Glutathione conjugates biotransformations

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. 

Slatter JG, Rashed MS, Pearson PG, et al. Biotransformation of methyl isocyanate in the rat. Evidence for glutathione conjugation as a major pathway of metabolism and implications for isocyanate-mediated toxicities. Chem Res Toxicol 1991 4(2) 157—161. 

A biological difference that could increase susceptibility of fetuses and premature or perinatal infants to 1,2-dibromoethane toxicity is developmental immaturity of the P-450 (microsomal enzyme) system. Biotransformation of xenobiotics occurs predominantly by glutathione conjugation (Benet and Sheiner 1985 Sipes and Gandolfi 1986). This pathway is known to generate a number of toxic intermediate metabolites of 1,2-dibromoethane. In addition, fetal mice have selective binding of... 

Kassahun K, Davis M, Hu P, Martin B, Baillie T. (1997) Biotransformation of the naturally occurring isothiocyante sulforaphane in the rat Identification of phase I metabolities and glutathione conjugates. Chem Res Toxicol 10 1228-1233. 

Different enzymatic reactions that occur during the metabolism of chemicals have been well categorized. The biotransformation and conjugation reactions may lead to either the detoxication of the toxicant and the excretion of its metabolites, or to the activation of the toxicant into more reactive intermediates. These may, in turn, react with glutathione, or tissue proteins, or nucleic acids (e.g., RNA, DNA) and undergo different metabolic reactions. 

Rietveld, E.C., Hendrikx, M.M.P., Seutter-Berlage, F. (1986). Glutathione conjugation of chlorohenzylidene malononitriles in vitro and the biotransformation to mercapturic acids, in rats. Arch. Toxicol. 59 228-34. 

An example of this approach was described by Carini et al. [7] in investigating the in vitro metabolism of an NO-releasing nonsteroidal anti-inflaimnatoiy drag (NCX 4016). Possible metabolites were postulated (Figure 10.1). An LC-MS system was developed for the separation of these components in extracts of various rat hver subcellular fractions (S9, microsomes, cytosol). LC-UV-DAD analysis of extracts after 90-min incubation revealed that only HBA, SA, and HBN were detected. In addition, an unknown metabolite was detected, which was identified as a glutathione conjugate at the benzyl carbon of HBA or HBN. Quantitative analysis was performed to study the kinetics of the biotransformation [7]. 

Biotransformations Occurring with Glutathione Conjugates (Table I)... 

U Renner, J Blanz, S Freund, D Waidelich, G Ehninger, K-P Zeller. Biotransformation of CI-937 in primary cultures of rat hepatocytes. Formation of glutathione conjugates. Drug Metab Dispos 23 94, 1995. 

Aromatic hydroxylation such as that depicted in figure 4,3 for the simplest aromatic system, benzene, is an extremely important biotransformation. The major products of aromatic hydroxylation are phenols, but catechols and quinols may also be formed, arising by further metabolism. One of the toxic effects of benzene is to cause aplastic anaemia, which is believed to be due to an intermediate metabolite, possibly hydroquinone. As a result of further metabolism of epoxide intermediates (see below), other metabolites such as diols and glutathione conjugates can also... 

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