*2.3.1 Mechanisms*

The colon is one of the major organs for the distribution of orally ingested alcohol, making intracolonic level of ethanol to be equal to that of the blood level [11, 12]. At elevated level, ethanol it is converted to acetaldehyde (a known carcinogen) by colorectum cytochrome P450 2E1 (CYP 2E1), as its activity is also expressed in the colon and rectum alongside other tissues (**Figure 2**) [13]. This carcinogen, classified as group 1 carcinogen to humans by the International Agency for Research on Cancer (IARC), induces oxidative stress through an increase in the production of reactive oxygen species (ROS), as against cellular antioxidant defense system [9]. Reactive oxygen species can lead to lipid peroxidation, protein modification or bind to DNA to form carcinogenic adducts; hence, inhibition of DNA synthesis and repair mechanism, alteration in structure and function of glutathione. These could therefore, increase the proliferation of colonic mucosal [8].

### **Figure 2.** *Metabolism of ethanol by intracolonic bacteria and role in colorectal carcinogenesis.*

Ethanol is also oxidized by bacterial alcohol dehydrogenase and catalase (expressed in the colon by colonic microbiota) to produce acetaldehyde in the colorectum [14, 15].

Acetaldehyde is therefore, accumulated in the colon (due to low activity of bacterial aldehyde dehydrogenase, which converts acetaldehyde to acetate in the colonic mucosa), and colorectal carcinogenesis is enhanced by binding to DNA and form carcinogenic DNA adducts [9, 11].

Alcohol can also act as a solvent for other dietary or environmental carcinogens into the mucosal cells, thereby inhibiting the metabolism of hormones, production of prostaglandins and lipid peroxidation [6].

Intracolonic ethanol is converted to acetaldehyde by colorectum cytochrome P450 2E1 (CYP2E1), alcohol dehydrogenase (ADH) and catalase, and the acetaldehyde is converted to acetate by aldehyde dehydrogenase (ALDH), while its accumulation results in carcinogenic DNA adducts, lipid peroxidation (LPO) or protein modification, and stimulates colorectal carcinogenesis.

### **2.4 Cigarette/tobacco smoking**

Compounds such as acetaldehyde, aromatic amines, benzo[a]pyrene, N-nitrosamines, aromatic amines, and polycyclic aromatic hydrocarbons are carcinogens found in cigarette smoke. Nicotine and nicotine-derived nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, are known compounds present in tobacco smoke that enhance CRC metastasis by promoting cell migration and transformation of epithelial–mesenchyma [16]. These compounds could also form DNA adducts and bind to DNA, thereby causing gene mutation [17] or induce gut microbiota dysbiosis leading to colorectal carcinogenesis.

### *2.4.1 Mechanisms*

Cigarette smoking could promote colorectal carcinogenesis due to alteration, imbalance, or disruption in gut microbiota composition (gut microbiota dysbiosis), leading to increase in stool and colonic levels of taurodeoxycholic acid (TDCA), a secondary bile acid. These changes could lead to activation of signaling pathways such as mitogen-activated protein kinase/extracellular signal-regulated protein kinase 1/2 (MAPK/ERK), interleukin 17 (IL-17) and tumour necrosis factor (TNF) in colonic epithelium, thereby promoting colonocyte proliferation [18]. Epigenetic modifications such as high microsatellite instability (MSI-H), the CpG island methylator phenotype, and the BRAF V600E mutation may reduce survival rate of CRC patient, as these have been reported to be functionally involved in colorectal carcinogenesis related to tobacco smoking. These modifications may result from (1) mutation of the glutathione S-transferase Mu 1 (GSTM1) gene, which results in impairment in the detoxification of tobacco carcinogens, thereby enhancing of carcinogenesis; (2) induction of aberrant promoter DNA methylation and silencing regulatory genes involved in tumor progression [16].

### **2.5 Animal fats**

Studies, although limited, have linked intake of animal fats to CRC risk. A diet high in animal fats affects colonic microbiome leading to intestinal inflammation, thereby increasing the risk of CRC.
