Results from several large epidemiological studies have firmly established that alcohol is associated with higher cancer incidence and mortality. The mechanisms underlying alcohol-related cancers are unclear but several factors have been suggested to play a role (Table I) [1], [2], [3] .
Table I – Role of alcohol in carcinogenesis
Alcohol may be important in the initiation of cancer, either by increasing the expression of certains oncogenes or by impiring the cell’s ability to repair DNA thereby increasing the likelihood that oncogenic mutations will occur.
The metabolism of ethanol leads to generation of acetaldehyde, which is highly toxic and carcinogenic. The amount of acetaldehyde to which cells or tissues are exposed after alcohol ingestion may be of great importance and may, among others, affects carcinogenesis.
The enzyme responsible for oxidation of acetaldehyde is aldehyde dehydrogenase (ALDH). Both formation and degradation of acetaldehyde depends on the activity of these enzymes. The total alcohol dehydrogenase activity is significantly higher in cancer tissues than in this healthy organs (e.g. liver, oesophagus, colorectum). The activity of ADH is much higher than the activity of ALDH. This suggests that cancer cells have a greater capability for ethanol oxidation but less ability to remove acetaldehyde than normal tissues [4], [5], [6] .
ADH and ALDH are encoded by multiple genes. Because some of these genes exists in several variants and the enzymes encoded by certain variants may result in elevated acetaldehyde levels, the presence of these variants may predispose to certain cancers (Table II) [2], [7].
Acetaldehyde itself is a cancer-causing substance and reacts with DNA to form cancer-promoting compounds.
Table II - Alcoholic liver disease and HCC: mutations and polymorphism genes
Alcohol may be act as a co-carcinogen by enhancing the effect of direct carcinogens such as those found in tobacco and the diet. This effect of alcohol is at least in part via induction of the cytochrome P450 family of enzymes that are found in the liver, lung and intestine and are capable of metabolizing various tobacco and dietary constituents into cancer promoting free radicals [1].
It has been shown that in the liver the concentration of CYP2E1 can be correlated with the generation of hydroxyethyl radicals and thus with lipid peroxidation. Lipid peroxidation leads to the generation of 4-hydroxy nonenal which may bind to pyrimidine and purine based of the DNA and lead to exocyclic etheno DNA adducts which are carcinogenic. It has clearly demonstrated a significant correlation between CYP2E1 induction and the occurrence of esocyclic etheno DNA adducts in hepatocytes.
Seitz affirms that CYP2E1 activity occurs at relatively low level of alcohol (40 gr/ day) and at these levels of intake, induction is already apparent after one week, although the extent varies interindividually. Some individuals exhibit a very low extent of induction of CYP2E1 activity, whereas others show a high extent of induction. Thus, it could well be that the variation in extent of induction of CYP2E1 activity may modulate alcohol-associated carcinogenesis in man [4].
Chronic alcohol consumption also leads to decreased retinoic acid levels. This is predominantly due to the induction of CYP2E1 which is responsible for the degradation of retinol and retinoic acid to polar metabolites such as 4-oxo- and 18-hydroxy retinoic acid. This increased retinoic acid metabolism decreases retinoic acid which by itself results in an increased expression of the AP1 gene associated with an increase in their proteins c-jun and c-fos, finally leading to an increase in cycline D1 which is associated with hyperproliferation, at least in liver. Thus, retinoic acid deficiency is associated with acceleration of carcinogenesis [4], [5].
DNA methylation is an important regulator of gene expression: decreased methylation is associated with increased gene expression. In particular, decreased methylation of tumor promoter genes has been proposed as a possible mechanism for development of cancers. The hepatic enzyme methyladenosyltransferase II is decreased in alcoholic diseases. This results in decreased production of S-adenosylmethionine (SAMe), the methyl donor for DNA methylation reactions. Furthermore, homocysteine levels are increased in alcoholic diseases, increasing the S-adenosylhomocysteine level and inhibiting the activity of DNA methyltransferase enzymes. In experimental models, SAMe defincency induced by methionine-choline-deficient diet caused DNA hypomethylation and increased DNA strand breaks with DNA instability, changes associated with an increased risk for cancer. In transgenic mice lacking methyladenosyltransferase II there is spontaneous development of HCC. These experimental models support a possible role for DNA methylation abnormalities contributing to cancer in alcoholic diseases [8].
Since reduced levels of iron, zinc and vitamins A, B and E have been experimentally associated with some cancers, the nutritional deficiencies associated with chronic alcohol intake may also radical related oxidative stress. Finally, alcohol consumption is associated with immunosuppression which makes chronic alcoholics more susceptible to infection and theoretically to cancer.
Chronic alcohol consumption is a strong risk factor for cancer in the upper aerodigestive tract (oral cavity, pharynx, hypopharynx, larynx, oesophagus) and also alcohol increases the risk for cancer of the colorectum and the breast.
A great number of epidemiological studies have demonstrated that the ingestion of all types of alcoholics beverages is associated with an increased cancer risk [9].
Most alcohol-induced disease increases in a linear fashion as intake increases: oral, oesophagus, breast and colon cancer fall into this pattern, with no “safe level” of consumption [10] .
Poschl and Seitz [5] have evidenced the following risk factors for alcohol associated carcinogenesis:
Alcohol intake has been definitely recognised as a cause of chronic liver diseases and hepatocellular carcinoma (HCC). It could be involved in the development of HCC through both direct (genotoxic) and indirect mechanisms (development of cirrhosis). Studies in the USA and in Italy suggest that alcohol is the most common cause of HCC (accounting for 32-45% of HCC).
A significant synergy between alcohol consumption (50-80 gr/day of ethanol), hepatitis virus infection (HBV, HCV) and metabolic alterations has recently been demonstrated.
Below 50 gr/ day it has been demonstrated an addictive effect in patients with HCV infection.
Hassan et al. have demonstrated a significant increase of the risk when alcohol intake is associated with hepatitis viruses and diabetes mellitus. It has been suggested a common pathway for hepatocarcinogenesis [11].
In case of heavy alcohol consumption (> 80 gr/ day) with chronic hepatitis virus infection (HBV or HCV) it has been evidenced an OR of 53.9 (virus alone OR 19.1, alcohol alone OR 2.4) and in case of heavy alcohol consumption with diabetes (insulin-dependent, non-insulin-dependent) it has been evidenced an OR of 9.9 (diabetes alone 2.4).
A model of liver carcinogenesis by alcohol intake has been proposed. It shows both its early (initiation) and late effects (promotion/ progression). We have recently evaluated the possible mechanism of initiation in patients affected by chronic alcoholic liver disease (ALD) [12] .
As alcohol causes an oxidative stress, and therefore the formation of reactive oxygen species, the comparison of the frequency of DNA lesions in lymphocytes in patients with alcoholic liver disease has been considered interesting. The degree of DNA fragmentation has been evaluated by means of the Comet Assay which gives two indexes of the frequency of breakages of a single-stranded DNA: the length of the tail and the moment of the tail. In ALD patients, a statistically significant increase of the frequency of DNA lesions has been noticed. The data suggest a direct genotoxic effect of alcohol. The close association between alcohol intake and oxidative DNA damage suggests that the free radical produced during ethanol metabolism may be the cause of DNA fragmentation in lymphocytes. Taken as a whole, these findings suggest that genotoxic mechanisms may operate in the liver in the subjects who use alcohol and thus contribute to the process of hepatocarcinogenesis.
In the late phase (promotion/ progression) the hyperproliferation may cause hepatocyte DNA to become susceptible to mutagenesis, resulting in gene instability. In fact, it has been demonstrated how HCC develops because chronic oxidative stess exert a selection pressure that favors the outgrowth of progenitor cell clones that are most resistant to oxidant damage [13] .
In clinical practice the clinician should advise patients with any other liver disease that they should abstain totally.
