The Phase Concept of Drug Metabolism and Its Importance for Toxification versus Detoxification

The phase concept of drug metabolism is described elsewhere in this book (see 5.05 Principles of Drug Metabolism 1: Redox Reactions; 5.06 Principles of Drug Metabolism 2: Hydrolysis and Conjugation Reactions). With respect to toxification versus detoxification it is important that depending on their chemical nature the functional groups introduced in the phase I of drug metabolism can be classified as electrophilic or nucleophilic (Figure 1). Functional groups with an electrophilic carbon are, for example, epoxides or a,b-unsaturated carbonyl groups. Nucleophilic substituents are, for example, hydroxyl, amino, sulfhydryl, or carboxylic groups. Owing to their ability to react with electron-rich substituents in important intracellular steering molecules such as proteins and nucleic acids, electrophilic metabolites can — depending on their individual chemical reactivity - be highly cyto-toxic and/or mutagenic. Nucleophilic metabolites, however, usually do not covalently modify endogenous macromolecules and are therefore generally less toxic. On the other hand, they are often determinants of receptor interactions and thus of the biological activity of a xenobiotic compound. Therefore, acutely toxic effects of xeno-biotics or their metabolites caused by receptor activation at the wrong time or wrong intensity can depend on specific nucleophilic groups in the compound.1 Electrophilic substrates (e.g., epoxides, a,b-unsaturated carbonyls) are conjugated by the glutathione S-transferases. Nucleophilic substrates (i.e., those with hydroxyl-, sulfhydryl-, amino- or carboxyl groups) are conjugated by UDP-glucuronosyltransferases (UGTs), sulfotransferases (SULTs), acetyltrans-ferases (ATs), and methyltransferases (MTs). Conjugation reactions usually terminate the potential of electrophiles to react with proteins and DNA, or the ability of nucleophiles to interact with a receptor. Conjugation to both types of substituents usually increases the water solubility of the respective compound greatly.1-3 Therefore, conjugation reactions usually are the major detoxification step in drug metabolism. However, there are exceptions that are important for predictions of toxification versus detoxification: glutathione conjugation strongly increases the electrophilic reactivity of vicinal dihaloalkanes and enzymatic sulfate ester formation with hydroxymethylated aromatic compounds and with aromatic hydroxylamines (metabolites of aromatic amines) leads to markedly and strongly mutagenic species, respectively.1

Electrophilic

Lipophilic

Typical functional groups: -OH -NH2 -SH -COOH

Hydrophilic

Nucleophilic

Typical functional groups: -OH -NH2 -SH -COOH

Figure 1 The phases of drug metabolism. Metabolism of lipophilic foreign compounds typically proceeds in sequential steps. In phase I, the compounds are functionalized via introduction or liberation of nucleophilic or electrophilic anchor groups by oxidoreductases or hydrolases, which allow conjugation with strongly polar endogenous building blocks, such as glucuronic acid or glutathione, in phase II of drug metabolism. The resulting metabolites are usually readily water soluble and therefore easily excretable in the urine or bile. The conjugation usually terminates the biological activity of compounds, such as the genotoxic effects of certain electrophiles or the pharmacological effects of therapeutic drugs. (Reproduced from Oesch, F.; Arand, M. Xenobiotic Metabolism. In Toxicology; Marquardt, H., Schafer, S. G., McClellan, R., Welsch, F., Eds.; Academic Press: New York, 1999, pp 83-109, with permission from Elsevier.)

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