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
published (1-3).
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.
References
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