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4
ALCOHOLISM: CLINICAL AND EXPERIMENTAL RESEARCH
Ethnic and Gender Differences in Ethanol Metabolism
Charles S. Lieber
O UR INTEREST IN gastric alcohol dehydrogenase
(ADH) originated with the observation that, to main-
tain a constant blood alcohol level, more alcohol was consis-
tently required via the intragastric than via the intravenous
route (Caballeria et al., 1987). Because the alcohol had not
been left behind in the GI tract and a steady state had been
reached, the question was raised where alcohol had been
metabolized. Specifically, it was known that a substantial
amount of alcohol is absorbed in the stomach, ranging from
20 80% of the dose administered, but it was not known what
happens to that ethanol when it goes through the wall of the
stomach, shown histochemically to contain ADH activity all
along the superficial layer of the gastric mucosa. When we
actually measured ADH activity in a standard fashion (with
alcohol concentrations below 100 mM), it was rather negligi-
ble compared to that of the liver. The gastric cells, however,
are close to the lumen of the stomach and thus exposed not
only to the alcohol in the blood, but also to that in the gastric
juice where the concentration is much higher. Accordingly,
the ethanol concentration used to test for ADH was increased
and, as a result, hepatic ADH activity decreased, consistent
with substrate inhibition. By contrast, for gastric ADH, there
was no substrate inhibition but, instead, there was progressive
increase in activity, resulting in convergence of the gastric and
hepatic values. More recently, significant gastric ADH activity
has also been shown in isolated gastric cells (Haber et al.,
1996; Mirmiran-Yazdy et al., 1995). Furthermore, using starch
gel electrophoresis, Hernandez-Mun oz et al. (1990) found a
difference in the ADH isozymes of the liver and the stomach:
whereas the Class I and Class III ADH isozymes of the liver
are also present in the stomach, Class II is not. By contrast, the
stomach contains a Class IV isozyme not found in the liver, as
confirmed by Yin et al., (1997). This new isozyme (named
sigma-ADH) was rapidly purified and characterized by several
groups, and was shown to have high activity, with a Vmax
considerably higher than that of the other enzymes (Stone et
al., 1993), and a Km of about 30 mM, which, for a gastric
From the Alcohol Research and Treatment Center, Section of Liver
Disease and Nutrition, Bronx Veterans Affairs Medical Center and Mount
Sinai School of Medicine, New York.
Received for publication December 10, 1999; accepted December 16,
1999.
Original studies reviewed here were supported, in part, by National Insti-
tutes of Health Grants AA05934, AA11115, AA07275, and the Department of
Veterans Affairs.
Reprint requests: Charles S. Lieber, M.D., Bronx VA Medical Center
(1512), Alcohol Research Center, 130 West Kingsbridge Road, Bronx, NY
10468; Fax: 718-733-6257; E-mail: liebercs@aol.com
Copyright 2000 by the Research Society on Alcoholism.
Alcohol Clin Exp Res, Vol 24, No 4, 2000: pp 417418
Vol. 24, No.
April 2000
enzyme, is reasonable and probably accounts for a substantial
fraction of the total ADH activity in the stomach. Further-
more, this Class IV enzyme predominates in the upper GI
tractthe mouth, the esophagus, the stomach. Teleologically,
one can view its presence in this location as a barrier against
the penetration of excess alcohol into the body. The corre-
sponding gene (ADH VII) was cloned (Satre et al., 1994;
Yokoyama et al., 1994) and localized on chromosome 4, close
to the centromere and part of the ADH cluster (Yokoyama et
al., 1996). We have found that the enzyme is usually present in
non-Asians, whereas in a majority of Asians, the enzyme
activity is either low or not detectable by the electrophoretic
methods used at that time (Baraona et al., 1991). This was
later confirmed by more quantitative methods (Dohmen et
al., 1996) including m-nitrobenzaldehyde reduction, which is
rather characteristic of the sigma-ADH activity. This ethnic
difference has a functional counterpart in terms of the first-
pass metabolism of ethanol, defined by the difference in bio-
availability between orally and intravenously administered
ethanol, found to be smaller in Asians than in the non-Asians
(Dohmen et al., 1996).
We also observed a gender difference in first-pass me-
tabolism of ethanol: blood alcohol was similar when the
alcohol was given intravenously, whereas levels were higher
in women than in men when taken orally (Frezza et al.,
1990). This gender difference was subsequently confirmed
but was shown to disappear after the age of 50 (Seitz et al.,
1993). The gender effect is not due to a difference in gastric
emptying that actually may be higher in women, depending
on the stage of the menstrual cycle. The women, however,
had a lower total gastric ADH in the stomach with a
significantly lesser activity for the Class III isoenzyme
(Baraona et al., 1998). The gender effect was exacerbated
by alcoholism (Di Padova et al., 1987; Frezza et al., 1990).
When alcohol was given orally, the blood level achieved in
alcoholic men was significantly higher than in nonalcoholics
for the same dose of alcohol, whereas blood levels were the
same when alcohol was given intravenously (Di Padova et
al., 1987; Frezza et al., 1990). The effect of alcoholism was
even more striking in women: for the same dose of alcohol,
blood levels were the same whether given intravenously or
orally (Frezza et al., 1990). Thus, alcoholic women have a
total loss of the gastric protective barrier provided by the
first-pass metabolism; and for an alcoholic woman to drink
alcohol is the same as taking the alcohol directly into a vein.
This may contribute to the well known greater vulnerability
of women to alcohol, which extends to many tissues, the
brain as well as liver. Indeed, Pequignot et al., (1978) found
417
418
that in men, a daily intake of at least 40 to 60 g of alcohol
is required to produce a statistically significant increase in
the incidence of alcoholic cirrhosis; in women, 20 g suffice.
Of course, women and men differ in many ways, including
size and distribution space for alcohol, with water space
being smaller in women. But these differences are not
sufficient to fully explain the gender effect that results, at
least in part, from the difference in gastric ADH activity.
In summary, the stomach has an ADH isozyme (sigma-
ADH) not present in the liver that has been well charac-
terized and its gene cloned. It is absent or decreased in
Asians and is associated with a lower metabolism of alco-
hol. In addition, women younger than 50 years of age have
a smaller first-pass metabolism of ethanol than men. This is
possibly because of a lesser Class III ADH activity, which
may contribute to the greater vulnerability of women to the
effects of ethanol, especially after chronic alcohol abuse
which decreases gastric ADH activity and the first-pass
metabolism of ethanol, thereby increasing blood levels even
further.
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