Xenobiotic metabolism glutathione, conjugation with

Xenobiotics are metabolized in two phases. The major reaction of phase 1 is hydroxylation catalyzed by a variety of monooxygenases, also known as the cytochrome P450s. In phase 2, the hydroxylated species are conjugated with a variety of hydrophihc compounds such as glucuronic acid, sulfate, or glutathione. The combined operation of these two phases renders lipophilic compounds into water-soluble compounds that can be ehminated from the body. 

With some of the phase 2 metabolizing enzymes, there may be strict ontogenetic patterns of expression. Sulfate conjugation ability occurs early in rats, whereas glucuronidation (of xenobiotics), and conjugation with glutathione and amino acids, only develop over about 30 days from birth. 

The oxidation of naphthalene was one of the earliest examples of an epoxide as an intermediate in aromatic hydroxylation. As shown in Figure 7.3, the epoxide can rearrange nonenzymatically to yield predominantly 1-naphthol, or interact with the enzyme epoxide hydrolase to yield the dihydrodiol, or interact with glutathione S-transferase to yield the glutathione conjugate, which is ultimately metabolized to a mercapturic acid. These reactions are also of importance in the metabolism of other xenobiotics that contain an aromatic nucleus, such as the insecticide carbaryl and the carcinogen benzo(a)pyrene. 

Glutathione can conjugate with xenobiotics in many ways. It may displace an electron-withdrawing group, putting GS in its place. It may add itself (GSH) to the substrate. It may also respond to a substrate formed from earlier metabolism. A xenobiotic may stereoselectively conjugate, removing one or more of the peptides. 

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