Main Enzymes in Alcohol Metabolism
Alcohol (ethanol) is primarily metabolized in the liver through oxidative pathways. The key enzymes are alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH), and cytochrome P450 2E1 (CYP2E1). ADH converts ethanol to acetaldehyde, ALDH then turns acetaldehyde into acetate, and CYP2E1 handles a minor pathway, especially at high alcohol levels.[1][2]
How ADH and ALDH Work Step by Step
ADH, mainly the class I isozymes (ADH1A, ADH1B, ADH1C), uses NAD+ as a cofactor to oxidize ethanol to toxic acetaldehyde in the cytosol. ALDH, particularly mitochondrial ALDH2, follows by oxidizing acetaldehyde to acetate using NAD+ again. Genetic variants like ALDH2*2 reduce activity, causing acetaldehyde buildup and flushing in some East Asians.[1][3]
Role of CYP2E1 in Heavy Drinking
CYP2E1 in the endoplasmic reticulum metabolizes about 10% of ethanol at low doses but ramps up to 20-30% during chronic heavy use. It generates reactive oxygen species, contributing to liver damage like fatty liver or cirrhosis.[2][4]
Minor Pathways and Catalase
Catalase in peroxisomes breaks down ethanol via hydrogen peroxide but accounts for less than 5% of metabolism. Microsomal ethanol oxidizing system (MEOS), driven by CYP2E1, overlaps here. These alternatives activate under induction from repeated exposure.[1][2]
Genetic Variations and Risks
Polymorphisms in ADH1B and ALDH2 alter metabolism speed. Fast ADH variants increase acetaldehyde exposure risk, while slow ALDH raises toxicity. This explains varying alcohol tolerance and links to alcoholism or cancer risks.[3][5]
Factors Affecting Enzyme Activity
Inducers like chronic alcohol boost CYP2E1. Inhibitors such as disulfiram block ALDH, causing aversion therapy buildup. Age, sex, and liver disease slow overall metabolism.[4]
Sources
[1]: National Institute on Alcohol Abuse and Alcoholism (NIAAA) - Alcohol Metabolism
[2]: Cederbaum AI. Alcohol Metabolism. Clin Liver Dis. 2012
[3]: Edenberg HJ. The genetics of alcohol metabolism. Hum Genet. 2007
[4]: Lieber CS. Cytochrome P-4502E1. Am J Med. 1999
[5]: Brooks PJ et al. The alcohol flushing response. PLoS Med. 2009