oral, pharyngeal, esophageal and gastric cancers was 1.27 million new cases, representing 14.7% of all cancers and with gastric cancer being the second most common cause of cancer-related death 68. Therefore, all measures aimed at the reduction of the known risk factors of these cancers might have a marked impact on cancer prevention worldwide. H. pylori infection without atrophic gastritis increases the risk of gastric cancer 4.2-fold. 69 The risk is 11.2 in patients with both atrophy and H. pylori infection. The highest risk (14.8) is found in H. pylori-negative patients with atrophic gastritis. 69 The eradication of H. pylori appears to reduce the incidence of gastric cancer among individuals without pre-existing precancerous lesions, defined as atrophy, intestinal metaplasia and dysplasia. 70 The treatment of H. pylori infection also prevents cancer development in patients with mild gastric atrophy identified by serum pepsinogen (PG) levels. 71 Furthermore, the serum PG measurement can be used to select patients for a gastroscopy, resulting in an improved detection rate of gastric cancer and, more importantly, in a particularly high proportion of earlystage gastric cancer among all cancers detected. 71 It has recently been estimated that screening young adults for H. pylori, followed by treatment of those who test positive, might prevent one in every four to six cases of gastric cancer in China and even to be cost effective. 79 As pointed out earlier, acetaldehyde derived from alcoholic beverages and tobacco smoke is the common denominator in the pathogenesis of upper digestive tract cancers. It has been estimated that if moderate or heavy drinking ALDH2-deficient East Asian heterozygotes instead became only light drinkers, 53% of esophageal cancers might be prevented in the Japanese male population. 73 An ALDH2 deficiency can be easily screened by using a two-question flushing questionnaire. 74,75 The test has 90% sensitivity in men and 88% in women. Corresponding specificities are 88% and 92%, respectively. Consequently, intervention studies aiming to reduce acetaldehyde exposure could easily be applied to specific groups at risk of upper digestive tract cancer. There are several ways to reduce acetaldehyde exposure both at the population and individual level (Table 2). An initial public health measure warrants new legislation, since acetaldehyde has been classified as a Class 1 carcinogen to humans. To that aim, the GRAS status of acetaldehyde should be re-evaluated. The as low as reasonably achievable principle, according to the Codex Alimentarius, should be applied to the acetaldehyde present as a congener in alcoholic beverages, as has recently been suggested. 28,65 Furthermore, the use of acetaldehyde as a flavoring and aroma agent should be prohibited. Equally important is the initiation of new health education programs aimed to reduce acetaldehyde exposure both at the population and the individual level and, most importantly, among the well-established groups at risk of upper digestive tract cancers. L-cysteine in the reduction of acetaldehyde exposure L-cysteine is a semi-essential amino acid that is able to eliminate the toxicity of acetaldehyde by binding to it covalently. The product is stable 2-methylthiazolidine- 4-carboxylic acid. 76 A buccal tablet slowly releasing cysteine is able to remove up to two-thirds of microbially formed carcinogenic acetaldehyde from saliva during an alcohol challenge. 77 A lozenge and chewing gum containing only 5 mg of L-cysteine eliminates acetaldehyde totally from saliva during smoking. 78,79 Most recently, it was shown that capsules releasing L-cysteine at a controlled rate can be used for the reduction of the acetaldehyde concentration of the gastric juice during an alcohol challenge in achlorhydric subjects with atrophic gastritis. 80 During a 40 min follow up the area under the curve for acetaldehyde decreased by a mean 63% with cysteine capsules as compared to a placebo. Furthermore, L-cysteine could be detected in the gastric juice of all volunteers for the whole observation period. Thus, medical devices slowly releasing cysteine provide a safe means for the reduction of acetaldehyde exposure in the gastrointestinal tract. Intervention studies involving L-cysteine and other measures aimed at the minimization of acetaldehyde exposure are warranted both at the population level and especially among high-risk groups such as heavy drinkers, smokers and those with ALDH2-deficiency.

7 Journal of Digestive Diseases 2011; 12; Acetaldehyde and gastric cancer 57 Table 2. Risk group Reduction of acetaldehyde exposure at the individual and the population level Tobacco smoking Excessive alcohol consumption Drinking habits Foodstuffs Groups at risk Genepolymorphisms Achlorhydric atrophic gastritis and Helicobacter pylori (H. pylori) infection L-cysteine releasing medical devices Recommended measures Reduction or quitting from tobacco smoking Moderation to light drinking Avoid drinking to intoxication Higher ethanol in saliva leads to higher acetaldehyde in saliva Prefer light drinks Local microbial acetaldehyde production increases with increasing ethanol concentrations (unpublished observation) Take a gulp of water after each drink Water dilutes acetaldehyde in the oral cavity Take care of good oral hygiene Decreased number of oral bacteria associates with decreased local production of acetaldehyde Use alcoholic beverages with nil or low acetaldehyde concentration Free acetaldehyde of the beverage dissolves in saliva (unpublished) Manufacturers should inform the consumers about the acetaldehyde concentration of alcoholic beverages Avoid drinking alcoholic beverages known to contain high levels of acetaldehyde, e.g. sherries, madeiras, Calvados, strong fruit spirits, some sakes. Avoid especially homemade products. Avoid use of foodstuffs and so-called non-alcoholic beverages without knowing their ethanol and acetaldehyde concentrations The generally regarded as safe status of acetaldehyde should be re-evaluated The as low as reasonably achievable principle according to the standards of Codex Alimentarius should be extended to the ethanol and acetaldehyde present in food stuffs and non-alcoholic beverages produced by fermentation. All the above mentioned measures should first be applied to those with the highest upper digestive tract cancer risk related to acetaldehyde exposure. Screening individuals with ALDH2-deficiency and low active ADH among East Asians and those with high active ADH among Caucasians. Use of serological tests and gastroscopy for the screening of individuals with atrophic gastritis and/or H. pylori infection especially among alcohol consuming ALDH2-deficient subjects. Decreases markedly acetaldehyde exposure through saliva and gastric juice during an alcohol challenge REFERENCES 1 Secretan B, Straif K, Baan R et al. A review of human carcinogens part E: tobacco, areca nut, alcohol, coal smoke, and salted fish. Lancet Oncol 2009; l10: Salaspuro M. Acetaldehyde as a common denominator and cumulative carcinogen in digestive tract cancers. Scand J Gastroenterol 2009; 44: Seitz HK, Stickel F. Acetaldehyde as an underestimated risk factor for cancer development: role of genetics in ethanol metabolism. Genes Nutr 2009; 5: Xue F-B, Xu Y-Y, Wan Y, Pan B-R, Ren J, Fan DM. Association of H. pylori infection with gastric carcinoma: a meta-analysis. World J Gastroenterol 2003; 7: Sipponen P, Kekki M, Haapakoski J, Ihamäki T, Siurala M. Gastric cancer risk in chronic atrophic gastritis: statistical calculations and cross-sectional data. Int J Cancer 1985; 35: International Agency for Research on Cancer, World Health Organization (IARC). Schistosomes, liver flukes and Helicobacter pylori. IARC working group on the evaluation of carcinogenic risks to human. Monogr Eval Carcinog Risks Hum 1994; 61: Jakszyn P, Conzales CA. Nitrosamine and related food intake and gastric and oesophageal cancer risk: a systematic review of the epidemiological evidence. World J Gastroenterol 2006; 12: Chao A, Thun MJ, Henley J, Jacobs EJ, McCullough ML, Calle EE. Cigarette smoking, use of other tobacco products and stomach cancer mortality in US adults: the cancer prevention study II. Int J Cancer 2002; 101: Conzales CA, Pera G, Agudo A et al. Smoking and the risk of gastric cancer in the European prospective investigation into cancer and nutrition. (EPIC). Int J Cancer 2003; 107: Sjodahl K, Lu Y, Nilsen TI, Hveem K, Lagergren J. Smoking and alcohol drinking in relation to risk of gastric cancer: a

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