Sex differences, alcohol dehydrogenase, acetaldehyde burst, and aversion to ethanol in the rat: a systems perspective.
Individuals who carry the most active alcohol dehydrogenase (ADH) isoforms are protected against alcoholism. This work addresses the mechanism by which a high ADH activity leads to low ethanol intake in animals. Male and female ethanol drinker rats (UChB) were allowed access to 10% ethanol for 1 h. Females showed 70% higher hepatic ADH activity and displayed 60% lower voluntary ethanol intake than males. Following ethanol administration (1 g/kg ip), females generated a transient blood acetaldehyde increase ("burst") with levels that were 2.5-fold greater than in males (P < 0.02). Castration of males led to 1) an increased ADH activity (+50%, P < 0.001), 2) the appearance of an acetaldehyde burst (3- to 4-fold vs. sham), and 3) a reduction of voluntary ethanol intake comparable with that of naïve females. The ADH inhibitor 4-methylpyrazole blocked the appearance of arterial acetaldehyde and increased ethanol intake. Since the release of NADH from the ADH.NADH complex constitutes the rate-limiting step of ADH (but not of ALDH2) activity, endogenous NADH oxidizing substrates present at the time of ethanol intake may contribute to the acetaldehyde burst. Sodium pyruvate given at the time of ethanol administration led to an abrupt acetaldehyde burst and a greatly reduced voluntary ethanol intake. Overall, a transient surge of arterial acetaldehyde occurs upon ethanol administration due to 1) high ADH levels and 2) available metabolites that can oxidize hepatic NADH. The acetaldehyde burst is strongly associated with a marked reduction in ethanol intake.
Quintanilla
María Elena
ME
Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile.
Tampier
Lutske
L
Sapag
Amalia
A
Gerdtzen
Ziomara
Z
Israel
Yedy
Y
D000079:Acetaldehyde / Q000097:blood* / Q000378:metabolism; D000426:Alcohol Dehydrogenase / Q000235:genetics* / Q000378:metabolism*; D000428:Alcohol Drinking / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000431:Ethanol / Q000097:blood / Q000494:pharmacology*; D005260:Female; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D009919:Orchiectomy; D051381:Rats; D017208:Rats, Wistar; D012727:Sex Characteristics
D000431:Ethanol; D000426:Alcohol Dehydrogenase; D000079:Acetaldehyde