Timeless and Stainless Alcohol: Concentric Waves from Its Oxidative Metabolism and Related Oxidative Stress

Alcohol is a molecule whose multiple effects in living organisms exemplify how profound biological complexity can arise from an exceptionally simple chemical structure interacting with the cellular biochemical machinery. This review was conceived to provide an up-to-date synthesis of the current knowledge on the multifaceted consequences of alcohol oxidative metabolism and alcohol-derived oxidative stress, ranging from disruption of subcellular and cellular homeostasis to impairment of organ function. This study primarily focuses on the consequences of alcohol metabolism and on the mechanisms by which the rise of its main metabolite, acetaldehyde, and of reactive oxygen species (ROS), generates oxidative stress by-products and molecular adducts responsible for compromising cellular energy balance and antioxidant defense mechanisms. In particular, this review aims to provide an exhaustive representation of the mechanisms, causes, and consequences of alcohol oxidative metabolism: this is accomplished by taking into account alcohol-induced modifications of gene expression of cellular antioxidant determinants, the role of epigenetic mechanisms, and that of gene polymorphisms linked to alcohol-dependent oxidative stress and responsible for serious diseases such as, among others, alcoholic hepatitis, cirrhosis, and hepatocellular carcinoma. In addition, this review highlights the role of alcohol oxidative metabolism in the brain, which, in the acute setting, activates the dopaminergic system mainly involved in alcohol reinforcing properties and, upon chronic exposure, contributes to neurodegenerative disorders. Finally, a dedicated paragraph explores autophagy as an integrative mechanism underlying the effects of alcohol-related oxidative stress across multiple organs, including the liver, heart, and brain.