Alcohol and Epatocarcinoma
Alcohol intake is described
as being one of the dietary factors epidemiologically linked to an increased
risk of cancer. A large number of studies investigating the correlation between
ethanol consumption and the risk of hepatocellular carcinoma (HCC) have been
Whether ethanol abuse "per se" is linked to an increased risk of liver cancer has not been clearly demonstrated. A large number of studies have suggested that there is a relationship between alcohol abuse and cirrhosis and between cirrhosis and HCC, but, in fact, they do not confirm the possible direct link between ethanol and liver cancer (4,5). From the experimental point of view, ethanol "per se" has never been shown to exert a carcinogenic activity, while it has been proved to be co-carcinogenic. Recently, it has indeed been shown that alcohol consumption may accelerate the evolution to hepatocellular carcinoma in patients with both HBV and HCV-mediated liver damage. (6,7).
Several plausible mechanisms have been suggested by various investigators to show the link between excessive consumption of alcoholic beverages and increased risk of cancer, including: 1. ethanol solvent effect (8); 2. exposure to carcinogens in alcoholic beverages (9); 3. dietary deficiences and decreased immunological responsiveness commonly associated with heavy drinking (10); 4. the possibility that ethanol itself may act as a co-carcinogen at one or more stages in the multiphase process of carcinogenesis.
Since 1990, we have focused our attention to the study of this latter aspect of the problem, in particular, we have shown that the co-carcinogenic activity of ethanol is supported by its capacity to increase the organism's capacity to activate environmental carcinogens, by inducing the cytochrome P450-dependent mixed function oxidase systems and to interfere with DNA repair mechanisms.
These effects have been obtained in experimental models utilizing microsome containing preparations from different organs, but the situation with respect to the liver is contradictory. Hepatic microsomes obtained from ethanol-fed animals show a greater capacity to activate dimethylnitrosamine (DMN), a potent liver carcinogen in animal models, but ethanol exposure in vivo fails to influence DMN-induced carcinogenesis. This inconsistency appears to be due to a competitive inhibition exerted by ethanol on DMN-demethylase, the enzyme involved in DMN activation. In our experience also human liver contains a DMN-demethylase which is not modified in cirrhotic or neoplastic liver disease and that is inhibited by ethanol to a lesser extent in human liver than what observed in other animals. However the presence of cirrhosis and ethanol interfere with glutathione (GSH) conjugation metabolism, an important detoxifying system. These two factors may well alter the balance between xenobiotic activation and detoxification, in favour of activation, particularly in alcohol-abuser patients, thus contributing to the higher risk for HCC in cirrhosis (2).
Again, the situation with respect to ethanol and liver carcinogenesis appears to be more complex than initially suspected. For example, ethanol exposure increases the activation of the most powerful liver carcinogen known, aflatoxin B1 (11), but in vivo, its administration does not modify the incidence of HCC in animals exposed to this particular carcinogen (12).
Chronic alcohol consumption may increase cancer risk by inhibiting the DNA repair enzyme, 06-methylguanine transferase, which removes alkyl groups from 06 position of guanine. In rats, chronic and acute alcohol consumption causes an increased persistence of DMN-induced hepatic 06-MeG enzyme activity. This is a consequence of ethanol consumption and suggests yet another mechanism through which ethanol might act as a co-carcinogen in the liver (5).
Another aspect that must be taken into account when examining the complex relationship between ethanol and HCC is the hepatic regeneration. In this respect, ethanol-induced imbalances in sex-hormones, involving distribution and the role of estrogen receptors leading to a hyperestrogenic state in alcoholic cirrhotic, may play a role. The hyperresponsiveness of ethanol-exposed liver to estrogen may enhance the risk of neoplastic evolution in alcoholic cirrhotic patients initiated by other environmental carcinogens (5).
During recent years, one of the areas in which we have been concentrated in terms of research involves free radical production and oxidative damage as other possible mechanisms involved in the pathogenesis of alcohol-related liver damage. The antioxidant defence pathways that protect cells against oxidative damage by reactive oxygen species and lipid peroxidation products have also been investigated.
Our results confirm that chronic alcohol intake increases malondialdeyde levels, a product of lipid peroxidation, and reduces GSH liver availability. This latter alteration, indicating a progressive loss of the liver capacity to provide an adequate scavanger response, is in association with an accumulation of hepatic cysteine, a glutathione precursor/metabolite in the liver, probably due to gamma-glutamil transpaptidase induction.
Therefore, alcohol intake correlates inversely with GSH levels and directly with lipid peroxidation products. In addition, liver iron levels have been found significantly higher in patients with alcohol abuse correlated with lipid peroxidation (13). In our experience, in a different model (HCV-related liver damage) an increased hepatic oxidative damage accompanied by iron overloading is coupled with the accumulation of DNA oxidative damage, a fact that is relevant in terms of liver carcinogenesis and that may well be important also in alcohol-abuse related liver carcinogenesis (14).
Finally, with respect to hepatocellular proliferation and apoptosis rate, other two factors that may be important in the process of carcinogenesis, we have recently shown that in chronic alcohol-mediated liver damage both MIB1 positive, proliferating hepatocytes and apoptotic, in situ end-labeling positive cells are less frequently detectable than in liver damage of viral etiology, thus excluding a specific role of these mechanisms in the process (15).
In summary, alcohol abuse per se or in association with viral infections plays a major role in liver carcinogenesis. Whether the effect of ethanol is only mediated by the mechanisms involved in the natural evolution of liver cirrhosis, i.e. hepatocyte proliferation and death or whether other, ethanol-specific mechanisms are involved in the process has not and probably will not be definitely ascertained. In any case ethanol abuse is to proscribed as a major determinant of liver cancer in the general population and alcohol consumption is to be avoided in patients with chronic liver damage of other etiology because this consumption might well be linked to an acceleration of the evolution to cirrhosis and HCC.
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