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Alcohol metabolism's various processes create harmful compounds that contribute to cell and tissue damage. In particular, the enzyme cytochrome P450 2E1 (CYP2E1) plays a role in creating a harmful condition known as oxidative stress. This condition is related to oxygen's ability to accept electrons and the subsequent highly reactive and harmful byproducts created by these chemical reactions. CYP2E1's use of oxygen in alcohol metabolism generates reactive oxygen species, ultimately leading to oxidative stress and tissue damage. KEY WORDS: Ethanol metabolism; alcohol liver disorder; toxicity; mitochondria; alcohol dehydrogenase; acetaldehyde; cytochrome P450 2E1 (CYP2E1); oxidative stress; reactive oxygen species (ROS); superoxide
Alcohol is processed in the body through various metabolic path-ways, producing toxic byprod-ucts that contribute to cell and tissue damage. This article examines alcohol metabolism in the liver by the enzyme cytochrome P450 2E1 (CYP2E1) and the role of this enzyme in creating a harmful condition known as oxidative stress. (For an overview of the other metabolic pathways by which alcohol is broken down, see the article by Zakhari in this issue.) The toxicological significance of CYP2E1 was first appreciated when it was shown that this enzyme was responsible for the metabolism of many compounds to toxic products, and the toxicity was increased after synthesis of the enzyme was induced. In addition, researchers have found that CYP2E1 is associated with an increase in the reaction by which oxygen gains an electron (i.e., reduction of oxygen), which creates compounds referred to as reactive oxygen species (ROS), that can damage other cellular molecules. Furthermore, research with alcohol (i.e., ethanol)-treated animals has shown that CYP2E1 increases the chemical damage done by reactive molecules called free radicals to the lipid components of cell membranes (i.e., lipid peroxidation) in liver cells (Dey and Cederbaum 2006). Results from animal studies have shown a strong correlation between the level of CYP2E1 in the liver and the degree of alcohol-induced liver injury. That is, when the level of CYP2E1 is high there is more extensive lipid peroxidation, which is reduced by inhibiting CYP2EI induction. To understand how the expression of this enzyme can generate oxidative stress, it is useful first to understand how oxygen functions as an acceptor of electrons in the body and how P450 uses oxygen in alcohol metabolism.
OXIDATIVE STRESS