Bioactivation glutathione conjugation

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. 

Dekant W, Vamvakas S, Anders MW. 1990a. Review section Bioactivation of hexachlorobutadiene by glutathione conjugation. Food Chem Toxicol 28 285-293. 

Van Bladeren PJ. Glutathione conjugation as a bioactivation reaction. Chem Biol Interact 2000 129 61-76. 

Van Bladeren PJ. Glutathione conjugation as a bioactivation reaction. Chem Biol Interact 2000 129 61-76. Walker RJ, Duggin GG. Drug nephrotoxicity. Annu Rev Pharmacol Toxicol 1988 28 331-345. 

A13. Anders, M. W., Vamvakas, S., and Dekant, W., Bioactivation of haloalkenes through glutathione conjugation. In Glutathione S-transferases and Drog Resistance (J. D. Hayes, C. B. Pickett, and T. J. Mantle, eds.), pp. 121-130. Taylor Francis, London 1990. 

Scheme 19) (Sun et al., 2008). The characterization of a hydroxycarboxylic acid metabolite of trovafloxacin in preclinical species (Dalvie et al., 1996) lends further support for the metabolism of the cyclopropylamine ring in trovafloxacin to a reactive intermediate. The formation of the hydroxycarboxylic acid can occur from the addition of water to the a,(3-unsaturated aldehyde via Michael addition followed by oxidation as depicted for the model compound (Scheme 19). However, the proposal for reactive metabolite formation with trovafloxacin remains a speculation since the bioactivation studies did not involve the parent fluoroquinolone and no a,(3-unsaturated aldehyde or the corresponding glutathione conjugate has been detected in trovafloxacin incubations in human liver microsomes (Sun et al., 2008). Furthermore, the primary pathways of trovafloxacin clearance in humans include phase II metabolism (iV-acetylation, acyl glucuronidation, and iV-sulfation) (Scheme 19) with very minor contributions from phase I oxidative pathways (Dalvie et al., 1997). 

Tang W, Steams RA, Bandiera SM, Zhang Y, Raab C, Braun MP, Dean DC, Pang J, Leung KH, Doss GA, Strauss JR, Kwei GY, Rushmore TH, Chiu SH, Baillie TA. Studies on cytochrome P-450-mediated bioactivation of diclofenac in rats and in human hepatocytes Identification of glutathione conjugated metabolites. Dmg Metab Dispos 1999 27(3) 365-372. 

J. Bock, M.G. Baillie, T.A. Prueksaritanont, T. Bioactivation of 2,3-diaminopyridine-containing bradyki-nin Bi receptor antagonists Irreversible binding to liver microsomal proteins and formation of glutathione conjugates. Chem. Res. Toxicol. 2005,18, 934-945. 

Dekant W, Martens G, Vamvakas S, et al. 1987. Bioactivation of tetrachloroethylene. Role of glutathione S-transferase-catalyzed conjugation versus cytochrome P-450-dependent phospholipid alkylation. Drug Metab Dispos Biol Fate Chem 15 702-709. 

As noted above, MDA is a potent stimulator of monoamine release (see Table 7.1), and recent reports indicate that a number of MDMA metabolites are bioactive. For example, Forsling et al.61 showed that the metabolite 4-hydroxy-3-methoxymethamphetamine (HMMA) is more potent than MDMA as a stimulator of vasopressin secretion from rat posterior pituitaries in vitro. The neuroendocrine effects produced by in vivo administration of MDMA metabolites have not been examined. Monks et al.62 demonstrated that catechol metabolites of MDMA and MDA, namely, 3,4-dihydroxymethamphetamine (HHMA) and 3,4-dihydroxyamphetamine (HHA), exhibit neurotoxic properties when oxidized and conjugated with glutathione. Further characterization of the biological effects of MDMA metabolites is an important area of research. 

Covalent protein adducts of quinones are formed through Mchael-type addihon reachon with protein sulfhydryl groups or glutathione. Metabolic activahon of several toxins (e.g., naphthalene, pentachlorophenol, and benzene) into quinones has been shown to result in protein quinone adducts (Lin et al, 1997 Rappaport et al, 1996 Zheng et al., 1997). Conversion of substituted hydroquinones such as p-aminophenol-hydroquinone and 2-bromo-hydroquinone to their respective glutathione S-conjugates must occur to allow bioactivation into nephrotoxic metabolites (Dekant, 1993). Western blot analysis of proteins from the kidneys of rats treated with 2-bromo-hydroquinone has revealed three distinct protein adducts conjugated to quinone-thioethers (Kleiner et al, 1998). 

Dekant, W., 1993, Bioactivation of nephrotoxins and renal carcinogens by glutathione S-conjugate formation. Toxicol. Lett. 67 151-160 Dooley, D.M., 1999, Stmcture and biogenesis oftopaquiones and related cofactors. J. Biol. Inorg. Chem. 4 1-11... 

Catechol may be oxidized by peroxidases to the reactive intennediate benzo-1,2-quinone, which readily binds to proteins (Bhat et al., 1988) this process, catalysed by rat or human bone-marrow cells in the presence of H2O2 (0.1 mM), is stimulated by phenol (0.1-10 mM), and decreased by hydroquinone and by glutathione, which conjugates with benzo-l,2-quinone. These phenols (phenol, catechol and hydroquinone) may play a role in benzene toxicity to bone marrow all three are formed as benzene metabolites (Smith et al., 1989) and they interact in several ways as far as their bioactivation by (myelo)peroxidases is concerned (Smith et al., 1989 Subrahmanyam et al., 1990). 

Weber, G.L., Steenwyk, R.C., Nelson, S.D. Pearson, PG. (1995) Identification of V-acetyl-cysteine conjugates of l,2-dibromo-3-chloropropane evidence for cytochrome P450 and glutathione mediated bioactivation pathways. Chem. Res. Toxicol., 8, 560-573... 

Patel, N., Bimer, G, Dekant, W. Anders, M.W. (1994) Glutathione-dependent biosynthesis and bioactivation of, S -(l,2-dichlorovinyl)glutathionc and. S -(1,2-dichlorovinyl)-i,-cysteine, the glutathione and cysteine S-conjugates of dichloroacetylene, in rat tissues and subcellular fractions. Drug Metab. Dispos., 22, 143-147... 

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