Symposium 6, Sunday Sept. 23rd 4 pm–5.30 pm; Room: Lecture Hall 2
Alcohol and cancer: Chairpersons: Seitz HK (Germany), Ishii H (Japan)
; |
Abstract |
|---|
Presentation S6-1
The role of retinoids in alcohol associated liver cancer
Wang XD (USA)
Aims. Hapatocellular carcinoma (HCC) is the most common type of primary liver cancer with a poor prognosis and high mortality. Over the past 25 years, the incidence of HCC has doubled in the United States, where the prevalence of alcohol abuse as the etiologic agent is more common than chronic viral hepatitis infection or carcinogen exposure. Although the precise mechanisms underlying alcohol-related hepatic carcinogenesis have not been well defined, recent studies including ours suggest that the sustained c-Jun N-terminal kinase (JNK) activation by alcohol-induced cytochrome P450 2E1, which is associated with the production of reactive oxygen species, and TNF-a stimulation plays a causative role in hepatocyte apoptosis, proliferation, inflammation and consequent HCC development. Further, there is a strong inverse association between the concentration of retinoids (vitamin A and its derivatives) in prediagnostic serum and the risk of developing hepatocellular carcinoma in humans. Disruption in retinoid metabolism and signaling by excessive alcohol consumption may play a promoting role in the process of hepatic carcinogenesis. This was supported by our observations that ethanol feeding increased the levels of phosphorylated JNK and MKK-4 and decreased levels of MAP kinase phosphatases-1 (MKP-1) in the liver of rats. Conversely, the restoration of hepatic all-trans-retinoic acid to normal levels greatly attenuated the ethanol-induced hepatic phosphorylation of MKK-4 and JNK by inducing MKP-1, and completely abolished the ethanol-enhanced c-Jun, cyclin D and activator protein 1-DNA binding activities. These results support that targeting JNK signaling by restoring normal retinoid statues via up-regulation of MKP-1 represents an effective approach to decreasing alcohol-promoted hepatic carcinogenesis.
Presentation S6-2
The role of disturbed methyl transfer in alcohol-associated cancer
Choi SW, Friso S (USA and Italy)
Chronic excessive alcohol consumption has been regarded as an important dietary risk factor for colorectal cancer. Epidemiologic studies demonstrated that alcohol consumption has an additive effect on folate-associated carcinogenesis, indicating that alcohol's co-carcinogenic effect might operate through derangements in folate metabolism, a concept consistent with the known adverse effects of alcohol on folate mediated one-carbon metabolism. One-carbon metabolism regulates the transfer of the one-carbon moiety (methyl group) into biochemical pathways essential for nucleotide synthesis and DNA methylation, an epigenetic phenomenon that has been regarded as an important mechanism for cancer development and progression. There are several means by which alcohol alters one-carbon metabolism and disturb methyl transfer; 1) Chronic alcohol exposure impairs folate absorption by inhibiting expression of the reduced folate carrier and decreasing the hepatic uptake and renal conservation of circulating folate, 2) Alcohol stimulates catabolism of methionine to generate cysteine and replenish glutathione, but at the same time, the cell attempts to conserve methionine through the choline and betaine pathway. This results in a drastic wastage of choline and B-6. Methionine, choline, and betaine are dietary methyl group donors to one-carbon metabolism. 3) Chronic alcohol ingestion diminishes methionine synthase activity in the liver, causing methyl folate trap. Thereby folate-mediated thymidylate synthesis is interrupted as well, and 4) Vitamin B-12 deficiency, assessed as low circulating concentrations, is less common in chronic alcoholics. Nonetheless, tissue deficiencies of this vitamin may occur, lending that chronic alcohol consumption may impair the availability of B-12 in tissues. Current evidence from an animal study and cultured cell studies indicates that chronic alcohol consumption can decrease genomic DNA methylation and enhance histone acetylation, another epigenetic phenomenon associated with DNA methylation and carcinogenesis. Thus, impairment of methyl transfer is a particularly likely candidate for the alcohol-associated carcinogenesis in view of the extensive adverse effects of alcohol on this metabolic network and subsequent alterations in epigenetic phenomena that are closely associated with carcinogenesis.
Presentation S6-3
The role of acetaldehyde in alcohol associated cancers
Salaspuro M (Finland)
Aims. Acetaldehyde is the first metabolite of alcohol oxidation that is produced locally in the oral cavity by some microbes representing normal oral flora. Furthermore, acetaldehyde is also found in tobacco smoke and it is an important component of food flavourings. Acetaldehyde is reasonably anticipated to be a human carcinogen based on sufficient evidence of carcinogenicity in experimental animals. Strongest evidence for the local carcinogenic action of acetaldehyde provide biochemical studies with individuals who have either a decreased ability to detoxify or an enhanced ability to produce acetaldehyde. ALDH2-deficient Asian alcohol consumers and Caucasian heavy drinkers homozygous for the fast ADH1C*1 allele have markedly increased risk for upper digestive tract cancers. These individuals also express considerably elevated salivary acetaldehyde levels after alcohol drinking as compared to those with the normal enzymes. Accordingly, these genetic variants form an exceptional human model for long term acetaldehyde exposure, which is associated with a particularly high risk of upper digestive tract cancers. Tobacco and alcohol are two independent and interactive causes of upper digestive tract cancers. Strong epidemiological and biochemical evidence indicates that acetaldehyde acts as a common denominator in the pathogenesis of these cancers. In the oral cavity alcohol is metabolized to acetaldehyde by many microbes representing normal oral flora. On the other hand, tobacco smoke contains high levels of acetaldehyde that during smoking becomes in part dissolved in saliva. According to indisputable evidence acetaldehyde derived either from alcohol or tobacco appears to act in the digestive tract as a local carcinogen in a dose-dependent and synergistic way. Via swallowing salivary acetaldehyde of either origin is distributed further to the pharynx, oesophagus and stomach and may thus explain also the tobacco and alcohol associated cancer risk of these organs. With regard to cancer prevention it is important to characterize all those factors that may have an effect on the local concentration of acetaldehyde in saliva.
Presentation S6-4
Contribution of the alcohol dehydrogenase-1B genotype and oral microorganisms to high salivary acetaldehyde concentrations in Japanese alcoholic men
Yokoyama A (Japan)
Aims. The slow-metabolizing homozygous alcohol dehydrogenase-1B (ADH1B*1/*1) increase the risk of upper aerodigestive tract cancer in Japanese, Chinese, Thai, and central European drinkers.
Methods. We evaluated associations between ADH1B genotype and the blood and salivary ethanol and acetaldehyde levels of 80 Japanese alcoholic men in the morning when they first visited our hospital after drinking the day before.
Results. Higher levels of ethanol persisted in the blood for longer periods in ADH1B*1/*1 carriers (n = 25) than in very fast-metabolizing ADH1B*2 allele carriers after adjustment of the amount and time of the preceding alcohol consumption [Median (25th–75th%): 20.5 mM (15.5–52.4) vs below detection level (<DL) (<DL-6.4), p = 0.0002]. The ethanol levels in blood and saliva were similar, but the acetaldehyde levels in saliva were strikingly higher than in the blood, and were higher in ADH1B*1/*1 carriers than in ADH1B*2 allele carriers [22.2–87.6 vs <DL (<DL-26.3) in the saliva, p = 0.0007]. The salivary acetaldehyde levels were correlated with salivary acetaldehyde production (p = 0.44, p < 0.0001). The oral bacteria and yeast counts were correlated with salivary acetaldehyde production. Both the microorganisms counts and acetaldehyde production decreased after 3 weeks of abstinence, and the decreases were correlated (p = 0.35, p = 0.042).
Conclusions. In conclusion, the high salivary acetaldehyde levels in the alcoholics in the morning after drinking the day before were partly attributable to prolonged ethanol exposure because of the slow-metabolizing ADH1B and increased salivary acetaldehyde production as a result of oral microorganism overgrowth, and may explain their high risk for upper aerodigestive tract cancer.
Presentation S6-5
The role of oxidative stress in the development of alcohol associated hepatic cancer
Seitz HK, Wang Y, Bartsch H, Nair J (Germany)
Aims. Various mechanisms contribute to oxidative stress in alcoholic liver disease including inflammation driven oxidative stress as well as the generation of reactive oxygen species (ROS) through an induced cytochrome P4502E1 (CYP2E1) ethanol metabolism. It has been shown in animal experiments that alcoholic liver disease can be inhibited when CYP2E1 is inhibited by chlormethiazol. However a contribution of CYP2E1 induction by ethanol and thus ROS generation to DNA damage has not been demonstrated. It is well known that ROS leads to lipid peroxidation and that lipid peroxidation products such as 4-hydroxynonenal results in the generation of exocyclic DNA etheno adducts (edA, edC).
Methods. In the present study CYP2E1-transfected and mock-transfected HepG2 cells were used (kindly supplied by Dr A. I. Cederbaum, Mount Sinai School of Medicine, New York, USA). Cultured cells were exposed to various concentrations of ethanol in the presence and absence of the CYP2E1 inhibitor chlormethiazol. After various time intervals exocyclic etheno DNA adducts were semiquantitatively determined using immunohistology.
Results. The data show that increasing concentrations of ethanol result in a dose and time-dependent increase in edA. The administration of chlormethiazol inhibits almost completely the generation of these adducts.
Conclusions. These results show for the first time a correlation between CYP2E1 concentrations and the generation of highly mutagenic DNA adducts in liver cells. Thus, the induction of CYP2E1 in hepatocytes by chronic alcohol consumption may be a major mechanism in the development of hepatocellular cancer in the alcoholic.