Women are more susceptible to the toxic effects of alcohol on the liver, heart muscle, skeletal muscle, and
likely the pancreas and the brain.
When men and women drink the same amount of alcohol, women develop higher blood alcohol levels than
men do.
The stomach's metabolism of alcohol may be a link between women's greater risk of certain alcohol-related
diseases and higher blood alcohol levels after drinking.

In most cultures, including the United States, alcohol is the most frequently used drug. Although American men with
alcohol-related problems continue to outnumber American women at a ratio of roughly three to one, women appear
to have a greater vulnerability to alcohol-related diseases. This may be due to the fact that, when both genders
drink the same amount of alcohol, women develop higher blood alcohol levels than men do. A study in the April
issue of Alcoholism: Clinical & Experimental Research searches for the mechanisms that may cause this effect,
concentrating on the stomach's role in metabolizing alcohol.

"It has been known for a long time," said Steven Schenker, professor of medicine and pharmacology at The
University of Texas, Health Science Center at San Antonio, "that, in general, both women and female animals are
more susceptible to the negative or toxic effects of alcohol. This is true for the liver, heart muscle, skeletal muscle,
and it may be true for the pancreas and the brain. In other words, there is something about the female gender that
makes them more susceptible to toxic amounts of alcohol."

Charles S. Lieber, professor of medicine and pathology at Mount Sinai School of Medicine, chief of the Alcohol
Research and Treatment Center at the Bronx VA Medical Center, and the study's lead author, agrees. "For
example," he said, "women have a higher propensity to develop liver disease than men. In fact, some studies have
shown that the minimal amount necessary to produce cirrhosis in the liver in women is two to three times less than in
men. Additionally, because of the higher blood level of alcohol in their blood, women are more vulnerable to the
alcohol's central nervous system effects. Accordingly, the brain is more affected in women than in men." This
phenomenon - where women need to drink a lesser amount of alcohol than men, or for a shorter amount of time, to
produce the same degree of damage - is referred to as "telescoping."

Women achieve higher blood alcohol levels than men do after drinking a similar amount of alcohol for several
different reasons. One reason is their body size. In general, women's weights are lower, while drink sizes are
standard. Another reason is that women tend to have more fatty tissue as a percentage of their body weight than
men do. Fat is inversely related to body water. Because alcohol is more soluble in water than in fat, the alcohol is
distributed throughout a lower water volume in women, resulting in less alcohol dilution. Third, it is believed that
women younger than the age of 50 have a greater bioavailability (blood circulation) of alcohol, or less first-pass
metabolism, than men do.

When people drink alcohol, a portion of it is metabolized in the stomach before it enters the blood stream. This
metabolism of alcohol is due to the activity of gastric alcohol dehydrogenase (ADH) isozymes. The stomach's
metabolism of alcohol decreases the amount of alcohol that reaches the blood stream, essentially functioning as a
kind of protective barrier against excessive rise of blood alcohol. This process is referred to as "first-pass
metabolism," because some of the alcohol is removed by metabolism on its 'first pass' through the stomach. As a
result of first-pass metabolism, the blood level achieved for any given dose of alcohol is less when given orally than
if it were to be given intravenously.

"In an earlier study, we found that women have less of this ADH activity than men do," said Lieber. "Accordingly,
women have a lesser first-pass metabolism and, therefore, for a given dose of alcohol, their blood level is higher
than it is for men. We also found that when individuals - men or women - drink large amounts of alcohol
chronically, there is a decrease in this ADH activity, resulting in lesser first-pass metabolism and increased blood
levels for a given dose. In alcoholic women, both effects are combined and, as a consequence, alcoholic women
totally lose their gastric protective mechanism. The blood level they achieve is the same as that obtained from the
same dose of alcohol given intravenously. Thus, for an alcoholic woman to drink alcohol, it is the same as injecting
the alcohol directly into a vein."

For this study, Lieber and his colleagues looked at three subcomponents of ADH in the stomach: acetaldehyde
(g-ADH), m-nitrobenzaldehyde (s-ADH), and glutathione-dependent formaldehyde dehydrogenase (c-ADH).
Only one of these three were what Schenker calls "significantly depressed" in women.

"These findings show that women had less first-pass metabolism than men when given 10 percent or 40 percent
alcohol, but not five percent," said Lieber. "In other words, women respond to beer in the same way than men, but
not to wine or hard liquor. This was associated with lower activity of a specific gastric ADH, namely c-ADH,
which can explain the greater gender difference in first-pass metabolism with high rather than with low
concentrations of imbibed alcohol. It is of interest that the higher blood alcohol levels were observed despite the
fact that women have a more rapid gastric emptying compared to men and a higher rate of hepatic oxidation of
ethanol which would, in part, oppose the effects of gastric ADH on blood levels."

"What Dr. Lieber has done is unequivocally shown that c-ADH is lower in women," said Schenker. "He's arguing
that the low amount of that enzyme in the stomach is related to the fact that you get a larger bioavailability of alcohol
in women than in men. In other words, more of the alcohol has gotten into the women's bloodstream than the men's,
and he correlates that with the c-ADH. He proposes that this is one of the mechanisms by which women may be
more sensitive to alcohol than males." Schenker added that one thing he hopes will be done in the future is to
measure the bioavailability of alcohol in males who also have lower concentrations of the enzyme.

In sum, said Schenker, the study shows that alcohol moderation has to be greater for women than it is for men.
"The present dictum of the National Institute on Alcohol Abuse and Alcoholism is that a man should consume no
more than two drinks per day, whereas a woman is supposed to consume no more than one drink per day. Women
simply need to be more cautious than males in terms of the amount of drinking that they do," he said. "This study
also teaches us a great deal about the processing of alcohol. So, mechanistically it's important, because if we can
understand mechanisms, we can understand therapy. Therapy is not going to be relevant to us if we don't
understand the 'why;' if we know why, then we may be able to do something about it."

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Co-authors of the Alcoholism: Clinical & Experimental Research paper included: Enrique Baraona, Chaim S.
Abittan, and Kazufumi Dohmen of Liver Disease and Nutrition at the Alcohol Research Center, Bronx Veterans
Affairs and Mount Sinai Medical Centers; Michelle Moretti and Gabriele Pozzato of the University of Trieste, Italy;
and Zev W. Chayes and Clara Schaefer of Nuclear Medicine, Bronx Veterans Affairs and Mount Sinai Medical
Centers. The study was funded by the National Institutes of Health, the Department of Veterans Affairs, and the
Kingsbridge Research Foundation.