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Page 4 of 16 Teschke. Hepatoma Res 2019;5:40 I http://dx.doi.org/10.20517/2394-5079.2019.0017

Figure 1. Purification of the MEOS and its separation from catalase and ADH activities. Separation was achieved by DEAE cellulose ion
exchange column chromatography after solubilization of liver microsomes. In the void volume eluted up to around 220 mL, the highest
peak represents the protein curve assessed as E280 nm, and the peak below that is the catalase peak, whereas ADH presents as the
lowest peak. Starting with an elution volume of around 330 mL, microsomal components begin to appear. The first peak represents
cytochrome P450, the second peak represents E280 nm, followed by a third peak with two shoulders and by a fourth peak representing
MEOS. At around 770 mL, the reductase peak emerges, followed by the phospholipid peak at around 790 mL elution volume. Adapted
from the original figure published in a previous report [21] . MEOS: microsomal ethanol-oxidizing system; ADH: alcohol dehydrogenase;
DEAE: diethyl-amino-ethyl

DNA mutagenic effect of acetaldehyde and the indirect carcinogenic effect of adducts may modulate
carcinogenesis leading to AHCC [5,6,26,27] . Other considerations focus on DNA methylation that modifies
the expression of genes: hypomethylation is related to enhanced gene expression, considered as an import
[6]
factor of cancer development . Prolonged alcohol use also causes a reduction of S-adenosylmethionine
[6]
in the liver, the methyl donor of DNA . Reviewing the relevant literature with inclusion of those
[5-7]
referenced , it is obvious that many mechanism have the potential of causing AHCC. In face of multiple
proposals and study data, and as expected, not all results are confirmative but even contradictory, not
allowing a valid uniform proposal how AHCC develops in the human liver during prolonged alcohol
abuse.

Principles of hepatic carcinogenesis
There is general believe that carcinogenesis of various organs including the liver is triggered by an
enhancement of oncogene expression or due to an impairment of cells to improve their DNA quality
leading to inappropriate DNA repair associated with DNA mutations, conditions that facilitate oncogenic
[5,6]
mutations . Conditions in the human and experimental setting of AHCC are complex due to a broad
range of variabilities. Although these variable DNA related modifications had been observed mostly in
animal models or human tissues, respective translation of these meaningful data to humans with AHCC
is warranted. The variability of proposed molecules damaging DNA as a result of alcohol consumption
and metabolism requires a closer look with focus on alcohol metabolism and more specifically electrophile
metabolites, in addition to the concomitant production of ROS to be discussed in general.

Microsomal components of MEOS
ROS production is closely connected with the degradation of ethanol via MEOS, which is not a single
enzyme but represents a system composed of the three microsomal components CYP 2E1, the reductase,