Detoxification glutathione conjugation

Together with glutathione conjugation, hydration is a major pathway in the inactivation and detoxification of arene oxides. Exceptions to this rule will be treated when discussing polycyclic aromatic hydrocarbons. Arene oxides are good substrates for microsomal EH, as evidenced in Table 10.1, where hydration of selected arene oxides, alkene oxides, and cy-cloalkene oxides by purified rat liver epoxide hydrolase is compared. The hy- ... 

Shimabukuro, R.H., G.L. Lamoureux, and D.S. Frear. (1978). Glutathione conjugation A mechanism for herbicide detoxification and selectivity in plants, pp. 133-149. In Pallos, F.M. and J.E. Casida, eds., Chemistry and Action of Herbicide Antidotes. New York Academic Press Inc. 

Because of its widespread industrial use and consequent worker exposure, the metabolism of acrylonitrile has been studied extensively.5 There are two major pathways of acrylonitrile metabolism in humans. The first of these produces a glutathione conjugate and is considered to be detoxification. The second pathway produces cyanoethylene oxide,... 

Figure 12.2. Interrelationships among Phase I (hydroxylation). Phase II (glucuronic acid, sulfate, and glutathione conjugation), and Phase III (ABC transporter-mediated efflux) detoxification processes leading to the inactivation and elimination of xenobiotics.

Figure 13.7. Glutathione conjugation to reactive metabolites by GSTs. Ultimate carcinogens such as benzo[a]pyrene 7,8-diol 9,10-epoxide and aflatoxin B1 8,9-epoxide are glutathione-conjugated for detoxification by GSTM1, GSTp, and GST A, respectively. Lipid peroxidation product 4-hydroxy-2-nonenal is preferentially detoxified by GSTA.

Biotransformation involves oxidation via the cytochrome P450 system and subsequent detoxification by conjugation with glutathione and cellular macromolecules. The oxidative metabolic pathway is saturable, occurring at an oral dose of 10-50 mg kg in the rat, and at inhalation exposures exceeding 200 ppm. Elimination of vinylidene chloride and its metabolites occurs primarily through the urine and in the expired air at a relatively rapid excretion rate. 

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). ... 

Glutathione conjugation. The involvement of glutathione transferases in OP metabolism was realized in the early 1960 s (35. 361. It was difficult to establish this fact because of similarities between glutathione transferase-and carboxylesterase-produced metabolites. Induction of glutathione transferase activity in the fall armyworm caused a 2- to 3-fold decrease in the toxicity of diazi-non, methamidophos, and methyl parathion (37.) This shows indirectly the importance of glutathione transferase activity in the detoxification of these OPs. 

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