Dose and time changes in liver alcohol dehydrogenase (ADH) activity during acute alcohol intoxication involve not only class I but also class III ADH and govern elimination rate of blood ethanol.
BACKGROUND
The elimination rate of blood ethanol usually depends on the activity of liver alcohol dehydrogenase (ADH). During acute alcohol intoxication, however, it is unclear how liver ADH activity changes with dose and time and what the involvement is of the two major isozymes of liver ADH: the classically known class I ADH and the very high Km class III ADH. We investigated dose- and time-wise changes in liver ADH activity and the contents of both ADHs by administering ethanol to mice, and analyzed the relationship among these ADH parameters to assess the contributions of these ADHs to liver ADH activity and ethanol metabolism in vivo.


METHODS
Mice were given ethanol doses of 0, 1, 3 or 5 g/kg body weight and killed 0.5, 1, 2, 4, 8 or 12 h after administration. The elimination rate of blood ethanol was calculated from the regression line fitted to the blood ethanol curve. The liver ADH activity of crude extract was conventionally measured with 15 mM ethanol as a substrate. The liver class I and class III ADH contents were determined by enzyme immunoassay. These three ADH parameters were statistically analyzed.


RESULTS
The change in liver ADH activity depended on both dose and time (P<0.001 by two-way ANOVA, n=74), but the change in the class I content depended on dose alone (P<0.0001). The class III content depended on both dose and time (P<0.001) with a time course similar to that of liver ADH activity for each dose. The sum of the class I and class III contents exhibited a higher correlation with liver ADH activity (r=0.882, P<0.0001) than the class I content alone did (r=0.825). The mean liver ADH activity during ethanol metabolism for each dose correlated significantly with the elimination rate of blood ethanol (r=0.970, P<0.0001).


CONCLUSIONS
Liver ADH activity changes dose and time dependently during acute alcohol intoxication and governs the elimination rate of blood ethanol through the involvement not only of class I but also of class III ADH.
Haseba
Takeshi
T
Department of Legal Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-Ku, Tokyo 113-8602, Japan. hasebat@nms.ac.jp
Tomita
Yukari
Y
Kurosu
Mitsuyasu
M
Ohno
Youkichi
Y
D000426:Alcohol Dehydrogenase / Q000378:metabolism*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000097:blood* / Q000378:metabolism / Q000506:poisoning; D007527:Isoenzymes / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D013997:Time Factors
D007527:Isoenzymes; D000431:Ethanol; D000426:Alcohol Dehydrogenase