doi:10.1111/j.1440-1746.2012.07017.x

G L O B A L H E A LT H : I M PA C T S O F A L C O H O L , S M O K I N G A N D O B E S I T Y

Interactions of alcohol and tobacco in gastrointestinal cancer Salaspuro Mikko Research Unit on Acetaldehyde and Cancer, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland

Abstract

Mikko Salaspuro

Key words acetaldehyde, alcohol, alcohol dehydrogenase, aldehyde, cancer, digestive tract, gene polymorhism, microbes, tobacco. Accepted for publication 9 November 2011. Correspondence Professor Mikko Salaspuro, Research Unit on Acetaldehyde and Cancer, Faculty of Medicine, P.O. Box 63 (Biomedicum), FIN-00014 University of Helsinki, Finland. Email: [email protected]

Cancer prevention is based on the identification of specific etiologic factors. Acetaldehyde derived from the alcoholic beverage itself and formed from ethanol endogenously has recently been classified by the International Agency for Research on Cancer/World Health Organization as a group 1 carcinogen to humans. This is based on the uniform epidemiological and biochemical evidence derived from individuals carrying alcohol and aldehyde dehydrogenase gene mutations. After drinking alcohol, these mutations are associated with increased exposure of the upper digestive tract to acetaldehyde and as well with a remarkably increased risk for upper gastrointestinal (GI) tract cancers. Acetaldehyde is the key intermediate in alcoholic fermentation and ethanol oxidation. Therefore, it is widely present in our environment. Furthermore, it is the most abundant carcinogenic compound of tobacco smoke. Most of the known risk factors for upper digestive tract cancer appear to be associated with an enhanced exposure of GI mucosa to locally formed acetaldehyde. In these process microbes, salivary glands and even mucosal cells appear to play an essential role. Consequently, in the presence of ethanol mutagenic acetaldehyde concentrations are found in the saliva, achlorhydric stomach and colon. Equal acetaldehyde concentrations are seen in saliva also during active smoking. ALDH2-deficiency and high active ADH1C result in two- to threefold salivary acetaldehyde concentrations after a dose of alcohol and this prevails for as long as ethanol is present in the blood and saliva. Regarding cancer prevention, the good news is that acetaldehyde exposure can be markedly reduced. This can be achieved by giving high priority for regulatory measures and consumer guidance.

Competing Interests: Author is a board member of Biohit Oyj

Introduction The yearly worldwide incidence of gastrointestinal (GI) cancers is over three million representing 25.1% of all cancers.1 The dismal prognosis of these cancers is well known, for instance stomach cancer alone is still the leading cause of cancer death in the world.1 Thus, the identification of specific etiological factors, possible risk groups and carcinogenetic mechanisms is essential for the prevention of these cancers. In Western countries, alcohol and tobacco are the main risk factors for oral, pharyngeal and esophageal cancers.2 Furthermore, there is convincing evidence suggesting that tobacco is an independent risk factor also for stomach cancer3,4 and alcohol is a significant risk factor for colororectal cancer.5 In October 2009, the International Agency for Research on Cancer (IARC), World Health Organization (WHO) concluded that acetaldehyde associated with alcoholic beverages is carcinogenic to

humans (Group 1) and confirmed the Group 1 classification of alcohol consumption and of ethanol in alcoholic beverages.6 Moreover, IARC stated that alcohol drinking results in exposure to acetaldehyde, derived from the beverage itself and formed from ethanol endogenously.6 Acetaldehyde is the key intermediate in alcoholic fermentation and ethanol oxidation. It is also widely used as a food additive and aroma agent.7 Furthermore, it is the most abundant carcinogenic compound of tobacco smoke. Consequently, acetaldehyde presumably is the most common human carcinogen that has been present in our environment already for tens of thousands of years. The group 1 carcinogen classification of acetaldehyde by IARC is based on the uniform epidemiological and biochemical evidence derived from individuals carrying aldehyde (ALDH2) and alcohol (ADH) dehydrogenase gene mutations. After drinking of alcohol, these mutations are associated with increased exposure of the upper digestive tract to acetaldehyde and as well with a remarkably

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Table 1

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Exposure to carcinogenic acetaldehyde exposure and preventive actions

Cancer risk factor Alcohol intake: Instant effect Prolonged effect Acetaldehyde as a congener Smoking Heavy drinking, chronic smoking and poor oral hygiene Smoking and drinking ALDH2-deficiency Low active ADH1B Homozygotes for high active ADH1C Atrophic gastritis, gastric acid secretor inhibitors H. pylori infection “Non-alcoholic” beverages and food stuffs

Acetaldehyde (Ach) exposure via saliva

Preventive action

Microbial Ach production starts instantly after each sip of alcoholic beverage and continues for at least 10 minutes.12 Microbial Ach production continues for as long as ethanol is present in saliva.13 Has a short term (1–2 min) peaking effect on salivary acetaldehyde.12,14 Mutagenic levels of Ach in saliva during active smoking.15 Modifies oral flora to produce more Ach from ethanol both in vitro and in vivo.15,16 Has a synergistic (sevenfold) effect on Ach exposure.15 Two- to threefold increase in salivary acetaldehyde after drinking of alcohol.19–21 Decreased ethanol elimination rate results in prolonged exposure to microbial Ach.22 Increased Ach level in saliva after drinking of alcohol.23

Avoid strong alcoholic beverages. Use water between the drinks. Avoid heavy drinking and drinking to intoxication. Avoid alcoholic beverages with Ach concentration. Quit of or reduce smoking. Take care of good oral hygiene.

Achlorhydric stomach is colonized by oral microbes, which produce acetaldehyde both from ethanol and glucose.24 H. pylori is able to produce Ach from ethanol.26 Many so called non-alcoholic beverages and food stuffs produced by fermentation may have small amounts of ethanol and mutagenic levels of Ach.7,27–30

increased risk for GI cancers.8–11 Acetaldehyde appears to act as a cumulative and local carcinogen especially in the oral cavity and esophagus.8 By and large, all known environmental and genetic risk factors of upper digestive tract cancer appear to be associated with enhanced exposure to carcinogenic acetaldehyde via saliva. During the last 15 years the basic mechanisms regulating the local acetaldehyde concentration in the upper digestive tract have been well characterized (Table 1). This provides several means for the minimization of acetaldehyde exposure both at individual and population levels (Table 1).

Exposure to acetaldehyde present in alcoholic beverages as a congener Acetaldehyde is a byproduct of fermentation process that is widely used in the production of alcoholic beverages from glucose under anaerobic conditions.31 The concentration of acetaldehyde in alcoholic beverages depends on the yeast used, fermentation procedure, distillation and preservation.31 In addition, some acetic acid and lactic acid bacteria are able to produce acetaldehyde from ethanol especially under aerobic or microaerobic conditions. Highest acetaldehyde concentrations are found in Sherry, Calvados and sweet fruit spirits.32–34 High acetaldehyde concentration of acetaldehyde present as a congener in Calvados has been suggested to explain the particularly high incidence of esophageal cancer in northwest France.32,35 As a water soluble substance acetaldehyde is rapidly dissolved into saliva after each sip of an acetaldehyde containing alcoholic beverage. This results in a peak type of acetaldehyde exposure of the upper digestive tract to acetaldehyde via saliva lasting for 136

Avoid both. L-cysteine.17,18 Risk group that should be screened and health educated. Risk group that should be screened and health educated. Risk group that should be screened and health educated. Risk groups that should be screened and health educated L-cysteine.25 Risk group that should be screened and health educated. Warrants for regulatory measures and consumer guidance both at population and individual level

1–2 min.12 The incidence of oral and esophageal cancers is particularly high in many East-European countries. Acetaldehyde concentration of the sweet spirits used widely in those countries has been shown to exceed even 1000 mg/L.34 This is over 200 times higher than the acetaldehyde concentration (4.4 mg/ L = 100 mM) known to be able to produce mutagenic changes in DNA.36 By using the European Food Safety Authority’s margin of exposure (MOE) approach, the average intake of acetaldehyde via different alcoholic beverages has been shown to greatly exceed the usual limits for cancer risks from the environment in the European Union.14

Instant and long-term acetaldehyde exposure via saliva after alcohol drinking Microbes (bacteria and yeasts) representing normal oral flora are responsible for most of the acetaldehyde present in saliva during and after drinking of alcoholic beverages. Many microbes possess alcohol dehydrogenase (ADH) activity and are able to oxidize ethanol to acetaldehyde, but their ability to remove it is limited.13,37 Furthermore, human oral and esophageal mucosa has been shown to possess high Km ADH activity but to lack low Km aldehyde (ALDH2) dehydrogenase activity.38 All of these factors favor the accumulation of acetaldehyde in the saliva and upper digestive tract in the presence of ethanol. Under normal conditions measurable levels of acetaldehyde are not found in saliva. However, carcinogenic concentrations of acetaldehyde are produced from ethanol in the mouth instantly after a small sip (5 mL) of a strong alcoholic beverage.12 Ethanol appears to become rapidly dissolved to the whole water phase

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of the oral cavity and is thereafter slowly diluted by saliva and absorption. Therefore, acetaldehyde exposure continues for at least 10 min after each sip of a strong alcoholic beverage.12 Acetaldehyde present in the alcoholic beverage has a shortterm (1–2 min) peaking effect on total instant acetaldehyde exposure.12 After its absorption from the duodenum and upper intestine, ethanol is evenly distributed to the whole water phase of the human body including saliva. Due to the microbial oxidation of ethanol to acetaldehyde even at very low (2–20 mM) ethanol concentrations, marked amounts of acetaldehyde are found in saliva (peak, ranging from 19 to 143 mM) 4 hours after normal social drinking.13 The use of an antiseptic mouthwash (chlorhexidine) significantly reduces in vivo acetaldehyde production from ethanol and as well the number of oral microbes.13 Chronic smoking, heavy drinking and poor oral hygiene are established risk factors for oral and esophageal cancers. These factors have also been shown to increase microbial acetaldehyde production in saliva. Smoking and heavy drinking independently increase in vitro acetaldehyde production from ethanol by 60–75% and their combined effect is about 100%.16 A well-established cancer risk factor, poor dental status, increases in vitro acetaldehyde production in saliva by 100%.39 Chronic smoking increases also in vivo acetaldehyde production from ethanol by about 100% after a moderate dose of alcohol.15

Effect of gene polymorphisms on acetaldehyde exposure ALDH2 deficiency First evidence highlighting the pivotal role of acetaldehyde in the pathogenesis of esophageal cancer among ALDH2deficient Japanese alcoholics and non-alcoholic drinkers was obtained in 1996.40 This original finding by Dr Ishii and his group has later confirmed in multiple studies and metaanalyses.41–43 In accordance with increased upper GI cancer risk, ALDH2-deficiency is associated also with an enhanced exposure of the upper digestive tract mucosa to carcinogenic acetaldehyde via saliva.19–21 After ingestion of a moderate dose of alcohol, ALDH2-deficient individuals have two to three times higher acetaldehyde levels in their saliva than those with the normal ALDH2 genotype.19 Sterile saliva obtained from the main duct of the parotid gland of ALDH2-deficient subjects contains acetaldehyde, but not the saliva obtained from those with the normal ALDH2 genotype.19 4-methylpyrazole, which is an effective inhibitor of somatic ADH enzymes but only a weak inhibitor of microbial ADH enzymes,13 prevents the increase in salivary acetaldehyde only in ALDH2deficient subjects.20 Additional salivary acetaldehyde of ALDHdeficient subjects can neither be derived from the blood, since blood acetaldehyde concentrations of ALDH2-deficient subjects are much lower than those in the saliva.19–21 All of these findings suggest that an enhanced exposure to endogenously formed acetaldehyde requires the presence of ethanol in the systemic blood circulation and that parotid glands presumably are responsible for the elevated acetaldehyde levels in the saliva of ALDH2-deficient subjects after an alcohol challenge.

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Low-activity ADH1B*1/*1 genotype The Vmax of the low-activity ADH1B is only 1/40 of that of the superactive genotype in vitro, and this has been shown to be associated with a significantly decreased rate of ethanol elimination. Consequently, after drinking of alcohol, ethanol remains elevated in the blood and saliva for hours longer in those with the low-activity ADH enzyme than in those with the normal enzyme, resulting in a longer exposure time to microbially formed acetaldehyde.22 High-activity ADH 1C*1 genotype The ADH 1C*1 allele with a 2.5-fold activity as compared with an ADH1C*2 allele has been shown to be associated with a significantly increased risk for squamous cell carcinoma of the head and neck among heavy drinkers.23,44 In accordance with this finding, homozygous subjects for the high-activity ADH1C*1 allele have been shown to have higher acetaldehyde levels in their saliva during an alcohol challenge than those with the low activity ADH genotype.23

Tobacco smoke and acetaldehyde exposure via saliva Acetaldehyde is the most abundant carcinogen of tobacco smoke, its concentration being more than 1000 times greater than that of some other well-known carcinogens, e.g. polycyclic aromatic hydrocarbons or tobacco-specific nitrosamines.45 As a water soluble agent acetaldehyde of tobacco smoke dissolves readily in saliva during smoking.15 After an alcohol challenge smoking results in 300–500 mM concentration of acetaldehyde in saliva lasting for as long as the active smoking continues.15 Because chronic smoking modifies the oral flora to produce more acetaldehyde from ethanol both in vitro and in vivo, the concomitant smoking and drinking have a synergistic, i.e. sevenfold, effect on the upper digestive tract’s exposure to carcinogenic acetaldehyde.15,16

Acetaldehyde exposure from food All so far published epidemiological studies on GI cancer appear to be biased, since they do not include acetaldehyde exposure derived from ethanol and acetaldehyde present in many beverages and food stuffs. Official alcoholic beverages contain 2.8% or more of ethanol. However, many so called non-alcoholic beverages and food stuffs produced by fermentation may contain 0.1%–2.5% of ethanol and mutagenic concentrations of acetaldehyde. Already 10 mM (0.05%) ethanol concentration is enough for significant microbial acetaldehyde production in the oral cavity.13 Furthermore, acetaldehyde may occur naturally, for example, in some fruits and it is widely used as a food additive and aroma agent.7,27 Microbial fermentation has been used for thousands of years to prepare beverages and food and as well for their preservation. Lactic acid is the most common end product of fermentation reactions, but many microbes are also able to produce acetaldehyde and ethanol from glucose under anaerobic conditions. Small amounts of ethanol and mutagenic concentrations of acetaldehyde containing beverages and food stuffs are widely used in everyday life, for example, home made mead and beer, vinegar, kefir, soya

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products, tofu, kimchi, yogurts and pickled vegetables.7,27–30 Neither ethanol nor acetaldehyde concentration of these products are known, since authorities responsible for food safety still classify acetaldehyde as a GRAS (Generally Regarded As Safe) product.46 This allows acetaldehyde to be used as a food additive and aroma agent.

Acetaldehyde exposure and stomach cancer Achlorhydric human stomach is the most important risk factor for stomach cancer.10 An acidic human stomach is free of microbes. However, oral microbes can survive and proliferate in increasing intragastric pH.47 In atrophic gastritis patients bacterial overgrowth may be associated with the production of endogenous acetaldehyde not only from ethanol but even from glucose.24 Helicobacter pylori infection is another established risk factor for gastric cancer.48 Many H. pylori strains possess ADH activity and are able to produce acetaldehyde from ethanol under microaerobic conditions.26 As stated before, many non-alcoholic beverages and foodstuffs may in fact contain low amounts of alcohol and function as a source for local microbial acetaldehyde production both in achlorhydric and H. pylori-infected stomach. This is a potential confounder that has not been considered in earlier epidemiological studies focusing on the risk factors of gastric cancer.10 The risk of stomach cancer increases with intensity and duration of cigarettes smoked.4 This is in accordance with the finding that acetaldehyde of tobacco smoke is easily dissolved into saliva and thus transported with other possible tobacco carcinogens via swallowing to the esophagus and stomach.15 In a prospective follow-up study from Japan, the risk for stomach cancer as compared with H. pylori-negative smokers was 11.4 among Helicobacter pyloripositive smokers, 5.8 among H. pylori-negative smokers and 6.9 among H. pylori-positive non-smokers.49 Highest gastric cancer risk has been found among H. pylori positive and ALDH2 deficient heavy drinkers and smokers, which also strongly supports the specific role of acetaldehyde in the pathogenesis of gastric cancer.50

Reduction of acetaldehyde exposure Acetaldehyde exposure can be markedly reduced both at the individual and population level. In both cases acetaldehyde exposure is cumulative and dependent both on environmental and genetic factors (Table 1). At the population level the use of all evidence based methods aimed at the reduction of tobacco and alcohol consumption should be encouraged. High priority should be given to regulatory measures and consumer guidance including worldwide screening of ethanol and acetaldehyde levels of thousands of beverages and food stuffs. Oral hygiene can be improved in many ways. Risk groups with the ADH and ALDH2 gene polymorphisms and/or hypo- or achlorhydric atrophic gastritis can be screened and health educated about the possible risks that are associated with cumulative acetaldehyde exposure. Acetaldehyde exposure can be decreased or even totally abolished by using special medical devices releasing slowly 17,18,25 L-cysteine. L-Cysteine is a semi-essential, natural and safe sulfur-containing amino acid that binds non-enzymatically to acetaldehyde forming inactive methyltiazolidinecarboxylic acid. Intervention studies focusing on the minimization of acetaldehyde 138

exposure both at the population and individual level are highly warranted especially among high-risk groups such as heavy drinkers, smokers and those with ALDH2-deficiency or achlorhydric atrophic gastritis.

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