Glutathione conjugation with xenobiotics

The conjugation of xenobiotics with glutathione (GSH) in higher plants was first demtxistrated to be a major enzymatic detoxication mechanism with the atrazine herbicide in sorghum, corn, and other atrazine resistant species (77-80) (Equation 15). Since this... 

The intracellular conjugation of xenobiotics with glutathione (GSH) results in their detoxication and adjusts their polarity to facilitate excretion from the cell (for recent reviews of GSH conjugation, see 1 and 2). Here the disposition of these GSH conjugates will be discussed. 

Substitution reactions of xenobiotics with glutathione are the most important and contribute efficiently to detoxification. Nevertheless, in some cases, such as vicinal dihalogenated compounds, glutathione conjugation produces monosub-stituted derivatives, which may cycUze into a highly electrophilic episulfonium ion (Figure 33.17). ... 

Fig. 14-42 Conjugation of xenobiotics with glutathione to form mercapturic acid.

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. 

Mainigi and Campbell (20) have shown that low protein diets depress hepatic glutathione levels. Since enzymatic conjugation and spontaneous reaction of certain xenobiotics with hepatic glutathione is an important detoxication step with certain compounds, this depression of glutathione levels may alter the toxicity of these compounds in animals fed low protein diets. 

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. 

In the past decade, several aspects of xenobiotic conjugation have been studied In aquatic animals. This paper will summarize and review recent findings, with particular emphasis on glycosylation, glutathione conjugation and mercapturlc acid biosynthesis, and amino acid conjugation. 

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