The effect of acute alcohol exposure on hepatic oxidative stress and function: prevention by micronutrients

Alcohol binge drinking, especially in teenagers and young adults is a major

public health issue in the UK, with the number of alcohol related liver disorders steadily increasing. Understanding the mechanisms behind liver disease

arising from binge-drinking and finding ways to prevent such damage are

currently important areas of research. In the present investigation the effect of acute ethanol administration on hepatic oxidative damage and apoptosis was

examined using both an in vivo and in vitro approach; the effect of micronutrient supplementation prior and during ethanol exposure was also studied. The

following studies were performed: (1) ethanol administration (75 mmol/kg body

weight) and cyanamide pre-treatment followed by ethanol to study elevated

acetaldehyde levels with liver tissue analysed 2.5, 6 and 24 hours post-alcohol; (2). Using juvenile animals, 2% betaine supplementation followed by acute

ethanol with tissue analysed 24 hrs post ethanol; and (3). Micronutrient

supplementation during concomitant ethanol exposure to hepG2 cells. It was

found that a single dose of alcohol caused oxidative damage to the liver of rats at 2.5 hr post-alcohol as evidenced by decreased glutathione levels and

increased malondialdehyde levels in both the cytosol and mitochondria. Liver

function was also depressed but there were no findings of apoptosis as

cytochrome c levels and caspase 3 activity was unchanged. At 6 hours, the

effect of ethanol was reduced suggesting some degree of recovery, however,

by 24 hours, increased mitochondrial oxidative stress was apparent. The effect

of elevated acetaldehyde on hepatic damage was particularly evident at 24

hours, with some oxidative changes at earlier time points. At 24 hours,

acetaldehyde caused a profound drop in glutathione levels in the cytosol and

hepatic function was still deteriorating. Studies examining ethanol exposure to

juvenile livers showed that glutathione levels were increased, suggesting an

overtly protective response not seen in with older animals. It also showed that

despite cytochrome c release into the cytosol, caspase-3 levels were not

increased. This suggests that ATP depletion is preventing apoptosis initiation.

Betaine supplementation prevented almost all of the alcohol-mediated changes,

suggesting that the main mechanism behind alcohol-mediated liver damage is

oxidative stress. Results using the hepG2 cell line model showed that

micronutrients involved in glutathione synthesis can protect against hepatocyte

damage caused by alcohol metabolism, with reduced reactive oxygen species

and increased/maintained glutathione levels. In summary, these results

demonstrate that both acute alcohol and acetaldehyde can have damaging

effects to the liver, but that dietary intervention may be able to protect against ethanol induced oxidative stress.