Abstract
Simple SummaryAlcohol consumption is a leading cause of lifestyle-induced morbidity and mortality worldwide. It is well-established that there is an association between alcohol consumption and an increased risk of colorectal cancer. Long-term alcohol consumption causes a spectrum of liver diseases, including steatosis, hepatitis, and liver cancer, and is detrimental to many other organs. In the body, alcohol can be metabolized to chemicals that exhibit biological activity, such as acetaldehyde. The intracellular accumulation of these compounds can result in suppression of antioxidant defense systems, and alterations in DNA. In addition, they can elicit changes at the tissue level, leading to reductions in nutrient absorption, inflammation, and impairment of the immune system. Together, these effects may increase the risk of cancer in a variety of organs. This review discusses the mechanisms by which alcohol may promote colorectal cancer. It is anticipated that a clearer understanding of the mechanisms by which alcohol induces cancer will facilitate the development of more effective therapeutic interventions.The etiology of colorectal cancer (CRC) is complex. Approximately, 10% of individuals with CRC have predisposing germline mutations that lead to familial cancer syndromes, whereas most CRC patients have sporadic cancer resulting from a combination of environmental and genetic risk factors. It has become increasingly clear that chronic alcohol consumption is associated with the development of sporadic CRC; however, the exact mechanisms by which alcohol contributes to colorectal carcinogenesis are largely unknown. Several proposed mechanisms from studies in CRC models suggest that alcohol metabolites and/or enzymes associated with alcohol metabolism alter cellular redox balance, cause DNA damage, and epigenetic dysregulation. In addition, alcohol metabolites can cause a dysbiotic colorectal microbiome and intestinal permeability, resulting in bacterial translocation, inflammation, and immunosuppression. All of these effects can increase the risk of developing CRC. This review aims to outline some of the most significant and recent findings on the mechanisms of alcohol in colorectal carcinogenesis. We examine the effect of alcohol on the generation of reactive oxygen species, the development of genotoxic stress, modulation of one-carbon metabolism, disruption of the microbiome, and immunosuppression.
Highlights
Colorectal cancer (CRC) is the third most common cancer diagnosed in the UnitedStates and the third leading cause of cancer-related deaths in men and in women
The mechanisms of alcohol-induced CRC are hypothesized to be through actions of ethanol metabolites—acetaldehyde, acetate, and alcohol-metabolizing enzymes
Genetic polymorphisms in ethanol-metabolizing enzymes such as ALDH2 can lead to a change in acetaldehyde production, whereas ALDH1B1 and ethanol-inducible cytochrome P450 2E1 (CYP2E1) have effects on Wnt/β-catenin signaling and the production of procarcinogens, respectively
Summary
States and the third leading cause of cancer-related deaths in men and in women. The etiology of CRC is complex, approximately 10% of individuals with CRC have predisposing germline mutations that result in familial syndromes, such as Lynch syndrome and familial adenomatous polyposis [1]. The development of sporadic CRC is likely due to a combination of environmental influences, genetic susceptibility, and immune response mechanisms. In 2020, the global incidence of alcohol-induced colon, rectal, and liver cancers were 1.0, 0.7 and 1.7 per 100,000 people, respectively [9]. The metabolism of ethanol can generate genotoxic metabolites including acetaldehyde that cause DNA mutations and oxidative stress in the colorectum that can lead to cancer. Ethanol may increase the susceptibility of tissues to carcinogenesis by activating enzymes that enable the production of procarcinogens (such as N-nitrosamines), altering the metabolism and distribution of carcinogens, interfering with the repair of carcinogenmediated DNA alkylation, suppressing the immune response to cancer stimulating cellular regeneration, and/or exacerbating dietary deficiencies [5,12]. This review aims to provide an analysis of cellular, genetic, metabolic, and microbial mechanisms by which ethanol is metabolized in the body and contributes to the development of CRC
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