Acetaldehyde-induced mitochondrial dysfunction sensitizes hepatocytes to oxidative damage

Abstract

Acetaldehyde (Ac), the main metabolite of ethanol oxidation, is a very reactive compound involved in alcohol-induced liver damage. In the present work, we studied the effect of Ac in mitochondria functionality. Mitochondria from Wistar rats were isolated and treated with Ac. Ac decreased respiratory control by 50% which was associated with a decrease in adenosine triphosphate content (28.5%). These results suggested that Ac could be inducing changes in cell redox status. We determined protein oxidation, superoxide dismutase (SOD) activity, and glutathione ratio, indicating that Ac induced an enhanced oxidation of proteins and a decrease in SOD activity (90%) and glutathione/oxidized GSH ratio (36%). The data suggested that Ac-induced oxidative stress mediated by mitochondria dysfunction can lead to cell sensitization and to a second oxidative challenge. We pretreated hepatocytes with Ac followed by treatment with antimycin A, and this experiment revealed a noticeable decrease in cell viability, determined by neutral red assay, in comparison with cells treated with Ac alone. Our data demonstrate that Ac impairs mitochondria functionality generating oxidative stress that sensitizes cells to a second damaging signal contributing to the development of alcoholic liver disease.

Protective Role of HO-1 for Alcohol-Dependent Liver Damage

“…It is generally accepted that lipid peroxidation, altered immune responses and antioxidant defenses play an important role in the pathogenesis of ethanol-induced cellular injury, as patients suffering from ALD show enhanced lipid peroxidation, protein carbonyl formation, production of the reactive products acetaldehyde [3] and 1-hydroxyl ethyl radical as well as lipid radicals. This goes along with mobilization of iron [4], induction of CYP2E1 [5] and reduction of antioxidant enzymes and chemicals, particularly mitochondrial and cytosolic glutathione (GSH) [6], representing a dysbalance between the cells’ ROI production and its own cellular defense mechanisms, consisting of various enzymatic and non-enzymatic mechanisms.…”

Regulation of Cytochrome P450 2E1 expression by ethanol: Role of oxidative stressmediated PKC/JNK/SP1 pathway

“…ARE, anti-oxidant response element; Nrf2, nuclear factor-E2-related factor 2; SMAF, small molecule activation factor acetaldehyde. 4 In addition to ROS, which is known to damage DNA and protein, acetaldehyde is associated with decreased DNA repair, impaired hepatic utilization of oxygen, and an increase of glutathione depletion. 4 Accumulation of acetaldehyde is known to have a key role in ethanol-induced brain damage.…”

“…4 In addition to ROS, which is known to damage DNA and protein, acetaldehyde is associated with decreased DNA repair, impaired hepatic utilization of oxygen, and an increase of glutathione depletion. 4 Accumulation of acetaldehyde is known to have a key role in ethanol-induced brain damage. 34 As ADH is not involved in alcohol metabolism in the brain, 10 CYP2E1 appears to have the dominant role in ethanol-mediated brain damage.…”

“…4 Low levels of alcohol in occasional or social mild-tomoderate drinkers are metabolized mainly by alcohol dehydrogenase (ADH), which also appears to cause oxidative stress-mediated liver toxicity.…”

“…3 The alcohol metabolism-mediated liver toxicity occurs through the formation of reactive oxygen species (ROS) and the reactive metabolite, acetaldehyde, which ultimately cause DNA damage and lipid and protein oxidations. 4 Low levels of alcohol in occasional or social mild-tomoderate drinkers are metabolized mainly by alcohol dehydrogenase (ADH), which also appears to cause oxidative stress-mediated liver toxicity. 5 However, alcohol-inducible CYP2E1 also has an important role in alcohol metabolism and mediate liver impairment among variety of alcohol drinkers.…”