Metabolism of Xenobiotics

Abstract

The action of most xenobiotics ends in either excretion or metabolic inactivation. Some compounds, on the other hand, require metabolic activation before they can exert any biological action. In most cases these biotransformations, activations as well as inactivations, are carried out by specialized enzyme systems. The essential role of these enzymes is to facilitate elimination of xenobiotics. Water-soluble compounds usually do not need to be metabolized, as they can be excreted in their original forms. Lipophilic compounds can be disposed of through biliary excretion, or they may undergo metabolism to become more polar and thus more water-soluble so that they can be disposed of through the kidneys. The metabolism of xenobiotics is usually carried out in two phases. Phase 1 involves oxidative reactions in most cases, whereas phase 2 involves conjugation (combination) with highly water-soluble moieties. Occasionally the products of biotransformation are unstable and decompose to release highly reactive compounds such as free radicals, strong electrophiles, or highly stressed three-member rings (epoxides, azaridines, episulfides, and diazomethane; Figure 3.1) that have a tendency toward nucleophilic ring opening. For order to be retained within the cells, the chemical reactions have to occur through enzymatic processes in which the substrate is activated while bound to the enzyme. Only after the desired reaction takes place is a stable product released. Freely roaming reactive compounds are not welcome in a living organism because they react randomly with macromolecules such as DNA, RNA, and proteins. Alteration of DNA leads to faulty replication and transcription. Alteration of RNA causes faulty messages that, in turn, lead to the synthesis of abnormal proteins and thus alter enzymatic and regulatory activity. Phase 1 processes are carried out by a series of similar enzymes (commonly designated as mixed-function monooxidases) or cytochrome P-450. The basic reactions catalyzed by cytochrome P-450 enzymes involve introduction of oxygen into a molecule. In most cases the oxygen is retained, but sometimes it is removed from the end product. The oxygen carrier is a prosthetic group containing porphyrin-bound iron. The overall reaction catalyzed by these enzymes is hydroxylation.