ACETALDEHYDE THE MOST COMMON HUMAN CARCINOGEN

Transcription

1 ACETALDEHYDE THE MOST COMMON HUMAN CARCINOGEN Mikko Salaspuro, prof., M.D., Ph.D., Research Unit on Acetaldehyde and Cancer University of Helsinki, Helsinki, Finland COI: Board member and stock owner of Biohit Oyj., Helsinki ESBRA 2015 Charles S Lieber Memorial Lecture mikko.salaspuro@helsinki.fi

2 PRINCIPLES OF SCIENCE WHAT WHY HOW

3 CONTENTS 1. What is acetaldehyde (AA) 2. Why AA is the most common human carcinogen 3. How upper digestive tract is exposed to AA 4. ALDH2-deficiency as a unique human model for local AA exposure and cancer 5. Tobacco smoking and AA 6. Inconsistent opinions of authorities on the carcinogenicity of AA 7. Stomach cancer and AA 8. Prevention of AA related cancers

4 ACETALDEHYDE Easily soluble to water and lipids Passes cell membranes Carcinogenic DNA adducts in oral mucosa in man Free aldehyde group Carcinogenic to animals

5 Acetaldehyde most common human carcinogen Either present or formed by oxidation from ethanol Aroma?

6 Acetaldehyde most common human carcinogen Last metabolite of alcohol fermentation from glucose to ethanol First metabolite of alcohol oxidation from ethanol to acetate

7 Particularly high concentrations in some alcoholic beverages Chinese spirits up to µM Mexican spirits up to µM Grappa, Calvados, Sherry 400 to µm

8 Zero or low concentrations in some other alcoholic beverages Zero acetaldehyde in well distilled spirits In beers may range from 0 to 1400µM Rather low levels in most wines, since free acetaldehyde is bound to sulphites

9 Ethanol and/or AA of Japanese fermented foods FOOD ETHANOL VOL. % ACETALDEHYDE µm Soya sauce 8, Miso 5, Nakazuke (Fermented rice brand) Narazuke (Vegetables pickled in sake lees) 1, , Umeboshi (Salted apricot) 3,94 96 Kimuchi (Korean pickles) 0, Salted fish guts 2, Traditional sake 15,07 146

10 Within 12 minutes cooking of rice with ethanol only 50 40% of ethanol is evaporated RICE

11 Effect of cooking on ethanol and AA of Japanese food SUKIYAKI HOT POT 0.5dl mirin (EtOH 0.37 %) 0.5dl sake (EtOH 15.5 %) 0.4dl soya sauce (EtOH 5.73%) 2 spoons sugar Cooked in hot pot for ten minutes MISO-MARINATED FISH 1 3/4 tea spoon miso paste 1 tea spoon sake, mirin and soya sauce 3 tea spoons sugar Marinated for 16 hours and cooked in oven

12 Ethanol and/or AA in Japanese food after cooking FOOD Miso-marinated fish - Fish - Soba Noodels - Marinade - Noodel soup Sukiyaki-hot pot dish - Marinade - Vegetables - Meat - Tofu ETHANOL VOL. % ACETALDEHYDE µm

13 Acetaldehyde exposure is localized to the upper G-I tract It is well known that ethanol is metabolized in the liver so effectively that no acetaldehyde is released to the blood Less well is known that a minor amount of ethanol is metabolized locally to acetaldehyde in the mouth and stomach

14 Salivary glands Microbes Salivary glands, oral microbes and mucosal cells are able to metabolize alcohol to acetaldehyde However, the ability microbes and mucosa to eliminate acetaldehyde is low Therefore, in the presence of any alcohol in the mouth or stomach carcinogenic levels of acetaldehyde accumulate in the saliva and gastric juice Mucosal cells

15 Acute effect of alcohol sipping on salivary acetaldehyde 5ml of alcoholic beverage in mouth for 5 seconds Ethanol stays in saliva for up to 15 minutes High acetaldehyde concentration of the beverage results in 2 minute s additional exposure of the mouth to acetaldehyde Mutagenic level 1 drink of alcohol daily increases significantly risk for oral cancer Linderborg et al. Food Chem Tox 2011;49:2103-6

16 Long-term effect of alcohol drinking on salivary acetaldehyde After a moderate dose µ M N o rm a l 4 0 (0.5g/kg) of alcohol: C h lo rh e x id in e + - normal with chlorhexidine rinsing 2 0 Ethanol is distributed 1 0 to saliva from the blood and stays in 0 saliva for up to 4 hours M in u te s Mutagenic level Homann et al. Carcinogenesis 1997

17 CARCINOGENICITY OF ACETALDEHYDE IS BASED ON A UNIQUE HUMAN CANCER MODEL CAUSED BY GENE ERROR Point mutation in ALDH2-gene Results in deficient ALDH2-enzyme Most common one point mutation related health risk in man Incidence 1:13 That of familiar hypercholesterolemia is 1:500 Equal model - randomized by nature - is not available for any other of group 1 human carcinogens (n = 113) Most importantly, possible confounding factors can be assumed to be evenly distributed among ALDH2- actives and -deficients

18 ALDH2 Ethanol ACETALDEHYDE Acetate Point mutation in ALDH2 gene took place in South China over 2000 years ago Results in deficient ALDH2 enzyme in all cells Affects about 600 million subjects with East Asian descent In ALDH2-deficient individuals alcohol drinking results in markedly elevated local acetaldehyde exposure of digestive tract mucosa via saliva and gastric juice Unique model for local AA exposure

19 Effect of a moderate dose (0.5g/kg) ethanol on salivary and gastric juice acetaldehyde levels in ALDH2-actives compared to ALDH2-deficients Väkeväinen et al. AlcClinExpRes 2000 Maejima et al PLOS ONE 2015 Saliva Gastric juice Mutagenic level Mutagenic level More alcohol-longer exposure

20 In lines with biochemical findings ALDH2-deficient alcohol drinkers have markedly higher upper digestive tract cancer risk than in those with the active ALDH enzyme Cancer risk in ALDH2-deficient heavy drinkers compared to ALDH2-actives RR Confirmed in 10s of studies and metaanalyses Yokoyama et al. Carcinogenesis 1998

21 High active ADH1C*1 Rate of ethanol oxidation 2.5-fold Increased salivary acetaldehyde levels after alcohol intake Significantly increased incidence of upper aerodigestive tract cancers among heavy drinkers Visapää et al. Gut 2004;53:871-6

22 Based on gene-epidemiological and gene-biochemical studies IARC concluded in 2009 that ACETALDEHYDE associating with alcohol is GROUP 1 human carcinogen Concerns oral-, pharyngealand esophageal cancers

23 Further evidence for the local carcinogenicity of AA in man Fmol/µmol dguo One oral dose of alcohol results in dose dependent increase in carcinogenic AA-DNA adducts (N 2 -ethylidene-dguo) in human oral mucosa One alcohol dose is known to result in 20 to 200µM levels of AA in the saliva Base line 5000 AA-DNA-adducts at 2hrs from alcohol drinking Dose of alcohol g/kg (Balbo et al. Cancer Epid Biomark Prev 2012;21:601-8)

24 Adduct level/10 7 bases Further evidence for the local carcinogenicity of AA from ALDH2-knock-out mice Drinking of 5% ethanol or water for 8 weeks Isolation of esophageal DNA 12-fold increase in mutagenic N 2 - ethylidene-dguo Major mutagenic AA-DNA adduct AA-DNA adducts Water Ethanol Control ALDH2- (Yakawa et al. Am J Cancer Res 2014;4: )

25 Tobacco smoking and acetaldehyde Tobacco smoking Independent risk factor for oral, pharyngeal, esophageal and stomach cancer Synergistic effect with alcohol on upper G-I tract cancer risk Acetaldehyde Most abundant carcinogenic compound of tobacco smoke Dissolves easily into the saliva Is distributed via saliva to the mucosa of the whole upper digestive tract

26 Synergistic effect of alcohol and tobacco on the risk for oesophageal cancer (Tuyns et al. Bull du Cancer 1977) RR > 30 Cigarettes/day >120 Alcohol g/day Tuyns et al. Bull du Cancer 1977

27 Smoking and alcohol have a synergistic effect on salivary acetaldehyde (Tobacco smoking modifies oral flora to produce more AA from ethanol) AUC: 7-fold in smokers as compared to non-smokers p < Smoking: about 5 min. Mutagenic level Alcohol 0.8g/kg Salaspuro V et al., Int J Cancer 2004;111:480-3

28 Inconsistent opinions of authorities IARC/WHO (2009) AA associated with consumption of alcoholic beverages is carcinogenic to humans (Group 1) Joint FAO/WHO Expert Committee on Food Additives (JEFCA) in 1998 AA is a GRAS product (Generally Regarded as Safe) Is not based on present scientific evidence Scientific Committee on Consumer Safety (SCCS/EC, 2012) Maximum concentration for acetaldehyde in the final finished cosmetic product 5mg/l (114µM) Not be intentionally used in mouth-washing products

29 Stomach cancer - third leading cause of cancer death in both sexes worldwide RISK CONDITIONS Helicobacter pylori Atrophic gastritis ALDH2- deficiency AA RISK FACTORS Smoking Heavy drinking Fermented food ACETALDEHYDE (AA) IS A COMMON DENOMINATOR

30 Atrophic gastritis acid free stomach Oral microbes Colonize acid free stomach Produce AA locally from any alcohol present in beverages or food Also glucose may serve as a source for AA Gastric juice AA, µm ethanol 15% 30 min. 60 min. Controls Achlorhydrics

31 Gastric juice AA in relation to g.j. ethanol in patients with atrophic gastritis (n=7) µ M 6 0 Alcohol (15 vol.%, 0.3g/kg 4 0 Gastric juice ethanol levels under the official limit for alcoholic beverages ( vol. %) Hellström et al. DDW 2014 M in u te s

32 Gastric juice AA in relation to g.j. ethanol in PPI treated ALDH2-deficient patients (n=10) µ M Alcohol (15 vol.%, 0.5g/kg Gastric juice ethanol levels under the official limit for alcoholic beverages (at 120min. 1.3 ) M in u te s Maejima et al. 2015, PLOS ONE

33 CONCLUSIONS with regard to stomach cancer 1. Many commercially available food stuffs contain marked levels of ethanol and acetaldehyde 2. Ethanol and acetaldehyde derived from these products expose upper digest tract mucosa to mutagenic concentrations of acetaldehyde 3. The fact that ethanol and acetaldehyde intake via widely used foodstuffs and beverages is not systematically recorded causes an obvious, but yet unrecognized, confounder and bias in cancer epidemiology of the upper digestive tract.

34 Basics for cancer prevention 1 Identification of spesific carcinogenic agent AA = Group 1 human carcinogen comparable to asbestos, benzene, formaldehyde and radon ALDH2-deficiency provides a unique human cancer model for local acetaldehyde exposure Recognition of the wide presence of carcinogenic agent (AA) in our daily environment Acetaldehyde probably is the most common and prevalent human carcinogen

35 Basics for cancer prevention 2 Knowledge of mechanisms regulating local AA concentration in the upper digestive tract Great individual variation in salivary AA after alcohol drinking is due to individual microbial flora Good oral hygiene results in lower AA exposure Risk factors enhancing AA exposure: ALDH2- deficiency, high active ADH, atrophic gastritis, H. pylori infection, use of drugs inhibiting secretion of gastric acid (PPIs, H2-blockers) Drinking habits: Higher ethanol higher AA longer exposure time

36 How to minimize acetaldehyde exposure Prefer beverages with low free acetaldehyde

37 How to minimize acetaldehyde exposure Avoid beverages and food containing low levels of ethanol Result in marked local production of AA Avoid beverages and food containing high levels of free acetaldehyde AA AROMA

38 L-CYSTEINE in the minimization of AA exposure Normal and safe amino acid that binds covalently and non-enzymatically to acetaldehyde and forms Inactive 2-methyltiazolidine-4-carboxylicacid (MTCA) +

39 Slow release l-cysteine (200mg) eliminates effectively AA from gastric juice of ALDH2-deficient PPI-users after intragastric dose of alcohol (0.5g/kg) Mutagenic level Maejima et al. 2015, PLOS ONE

40 Slow release L-cysteine (200mg) effectively eliminates AA from gastric juice of patients with atrophic gastritis after intragastric installation of alcohol (0.3g/kg) 68 % decrease P < Mutagenic level Hellström et al. DDW 2014

41 L-cysteine and MTCA levels of gastric juice after slow release L-cysteine (200mg) and intragastric installation of alcohol (0.3g/kg) L-cysteine and MTCA persist in the stomach for up to 3 hours Min. Hellström et al. DDW 2014

42 FINAL CONCLUSIONS 1. Acetaldehyde (AA) associated with alcohol is the most prevalent human carcinogen (Group 1) 2. Local carcinogenicity of AA in the upper digestive tract is based on a unique human model 3. There is no evidence that easily water soluble AA derived from tobacco or low ethanol/high AA beverages and food is less carcinogenic than AA associated with use of alcoholic beverages 4. AA is a cumulative carcinogen 5. AA exposure can be markedly decreased both at population and individual level

43 CARCINOGENICITY OF ACETALDEHYDE STRONG EVIDENCE MISSING ACTIONS

44 Acknowledgements Research Unit on Acetaldehyde and Cancer, University of Helsinki Katja Salmela, Risto Roine, Nils Homann, Kalle Jokelainen, Jyrki Tillonen, Jukka-Pekka Visapää, Ville Salaspuro, Tiina Koivisto, Tatiyna Nosova, Klas Linderborg, Johanna Uittamo (Kurkivuori), Pertti Kaihovaara, Satu Väkeväinen, Mikko Nieminen, Andreas Helminen, Kalle Nummi Department of pharmacy, University of Helsinki Martti Marvola, Alma Kartal, Tuuli Marvola Department of Gastroenterology, Helsinki University Central Hospital Martti Färkkilä, Hannu Nuutinen Salem Medical Center, Heidelberg, Germany Helmuth Seitz National Cancer Institute, NIH Neal Freedman, Christian Abnet, Sandy Dawsey Division of Gastroenterology, Tohoku University, Sendai, Japan Ryehui Maejima, Katsunori Iijima, Tooru Shimosegawa Department of Medical Sciences, Uppsala University, Sweden Per Hellström