A Pirot Study on Subacute Ethanol Treatment of Aldh2 Ko Mice

Abstract

-Aldh (aldehyde dehydrogenase ) 2 knockout (KO) mice have been generated in our laboratory. We evaluated the effects of subacute ethanol treatment on the survival rate, expression of Aldh1, Aldh2, Cytochrome P450 (Cyp) 1A1, Cyp2e1 and Cyp4b1 in wild (Aldh2 +/+) mice (C57BL/6) and Aldh2 knock out (Aldh2 −/−) mice. Physiological saline (0.3 mL/day) was administered to 4 Aldh2 +/+ and 4 Aldh2 −/− mice for 8 days as a control. Forty percent ethanol (0.3 mL/day; ethanol 2 g/kg/day) was then administered to 5 Aldh2 +/+ and 9 Aldh2 −/− mice for 8 days. Three mice of the ethanol administered Aldh2 +/+ group and eight mice of the ethanol administered Aldh2 −/− group died during the 8 days. The weights of mice were decreased by ethanol exposure to 85% and 74% in Aldh2 +/+ and Aldh2 −/− group, respectively. The survival rates of the ethanol administered Aldh2 +/+ and Aldh2 −/− group were 40 and 11%. Liver and pancreas disorder was revealed in the ethanol administered Aldh2 +/+ and Aldh2 −/− group in the results of serum chemical examination, immunohistochemical staining and western blot analysis. Cyp2e1 is more inducible to ethanol toxicity in Aldh2 −/− mice compared with Aldh2 +/+ mice when ethanol is administered according to the results of quantitative PCR.

Mitochondrial aldehyde dehydrogenase and cardiac diseases

“…80 As expected, these ALDH2-null mice lacked any detectable ALDH2 enzyme activity, accumulated a high level of acetaldehyde when exposed to ethanol, and were significantly more sensitive to alcohol and acetaldehyde toxicity and damage. 81–83 Surprisingly, in these ALDH2-null mice, both acute and chronic administration of ethanol seem to produce a smaller extent of oxidative stress in the liver as measured by the decreased levels of MDA, alanine aminotransferase, TNF-α in the serum and increased level of the anti-oxidant, glutathione, when compared with the wild-type ALDH mice. 84,85 The molecular mechanism for the reduction of these oxidative stress biomarkers is not clear, but may be associated with the metabolism of ethanol itself through the microsomal CYP2E1 pathway in the liver.…”

Transgenic Mouse Models for Alcohol Metabolism, Toxicity, and Cancer

“…Following oral administration of ethanol, Aldh2 −/− mice exhibit higher ethanol and acetaldehyde levels and lower acetate levels in the blood, brain and liver than Aldh2 +/+ mice [57, 58]. Further, they are more susceptible to ethanol-induced body weight loss [59], but show no change in mortality [60]. Aldh2 −/− mice are more sensitive to the toxic effects of inhaled acetaldehyde [61] and exhibit more frequent mutations in the T cell receptor site than their corresponding wild-type [62].…”

Characteristics of aldehyde dehydrogenase 2 (Aldh2) knockout mice

“…According to the study of Oyama et al (2007b), 40% ethanol (0.3 ml/day; ethanol 2 g/kg/day) was administered to five Aldh2 +/+ (wild type, C57BL/6) and nine Aldh2 −/− mice for 8 days, the weight of the mice were decreased to 85% and 74% in the Aldh2 +/+ and Aldh2 −/− groups, respectively. Compared to the control Aldh2 +/+ group, the survival rates of the Aldh2 +/+ and Aldh2 −/− groups were 40% and 11%, respectively.…”

“…Ingested ethanol is oxidized by cytosolic class I alcohol dehydrogenase 2 to acetaldehyde, which is subsequently oxidized by mitochondrial aldehyde dehydrogenase 2 to produce acetate (Agarwal and Goedde 1992;Yin 1994;Oyama et al 2007b). More than 95% of ethanol-derived acetaldehyde is oxidized by the liver mitochondrial ALDH2 (Eriksson 1977;Isse et al 2005b).…”