Two reactions (phase I and II), catalyzed by different enzyme systems, are involved in the conversion of xenobiotics and drugs into hydrophilic compounds. In phase I reactions, the parent compound is biotransformed into more polar compounds by the introduction of one or more polar groups. The common polar groups are hydroxyl (OH) and carboxyl (COOH). Most phase I reactions involve oxidation of the parent compound. The enzymes involved are mostly located in the smooth ER; some are located in the cytoplasm. For example, alcohol dehydrogenase is located in the cytoplasm of hepatocytes and catalyzes the rapid conversion of alcohol to acetaldehyde. It may also play a role in the dehydrogenation of steroids.
The enzymes involved in phase I reactions of drug biotransformation are present as an enzyme complex composed of the NADPH-cytochrome P450 reductase and a series of hemoproteins called cytochrome P450 (Fig. 28.2). The drug combines with the oxidized cytochrome P450+3 to form the cytochrome P450+3-drug complex. This complex is then reduced to the cytochrome P450+2-drug complex, catalyzed by the enzyme NADPH-cytochrome P450 reductase. The reduced complex combines with molecular oxygen to form an oxygenated intermediate. One atom of the molecular oxygen
then combines with two H+ and two electrons to form water. The other oxygen atom remains bound to the cytochrome P450+3-drug complex and is transferred from the cytochrome P450+3 to the drug molecule. The drug product with an oxygen atom incorporated is released from the complex. The cytochrome P450+ 3 released can then be recycled for the oxidation of other drug molecules.
In phase II reactions, the phase I reaction products undergo conjugation with several compounds to render them more hydrophilic. Glucuronic acid is the substance most commonly used for conjugation, and the enzymes involved are the glucuronyltransferases. Other molecules used in conjugation are glycine, taurine, and sulfates.
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This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.