User:Egraham1001/Alcohol and cancer

Introduction
Alcoholic beverages were classified as a Group 1 carcinogen by the International Agency for Research on Cancer (IARC) in 1988 and are attributed to 740,000 cases of cancer in 2020 or 4.1% of new cancer cases. Heavy drinking consisting of 15 or more drinks per week for men or 8 or more drinks per week for women beverages/week contributed the most to cancer incident compared with moderate drinking. The rate of alcohol related cases is 3:1 in males compared with females, especially in oesophageal, and liver cancers. Breast cancer is also related to alcohol consumption in women. IARC additionally classifies alcoholic beverage consumption as a cause of Oesophagus, Liver, female breast, colon, Oral cavity, Rectum, Pharynx and Larynx cancers and as a probable cause of pancreatic cancer.

3.6% of all cancer cases and 3.5% of cancer deaths worldwide are attributable to consumption of alcohol (specifically, acetaldehyde a derivative of ethanol).

Alcohol is thought to cause cancer through three main mechanisms:


 * 1) DNA methylation
 * 2) Oxidative stress
 * 3) Hormonal alteration

as well as secondary mechanisms of Liver cirrhosis, Microbiome Dysbiosis, reduced immune system function, Retinoid metabolism, Increased levels of inflammation, 1-Carbon metabolism and disruption of folate absorption.

Some nations have introduced alcohol packaging warning messages that inform consumers about alcohol and cancer.

The alcohol industry has tried to actively mislead the public about the risk of cancer due to alcohol consumption, in addition to campaigning to remove laws that require alcoholic beverages to have cancer warning labels.

Acetaldehyde
Acetaldehyde is a byproduct of ethanol breakdown in the liver, metabolized by Alcohol dehydrogenase (ADH), Cytochrome P-450 2E1 and bacterial catalases. The liver then normally eliminates 99% of the acetaldehyde. ALDH2 converts Acetaldehyde into acetate which is a byproduct that can be excreted through the liver. Those with ADH1B*1 have higher rates of conversion of ethanol into Acetaldehyde while, people with ALDH2*2 have a slower conversion rate of acetaldehyde to acetate causing faster build up of acetaldehyde concentrations. 28-45% of east asian populations carry the ALDH2*2 allele. An average liver can process 7 grams of ethanol per hour. For example, it takes 12 hours to eliminate the ethanol in a bottle of wine, giving 12 hours or more of acetaldehyde exposure.

The Acetaldehyde motif can bind DNA to alter its physical shape or block repair and synthesis mechanisms to induce mutations, breaks and exchanges. Acetaldehyde and Ethanol both inhibit S-adenosyl-L-methiodine (SAMe) synthesis which is a methyl group transferase.

DNA Methylation:
DNA Methylation is the addition of a methyl group to the the carbon-5 of nucleotides. the most common methylation site is onto a cystine preceding guanine nucleotides. This methylation is catalyzed by DNA methyltransferase enzymes taking a methyl group from SAMe. Heavy alcohol consumption is thought to cause epigenetic changes by decreasing the availability of SAMe thereby changing the methylation pattern of DNA causing hypo or hypermethylation resulting in alteration of DNA transcription.

Oxidative Stress
Oxidative stress and ROS accumulation is a major player in cancer growth. the metabolism of ethanol by CYP450 2E1 into acetaldehyde has a byproduct of ROS. The presence of ROS in the cellular environment causes lipid peroxidation which can lead to exocyclic adducts. ROS in a tumor microenvironment can also act as an intercellular signal leading to up-regulation of vascular endothelial growth factors and monocyte chemotactic protein-1. The accumulation of iron is also found to correlate to alcohol consumption which leads to higher levels of peroxidation and resulting oxidative damage.

Hormonal regulation
High levels of hormones in serum have been associated with heavy alcohol use. Especially Oesterogen and estradiol which can increase transcriptional activity in ER+ cells which promote cell proliferation. Those in pre-menopause using progestin contraceptives have some compensation for the high levels of estradiol, though after menopause those with heavy alcohol consumption have higher risk for breast cancer and estrogen dependent cancers.

Other mechanisms
Additional mechanisms contribute to cancer risk with alcohol consumption. It is thought that heavy alcohol consumption can cause a decrease in folic acid availability which can decrease the availability of nucleotides for DNA repair. Additionally ethanol can decrease the conversion of homocysteine to methionine which is an essential amino acid that is part of the formation of SAMe.

Increased inflammation due to alcohol consumption can increase various cytokine formations especially NF-κB which is a transcription factor.

Additionally Alcohol usage is associated with lower Vitamin A levels which causes a reduction in retinoid conversion and signaling.

Individuals who both smoke and drink are at a much higher risk of developing mouth, tracheal, and esophageal cancer. Ethanol is thought to potentially be a solvent for carcinogenic factors in smoking. Research has shown their risk of developing these cancers is 35 times higher than in individuals who neither smoke nor drink. This evidence may suggest that there is a cocarcinogenic interaction between alcohol and tobacco-related carcinogens.