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Teschke. Hepatoma Res 2019;5:40 I http://dx.doi.org/10.20517/2394-5079.2019.0017 Page 3 of 16

liver is prepared to oxidize exogenous and endogenous alcohol using two different enzymes: ADH [5,8,13-17] and
microsomal ethanol-oxidizing system (MEOS) [8,14-16,18-21] . Through both reactions, acetaldehyde is produced
+
and its oxidation proceeds via the mitochondrial ALDH [8,15,16,18] , requiring NAD as cofactor but it can also
[15]
be metabolized in the endoplasmic reticulum of the liver .

ADH
Hepatic ADH is present in the cytosol of human liver cells and metabolizes ethanol according to the
following equation:

+
C H OH + NAD → CH CHO + NADH + H +
5
2
3
Ethanol Acetaldehyde
Additional information of ADH and its role in alcohol metabolism is provided in various other
reports [5,8,13-17] . Evidence is lacking that in the course of this reaction reactive radicals are generated.

MEOS
MEOS is a constituent of the endoplasmic reticulum membranes in the human liver that correspond to the
microsomal fraction following ultracentrifugation of the liver homogenate [8,14-16,18] . The oxidation of ethanol
precedes via the following equation:

+
+
C H OH + NADPH + H + O → CH CHO + NADP + 2H O
3
5
2
2
2
Ethanol Acetaldehyde

MEOS is different from ADH as well as catalase [19,20] and was isolated from these two enzymes using
[21]
column chromatography [21-24] , providing a typical elution pattern [Figure 1] .
MECHANISTIC CONSEQUENCES OF ALCOHOL METABOLISM RELATED TO CARCINOGENICITY
Alcohol has a direct contact to the mucosal cells of the gastrointestinal tract with its MEOS and
cytochrome P450 2E1 (CYP 2E1), and generated ROS may increase leakage of endotoxins, chemically
known as lipopolysaccharides (LPS), out of the intestinal tract directed to the liver [8,15,16,25] , modifying also
the intestinal microbiome and the gut-liver axis. There is experimental and clinical evidence that Toll-
[5,7]
like receptor 4 (TLR4) could be involved in AHCC development via signaling activation of LPS-TLR4 ,
whereby coexistence of hepatitis B virus (HBV) an hepatitis C virus (HCV) infection could represent a risk
[7]
factor .
Overall, alcohol dependent inflammation of the liver is responsible for non-maligant stages of alcoholic
[5]
liver disease (ALD) but is a contributory factor of AHCC initiation through hepatocellular DNA damage .
Specific liver macrophages are involved in AHCC development triggered by activated hepatic Stellate cells
[5]
(HSCs) , which are also known as promoters of liver alcoholic fibrosis [8,15] . Ectopic expression of TLR4 in
hepatocytes and its activation by LPS triggers AHCC through production of TLR4 and tumor-initiating
stem-cell like cells . It has been reported that activated HSCs may also promote AHCC development via
[5]
[5]
matrix or soluble factors that help tumor cell survival and growth .
Most importantly, ROS can bind to and damage DNA and cause lipid peroxidation with the generation
of highly carcinogenic exocyclic etheno-DNA adducts . Other DNA adducts of interest include N -
2
[5]
2
ethyl-deoxyguanosine and N -propano-2’-deoxyguanosine, which may modify the DNA integrity,
[7]
whereas acetaldehyde protein adducts may impair the DNA repair system . Consequently, the direct