Glutathione, conjugation

Source From Yu, S.J. and Abo-Elghar, G.E., Pestic. Biochew. Physiol., 68,173, 2000. With permission. 

Glutathione S-transferases have received considerable attention because of their roles in insecticide detoxification and resistance in insects. Cytosolic glutathione S-transferases have been purified from more than two dozen insect species, including Lepidoptera, Diptera, Coleoptera, Dictyoptera, and Hymenoptera. These transferases exist in multiple forms as many as nine isozymes were found in midguts and fat bodies of fall army worm 

In this section, we will review the current knowledge of the metabolism of some typical insecticides without regard for the species of animal involved. This will not affect the understanding of metabolic fate, because most organisms possess all of the enzymes required for metabolism. Therefore, we can expect that any of the metabolites shown will be produced by any species. Although the proportions of the various metabolites may not be the same in every species, the quality of metabolites will not be greatly different (Ter-riere, 1982). 

Formation of glycoside conjugates does not necessarily represent the termination of a particular herbicide detoxification sequence in plants, and the glycoside conjugates are frequently subjected to further modification. Thus, 25 was acylated to the N-malonylglucoside in tomato plants, as was the )8-D-glucosyl conjugate of pentachlorophenol in suspension cultures of soybean and wheat. 

Other classes of herbicide for which glutathione conjugation constitutes a major detoxification mechanism include the nitrodiphenyl ethers acifluor-fen, fluorodifen, and fomesafen, the chloroacetanilides metola-chlor, alachlor, and propachlor, the oxirane derivative tridiphane, and the sulfonylurea chlorimuron-ethyl (Classic). The last 

Studies with other soybean cultivars referred to in previous sections of this chapter implicated reductive deamination or N-glucosidation as the dominant metabolic routes conferring tolerance. Though all of these studies on the fate of metribuzin in soybean agree on a major role for differential metabolism in determining cultivar response, it would appear that tolerant cultivars differ with respect to the relative importance of the three detoxification routes. 

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FIGURE 2.14 Phase 2 biotransformation—conjugation. (1) Glucuronide formation. (2) Sulfate formation. (3) Glutathione conjugation. 

Residues of PCBs in animal tissues include not only the original congeners themselves, but also hydroxy metabolites that bind to cellular proteins, for example, transthyretin (TTR Klasson-Wehler et al. 1992 Brouwer et al. 1990 Fans et al. 1993). Small residues are also found of methyl-sulfonyl metabolites of certain PCBs (Bakke et al. 1982, 1983). These appear to originate from the formation of glutathione conjugates of primary epoxide metabolites, thus providing further evidence of the existence of epoxide intermediates. Further biotransformation, including methylation, yields methyl-sulfonyl products that are relatively nonpolar and persistent. 

In terrestrial animals, the excreted products of PAHs are mainly conjugates formed from oxidative metabolites. These include glutathione conjugates of epoxides, and sulfate and glucuronide conjugates of phenols and diols. 

Oakley AJ, Lo Bello M, Mazzetti AP, Federici G, Parker MW. The glutathione conjugate of ethacrynic acid can bind to human pi class glutathione transferase Pl-1 in two different modes. FEES Lett 1997 419 32-6. 

Dekant W, Koob M, Henschler D. 1990. Metabolism of trichloroethene—vivo and in vitro evidence for activation by glutathione conjugation. Chem Biol Interact 73 89-101. 

Elfarra AA, Anders MW. 1984. Renal processing of glutathione conjugates. Role in nephrotoxicity. Biochem Pharmacol 33 3729-3732. 

Iverson, S. L. Shen, L. Anlar, N. Bolton, J. L. Bioactivation of estrone and its catechol metabolites to quinoid-glutathione conjugates in rat liver microsomes. Chem. Res. Toxicol. 1996, 9, 492-A99. 

Glucuronidation Sulfation Acetylation Peptide conjugation Glutathione conjugation... 

Suzuki, H., Sugiyama, Y., Excretion of GSSG and glutathione conjugates mediated by MRP1 and cMOAT/ MRP2, Semin. Liver Dis. 1998, 18, 359-376. 

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