Alcohol metabolism's damaging effects on the cell: a focus on reactive oxygen generation by the enzyme cytochrome P450 2E1

Alcohol Research & Health,  Winter, 2006  by Dennis R. Koop

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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

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Alcohol is processed in the body through various metabolic pathways, producing toxic byproducts 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

Oxidative stress occurs in the presence of an excess of reactive molecules called free radicals or a lack of molecules that can eliminate free radicals (i.e., antioxidants). Free radicals are highly reactive molecules that interact with other cellular structures. They contain unpaired electrons and therefore seek to obtain other electrons so that a stable pair is produced. For example, oxygen has two unpaired electrons. As the ultimate electron acceptor in cellular metabolism for organisms that use oxygen (i.e., aerobic organisms), oxygen can accept four electrons before becoming a neutral molecule (i.e., it can be reduced by four electrons). The intermediate steps to give the final four-electron-reduced molecule produces ROS. Figure 1 shows this process and its products. An increase in free radicals usually is the result of an increased reduction of oxygen to ROS, which can react with other cellular molecules. Recent reviews (Lieber 2004; Gonzalez 2005; Dey and Cederbaum 2006) have examined the mechanisms of alcohol-induced damage resulting from the generation of these reactive species.

Superoxide. The addition of one electron to oxygen (i.e., a one-electron reduction of oxygen) produces superoxide, abbreviated [O.sub.2.sup.-[dot]]. The dot indicates a radical species, and superoxide is usually shown with a negative sign, indicating that it carries a charge of negative one as a result of the one-electron reduction. Superoxide can either accept an electron (i.e., it can act as an oxidant) or it can donate the extra electron to another molecule (i.e., it can act as a reductant). Superoxide radicals are formed most often in the part of the cell called the mitochondria during normal cellular energy-producing processes and, to a much lower extent, in the fluid of the cell (i.e., cell cytosol). Cells also have enzymes called superoxide dismutases. These enzymes are among the first line of defense in the detoxification of products resulting from oxidative stress. They convert superoxide radicals to hydrogen peroxide and protect the cell from high concentrations of this one-electron-reduced form of oxygen. One form of the enzyme, a copper/zinc (Cu/Zn) superoxide dismutase, is present in the cytosol; manganese (Mn) superoxide dismutase is present in the mitochondria. If the concentration of superoxide becomes too high, it can participate in the formation of the highly reactive hydroxyl radical (H[O.sup.[dot]]). Superoxide does this by donating the extra electron to metal ions (for example, ferric iron or [Fe.sup.3+]) that then can act as the catalyst to convert hydrogen peroxide into the hydroxyl radical (H[O.sup.[dot]]).