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Teschke. Hepatoma Res 2019;5:40 I http://dx.doi.org/10.20517/2394-5079.2019.0017 Page 7 of 16

Putative procarcinogens and ultimate carcinogens
As a reminder, CYP 2E1 metabolizes not only alcohols but also a bundle of other substrates, some of
these are carcinogens or procarcinogens [Table 3], with references for each listed chemical provided in
[16]
a previous publication . Abundant clinical and experimental publications relate to alcohol and liver
cancer but further specification is often missing and major questions remain: (1) are alcoholic beverages
globally carcinogenic or only specific ingredients like contaminating carcinogens? or (2) is the chemical
ethanol per se carcinogenic or is it merely a procarcinogen? or (3) is acetaldehyde as the first metabolite in
its original form and per se carcinogenic or is metabolic activation to a reactive intermediate prerequisite
to be classified as procarcinogen? or (4) can ROS be considered as carcinogen either alone or perhaps
together with an activated membrane protein or a membrane phospholipid that can easily be converted to
a reactive lipidperoxide, considering that ROS alone in the absence of alcohol may play a role for HCC in
nonalcoholic steatohepatitis (NASH).

Officially, alcohol is now classified as a human carcinogen rather than as a clear procarcinogen by the
International Agency for Research in Cancer in a global context [5,39-41] , disregarding the known complexity
of metabolic events leading to a variability of compounds as outlined above.

Cocarcinogens
[42]
Humans with an alcohol problem are often heavy smokers and confronted with potential mutagenic
[43]
and carcinogenic compounds in the tobacco smoke may enter the body and act as cocarcinogens . On
theoretical backgrounds but difficult to evaluate in patients, mutagenic and carcinogenic compounds
may contaminate alcoholic beverages and could function upon ingestion as cocarcinogens, contributing
[41]
to initiation and promotion of AHCC . However, in the majority of alcoholic beverages mutagenic
and carcinogenic chemicals are not found, but if detected, respective amounts are very small and
unlikely causing harm the liver. In experimental studies, tumor incidence in the liver caused by
dimethylnitrosamine (DMN) is influenced by prolonged alcohol use as evidenced by a specific study
[44]
protocol : rats were pair-fed for 3 weeks a nutritionally adequate liquid diet containing either ethanol
(36% of total calories) or isocalorically substituted carbohydrates as control diet. Thereafter, the animals
were maintained on laboratory chow and tap water ad libitum for another 2 weeks and received 1.5 mg
DMN intraperitoneally per day for the first 5 days. This 5-week cycle was repeated three more times.
Chronic pretreatment with the alcohol-containing diet significantly improved the mean survival time of
DMN-treated rats compared with identically treated animals fed before with the control diet, but the total
number of tumors observed under these experimental conditions and the target organ remained virtually
[44]
unchanged . The partially positive and protective effect on survival in DMN treated animals elicited
by prolonged alcohol consumption was unexpected, as was the reduced liver injury by DMN following
prolonged pretreatment with the alcohol containing diet [45,46] .

CASCADES OF EVENTS: FROM LIVER INJURY AND ALCOHOLIC FATTY LIVER TO AHCC
The spectrum of ALD is broad and well described in various reports provided by experts in the
field [2,5-8,15-17,47-59] , starting with the most frequent stage of alcoholic fatty liver (AFL) [47-49] , and the transition
to alcoholic steatohepatitis (ASH) and alcoholic hepatitis (AH), both of which follow different criteria [50-53] ,
with alcoholic cirrhosis (AC), the most known end stage of ALD [54-57] and often precursor of AHCC [2,5-8,58,59] .
Delineating a 5-hit proposal has the advantage of a clear structure and better overview and has been
[8]
published previously [Figure 5] .
All 5-hit stages are well defined by both, clinical and histology evaluations, but some overlap among the
[8]
stages is unavoidable. Pathogenic details of all ALD stages have been published in a recent review article ,
some additional details are presented for AFL, ASH, AH, AC and AHCC for a brief overview [Table 4].