ABSTRACTS I11

GENDER AND ETHNIC DIFFERENCES weight (p < 0.0001) than blacks, and females had a greater
IN ALCOHOL METABOLISM liver mass per kg body weight than males (p < 0.0001).
In a second study,8seven men and 10 women, all nonalco-
Ting-Kai Li, James D. Beard, William E. On-, holic white subjects (22-30 years old) had AERs that had been
Paul Y. Kwo, and Vijay A. Ramchandani determined by clamping the breath alcohol concentration at
50 mg% by intravenous infusion of 6%(vh) ethanol after an
Department of Medicine oral loading dose.9 Liver volume was determined by spiral
Indiana University School of Medicine computerized tomography without contrast. We used a slice
Indianapolis, Indiana width of 5 mm and a reconstruction increment of 4 mm. Liver
and Departments of Psychiatry, volume was computed in liters (L), and lean body mass was
Physiology, and Biophysics calculated by standard techniques. There were no significant
University of Tennessee College of Medicine differences in breath alcohol concentration between males
Memphis, Tennessee and females (M, 5 1 ? 0.5 mg%; F, 50 ? 0.3 mg%) (mean ?
SE) during clamping. Liver volume was 6%greater in males
(M, 1.57 ? 0.11 L; F, 1.48 ? 0.06 L), but mean liver volume
There is a clinical impression that women and persons of per unit lean body mass was 38% smaller (M, 0.024 ? 0.001
African descent are more susceptible to alcoholic liver dis- Lkg; F, 0.033 ? 0.01 Lkg) in males. There was no differ-
ease than are men and persons of Caucasian descent, respec- ence in AER between males and females (M, 7.7 ? 0.5 g/hr;
tively. It has been hypothesized that gender and ethnic F, 7.3 ? 0.5 g/hr). However, the mean AEFUkg lean body mass
differences in alcohol metabolic rate may be contributing fac- was 40%higher in females (M, 0.12 ? 0.01 g/hrkg; F, 0.16
tors. There is now good agreement in the literature that women ? 0.01 g/hrkg). When AER was calculated per unit liver vol-
have higher alcohol elimination rates (AERs) than men, as ume, no difference between males and females was seen (M,
revealed by studies in which doses of alcohol were determined 5.0 ? 0.4 g/hr/L;F, 4.9 ? 0.3 g/hr/L).These data demonstrate
on the basis of body mass or total body water distribution.' that there is greater clearance of ethanol in females per unit
On the other hand, we recently found that black Americans lean body mass, confirming previous oral alcohol adminis-
have lower AERs than white Americans, when doses were de- tration studies. However, women have a higher liver mass per
termined in the same manner (Beard, Thomasson, and Li, unit body weight than men, explaining the equivalent AERs
manuscript in preparation). seen when genders are compared.
The gender and ethnic differences in alcohol metabolism We conclude from these studies that liver size (and total
can be accounted for, in part, by hormonal2and enzyme-geno- alcohol-metabolizingenzyme activity in liver) is a major de-
typic difference^,^.^ respectively. However, studies in rats have terminant of AER. The gender and ethnic differences are at-
shown that liver mass and total content of alcohol-metabo- tributable in large measure to gender and ethnic differences
lizing enzymes in liver correlate directly with alcohol meta- in body mass (lean and total) relative to liver mass.
Accordingly,we have performed studies in humans
bolic rate.5*6
to determine whether liver mass (and total liver enzyme ac-
tivity, by inference) would correlate with alcohol elimination Acknowledgment
rate across gender and ethnic groups. Supported by U.S. Public Health Service grant AA02342.
In the first study,7 we analyzed autopsy findings on 614
well-nourished, healthy individuals, 21 to 29 years old, who
had died primarily from accidental causes. Age, body weight, References
height, and liver weight were recorded, and we calculated 1. Li T-K, Lumeng LL, Thomasson HR: Genetic and gender differ-
body mass index (BMI) for each person by using their height ences in alcohol consumption and metabolism, in Hunt WA, Zakhari S
and body weight. There were 352 individuals who were within (eds): Stress, Gender and Alcohol Seeking Behavior, NIAAA Research
the normal range of BMI for males (M) and females (F). This Monograph 29. Washington, DC, US Government Printing Office, 1995,
sample contained 152 white (47 F, 105 M) and 200 black sub- pp 87-100
jects (57 F, 143 M). No significant differences were found- 2. Mezey E, Oesterling JE,Potter JJ: Influence of male hormones on
with regard to age, body weight, height, or BMI-between rates of ethanol elimination in man. Hepatology 8:742-744,1988
the ethnic groups or between those of the same sex within the 3. Mizoi Y,Yamamoto K, UenoY, Fukunaga T, Harada S: Involvement
two ethnic groups. However, significant differences were found of genetic polymorphism of alcohol and aldehyde dehydrogenase in
individual variation of alcohol metabolism.Alcohol Alcohol 29:707-7 10,
for both total liver weight and liver weight per kilogram body
1994
weight. For total liver weight, white males had the highest 4. ThomassonHR,Beard JD, Li T-K: ADH2 gene polymorphisms are
mean value, followed by white females and black males and determinants of alcohol pharmacokinetics.Alcohol Clin Exp Res 19:
then by black females. On a g k g body weight basis, white 1494-1499,1995
females had the highest value, followed by white males, black 5. Hawkins RA, Nielsen RC, Veech RL: The increased rate of ethanol
females, and black males. A two-way analysis of variance re- removal from blood of clofibrate-treated rats. Biochem J 140:117-120,
vealed that whte subjects had a greater liver mass per kg body 1974
112
6. Lumeng L, Bosron WF, Li T-K: Quantitative correlation of ethanol
elimination rates in vivo with liver alcohol dehydrogenase activities in
fed, fasted and food restricted rats. Biochem Pharmacol28:1547-1551,
1979
7. Beard JD, Orr WE, Li T-K: Does liver weight play a role in the eth-
nic and gender differences in ethanol pharmacokinetics?Alcohol Clin
Exp Res 21:51A, 1997
8. Kwo PY, Ramchandani VA, Amann D, Cam LG, Sandrasegara K,
Kopecky K, Li T-K: Gender differences in alcohol metabolism are ex-
plained in part by computed liver volume and lean body mass. Alcohol
Clin Exp Res 21:51A, 1997
9. O'Connor S, Morzorati S, Christian J, Li T-K: Clamping BrAC re-
duces experimental variance: Application to the study of acute tolerance
to alcohol and alcohol elimination rate. Alcohol Clin Exp Res 22:202-210,
1998
BACTERIOCOLONIC PATHWAY FOR
ETHANOL OXIDATION
Mikko Salaspuro
Research Unit of Alcohol Diseases
University Central Hospital of Helsinki
Helsinki, Finland
Correspondence: Mikko Salaspuro, M.D.
Research Unit of Alcohol Diseases
University Central Hospital of Helsinki
Tukholmankatu 8F
00290 Helsinki, Finland
After the oral intake of alcohol, it is absorbed to the portal
blood from the stomach and upper part of the small intestine.
Thereafter, it is rapidly transported by blood circulation to
other organs, including the large bowel. Ethanol is evenly dis-
tributed to the water phase of all organs, and accordingly, after
the distribution phase, ethanol levels in the terminal ileum and
colon are equal to those of the blood and liver. There is more
and more evidence that alcohol is not merely an innocent by-
stander in the large intestine. Ethanol can be metabolized
to acetaldehyde by many intracolonic microbes and also by
colonic mucosal cells. However, compared with the liver,
the colonic oxidation of the first metabolite of ethanol-
acetaldehyde-is limited. This results in strikingly high
intracolonic levels of reactive, toxic, and carcinogenic
acetaldehyde.
The most richly colonized site of the digestive tract is the
large intestine. More than 400 different bacterial species and
1014individual bacteria inhabit a single human colon at any
given time. Accordingly, the number of intestinal bacteria is
10-fold the number of cells in the human host. The metabolic
capability of the colonic microflora has been estimated to be
at least as great as that of the liver, or even to exceed that of
the whole human body. A number of bacteria and yeast pos-
sess alcohol dehydrogenase (ADH) activity. Under anaerobic
conditions, these microbes are capable of producing energy
through fermentation. In alcoholic fermentation, the end prod-
THURMAN
uct is ethanol, which is derived from acetaldehyde in a re-
ductive reaction mediated by bacterial ADH. The reaction
runs as follows:
Alcoholic fermentation
ADH
Glucose + Acetaldehyde H Ethanol
Because of alcoholic fermentation,small amounts of ethanol
have been found in the alimentary tract and portal blood of
normal rats.
As shown above, the last reaction catalyzed by microbial
ADH in alcoholic fermentation can also run in the opposite
direction, with acetaldehyde as an end product. This reversed
microbial ADH reaction produces striking amounts of ac-
etaldehyde when human colonic contents are incubated in
vitro at 37C with increasing ethanol concentrations.2The re-
action is already active at comparatively low (10-100 mg%)
ethanol concentrations known to exist in the colon during nor-
mal Colonic acetaldehyde formation takes place at
a pH normally found in the colon, and it is rapidly reduced with
lowering of the pH? After the administration of ethanol to pigs,
intracolonic acetaldehyde levels increase in parallel with in-
creasing blood and intracolonic ethanol concentration^.^
Bacteriocolonic pathway for ethanol oxidation
bacterial, mucosal ADH
bacterial catalase
Ethanol + Acetaldehyde
mucosal or bacterial
ALDH
Acetaldehyde + Acetate
Absorption to portal blood
-+ Liver
There are marked differences in the ADH activity and
acetaldehyde-producing capacity among the aerobic bacteria
representing the normal human colonic flora." The mean cy-
tosolic ADH activity of some microbes can be up to 30 times
higher than that of the rat liver when determined under simi-
lar conditions! The highly significant positive correlation be-
tween bacterial ADH activity and the acetaldehyde-producing
capacity from ethanol strongly suggests the catalytic role of
microbial ADH in the production of acetaldehydefrom ethanol!
Alcohol dehydrogenases of the bacteria representing human
colonic flora (that have thus far been tested) show a variety of
K, values for ethanol ranging from 0.06 to 29.9 M.5 These
values are comparable to the ethanol concentrations that are
found in the large intestine during moderate drinking. Under
these circumstances, bacterial ADHs are able to metabolize
ethanol to acetaldehyde with a near-maximal velocity and, ac-
cordingly, to produce marked amounts of a~etaldehyde.~
Acetaldehyde administered intracolonically to pigs is rapidly
eliminated in association with an increase in intracolonic ac-
etate and ethanol level^.^ Obviously, intracolonicacetaldehyde
is effectively metabolized, in part, by colonic mucosal cells
and, in part, by intracolonic microbes. Indeed, many aerobic