Colorectal Cancer and Alcohol Consumption-Populations to Molecules

Abstract

Colorectal cancer (CRC) is a major cause of morbidity and mortality, being the third most common cancer diagnosed in both men and women in the world. Several environmental and habitual factors have been associated with the CRC risk. Alcohol intake, a common and rising habit of modern society, is one of the major risk factors for development of CRC. Here, we will summarize the evidence linking alcohol with colon carcinogenesis and possible underlying mechanisms. Some epidemiologic studies suggest that even moderate drinking increases the CRC risk. Metabolism of alcohol involves ethanol conversion to its metabolites that could exert carcinogenic effects in the colon. Production of ethanol metabolites can be affected by the colon microbiota, another recently recognized mediating factor to colon carcinogenesis. The generation of acetaldehyde and alcohol's other metabolites leads to activation of cancer promoting cascades, such as DNA-adduct formation, oxidative stress and lipid peroxidation, epigenetic alterations, epithelial barrier dysfunction, and immune modulatory effects. Not only does alcohol induce its toxic effect through carcinogenic metabolites, but alcoholics themselves are predisposed to a poor diet, low in folate and fiber, and circadian disruption, which could further augment alcohol-induced colon carcinogenesis.

Keywords: CRC; alcohol; epigenetics; immunity; metabolism; polyposis.

Figure 1

The majority of ethanol metabolism is oxidative where carcinogenic acetaldehyde is produced via alcohol dehydrogenase (ADH), CYP2E1, or bacterial catalases. The acetaldehyde is reduced by being converted to acetic acid by aldehyde dehydrogenase (ALDH), CYP2E1, or the combination of aldehyde oxidase (AO) and xanthine oxidase (XO). Conversion with CYP2E1 tends to produce reactive oxygen species (ROS), adding to carcinogenesis. Polymorphisms in the ADH and ALDH enzymes increase acetaldehyde concentrations (red arrow). Non-oxidative metabolism leads to the production of metabolites using various types of molecules. In the case of nucleotides, EtG and EtS are produced. For lipids, PEth and FAEE are produced. EtS = ethyl sulfate; SULT = sulfotransferase; PAP Sulfate = 3′-phosphoadenosine-5′-phospho sulfate; PEth = phosphatidylethanol; PC = phosphatidylcholine; PLD = phospholipase D.

Figure 2

Ethanol indirectly interferes with DNA integrity by affecting key points (labeled in red) or enzymes in folate metabolism. From these key points, DNA synthesis and methylation are hindered. A reduction in folic acid levels decreases all reactions in the above pathway. Reducing methionine synthase (MTR) activity inhibits both DNA synthesis and DNA methylation. Reducing methionine synthase (MAT) and DNA methyltransferase (DNMT) activities inhibits DNA methylation.

Figure 3

Genetic abnormality, epigenetic dysregulation, cell signaling, and the tumor microenvironment are the hallmark effects that ethanol produces to instigate colorectal carcinogenesis. These hallmark mechanisms interact and lead into each other to further increase the carcinogenic state.