CYP2E1 is represented by the heme iron in the blue ovals. When CYP2E1 uses oxygen to metabolize alcohol, reactive oxygen species (ROS) can be generated by the following chain of events: ethanol binds to the enzyme (step 1). As the first electron is passed to the heme of CYP2E1 and oxygen is bound (step 2), the electron can move and exist on the oxygen, essentially generating superoxide bound to the heme of CYP2E1 (step 3). Occasionally, the superoxide will break down, releasing free superoxide and generating the starting enzyme. If the second electron is added to the enzyme (step 4), then a second form of reduced oxygen is produced that is identical to a heme-bound form of the twoelectron– reduced oxygen (i.e., peroxide) (step 5). When this product breaks down, it picks up two hydrogens to generate hydrogen peroxide. The production of these ROS by CYP2E1 is referred to as an “uncoupled reaction” because the oxygen does not end up in the substrate. If the reduced oxygen species remains bound, then the enzyme will transfer one oxygen atom to the substrate and the other atom becomes water, producing an unstable intermediate (i.e., a gem-diol) product that decomposes to acetaldehyde (step 6).

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Prepared: December 2008