Molecular Mechanisms of Alcohol-Induced Colorectal Carcinogenesis

Abstract

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.

Keywords: ALDH1B1; CRC; CYP2E1; DNA damage; acetaldehyde; alcohol; carcinogenesis; immunosuppression; microbiome; oxidative stress.

Figure 1

Role of ethanol and its metabolism in colorectal carcinogenesis. Ethanol is metabolized to acetaldehyde by alcohol dehydrogenase (ADH), cytochrome P4502E1 (CYP2E1), and catalase. Acetaldehyde is oxidized further to acetate primarily by acetaldehyde dehydrogenases (ALDHs). Acetaldehyde promotes the generation of reactive oxygen species (ROS)/reactive nitrogen species (RNS) and the formation of DNA and protein adducts, which contribute to the initiation and growth of colorectal cancer. It also modulates one-carbon metabolism and affects DNA methylation. Acetate contributes to the pool of acetyl CoA in hypoxic cancer cells and thereby sustains the synthesis of macromolecules required for cancer growth. Ethanol oxidation by CYP2E1 generates ROS/RNS and thus increases the production of DNA and protein adducts. Red arrow indicates the induction of CYP2E1 expression by ethanol and the activation of procarcinogens. Adapted from [16].

Figure 2

Effect of CYP2E1- and acetaldehyde-mediated generation of reactive oxygen species (ROS)/reactive nitrogen species (RNS) and DNA adducts on DNA damage. Induced expression of CYP2E1 results in the oxidation of ethanol, and the formation of acetaldehyde and reactive species (ROS/RNS). Acetaldehyde inhibits DNA repair mechanism and anti-oxidative defense system (AODS) [5]. Acetaldehyde and inflammation-derived cytokines activate nuclear factor kappa-B (NF-κB) in colon cells [31]. NF-κB stimulates the expression of cyclooxygenase 2 (COX-2) and inducible nitric oxide synthase (iNOS), which promote the additional formation of ROS, RNS, and lipid peroxidation products, such trans-4-hydroxy-2-nonenal (4HNE) and malondialdehyde (MDA), that interact with DNA bases to form adducts [16,24]. N-hydroxyethyl (HE) radicals and acetaldehyde (AA) adducts are formed during ethanol metabolism. Pyrimido-[1,2-a] purin-10(3H)-one (M₁G) and MDA-acetaldehyde (MAA) adducts are generated by the reaction of DNA and protein with MDA [16,24]. Additional adducts are formed by the reaction of DNA with 4HNE. DNA adducts formed as a result of MDA and 4HNE are marked as in a rectangle. The generated DNA and protein adducts may react with DNA bases to form etheno-DNA adducts, which can promote DNA damage [5]. DNA repair mechanism refers to O6-guanine-methyltransferase and 8-oxo-guanine-DNA-glycosylateis, which are both inhibited by AA and nitric oxide (NO) [5]. Ethanol produces a nitric oxide system (iNOS) that generates NO [5]. Figure adapted from [16].

Figure 3

The influence of alcohol consumption on one-carbon metabolism. A schematic representation of the impact of ethanol on the main components of one-carbon metabolism (1CM) consists of three interlinked modules, folate and methionine cycles, and the transsulfuration pathway. Ethanol decreases the bioavailability of folate, a crucial “fuel” in 1CM. This is thought to occur by reducing the uptake of dietary folate and inhibiting enzymes involved in the folate cycle [102,103,104]. Ethanol inhibits methionine synthase (MS/MTR) [105] causing hyperhomocysteinemia and disrupts the production of S-adenosyl-methionine (SAM), a global methyl donor. Ethanol may also lower SAM production in a more direct manner by inhibiting methionine S-adenosyltransferase (MAT). DNA methyltransferases (DNMTs) and histone methyltransferases (HMTs) can also be inhibited by ethanol to result in DNA and histone hypomethylation, which would affect gene regulation and expression. This would have a resultant effect on decreasing cellular glutathione levels, augmented by the inhibitory effects of ethanol on cystathionine-β-synthase (CBS) and cystathionine-γ-lyase L (CGL) indicated with red arrow. The resulting elevated levels of ROS and RNS would increase the oxidative and nitrosative damage, further diverting 1CM away from SAM production to augment hypomethylation [106]. Genetic polymorphisms in methylenetetrahydrofolate reductase (MTHFR) can alter THF production [16]. Alcohol consumption can decrease THF production by inhibiting MTHFR [16]. Enzymes are shown in green text and metabolites in black text. DHF: dihydrofolate, THF: tetrahydrofolate, DHFR: dihydrofolate reductase, 5,10-meTHF: 5,10-methylenetetrahydrofolate, 5-meTHF: 5-methylenetetrahydrofolate, MTHFR: methylenetetrahydrofolate reductase, SAH: S-adenosyl-homocysteine. Figure adapted from [16].