Biochemical Mechanisms Associating Alcohol Use Disorders with Cancers

Abstract

The World Health Organization identifies alcohol as a cause of several neoplasias of the oropharynx cavity, esophagus, gastrointestinal tract, larynx, liver, or female breast. We review ethanol’s nonoxidative and oxidative metabolism and one-carbon metabolism that encompasses both redox and transfer reactions that influence crucial cell proliferation machinery. Ethanol favors the uncontrolled production and action of free radicals, which interfere with the maintenance of essential cellular functions. We focus on the generation of protein, DNA, and lipid adducts that interfere with the cellular processes related to growth and differentiation. Ethanol’s effects on stem cells, which are responsible for building and repairing tissues, are reviewed. Cancer stem cells (CSCs) of different origins suffer disturbances related to the expression of cell surface markers, enzymes, and transcription factors after ethanol exposure with the consequent dysregulation of mechanisms related to cancer metastasis or resistance to treatments. Our analysis aims to underline and discuss potential targets that show more sensitivity to ethanol’s action and identify specific metabolic routes and metabolic realms that may be corrected to recover metabolic homeostasis after pharmacological intervention. Specifically, research should pay attention to re-establishing metabolic fluxes by fine-tuning the functioning of specific pathways related to one-carbon metabolism and antioxidant processes.

The Status of Oxidative Stress in Patients with Alcohol Dependence: A Meta-Analysis

“…Excessive consumption can cause neuropathological symptoms [ 67 ], cardiovascular diseases [ 68 ], liver diseases [ 69 ], intestinal diseases [ 70 ], liver cancers [ 71 ], and infectious diseases due to the weakened immune system of the body [ 72 ]. The main component of alcoholic drinks is ethanol, which has shown to exert oxidative damages to biological macromolecules via acetaldehyde-DNA/RNA/protein adduct formation, thereby drastically inducing cellular ROS production and systemic OS [ 14 , 19 , 22 ]. These toxic conditions can then lead to abrupt changes in the levels of antioxidant enzymes and other forms of antioxidant molecules in the body.…”

“…The mechanistic functions of CYP2E1 and ADH reportedly produce RNS and ROS, which in turn activate downstream enzymes such as nitric oxide synthase, nicotinamide adenine dinucleotide phosphate (NADP) oxidase, and xanthine oxidase [ 17 ]. Furthermore, acetaldehyde consumes reduced glutathione (GSH), perturbing the intracellular redox balance, resulting in oxidative stress (OS) [ 22 ]. Therefore, alcohol and its toxic metabolites may be the sole cause of increased cellular burdens of ROS/RNS and other types of highly reactive free radicals and superoxides, leading to the OS injuries to the vital organs of the body [ 23 ].…”

Active molecular network discovery links lifestyle variables to breast cancer in the Long Island Breast Cancer Study Project

“…Dietary exposures have been shown to interact with each other and resultant biology linked with cancer. Mechanisms for alcohol-induced carcinogenesis suggest that one-carbon (folate) metabolism may play an important role 42 , and the formation of aldehydes and ROS that promote carcinogenesis by covalently modifying DNA, proteins, and lipids resulting in altered function 43,44 . Interestingly, alcohol consumption was shown to increase blood beta-carotene levels, likely due to interference by ethanol in its conversion to vitamin A even at moderate alcohol intake, potentially promoting carcinogenesis 45 .…”

Current View on the Mechanisms of Alcohol-Mediated Toxicity

“…In addition, lipoperoxidation products non-enzymatically react with proteins through Michael additions and Schiff base formation and generate lipid and DNA adducts. [ 110 ]. HNE has been linked to site-specific mutations of the p53 gene [ 111 ].…”

“…At the same time, unrepaired DNA adducts propagate as mutations after DNA replication. [ 110 ]. Recently, Guidolin et al [ 118 ] identified by DNA adductomic approach 22 DNA adducts in DNA exposed to acetaldehyde, and adduct levels were observed to generally increase with acetaldehyde concentration for all the detected modifications.…”