Glutathione metabolite identification

Gan, J. et al. 2005. Dansyl glutathione as a trapping agent for the quantitative estimation and identification of reactive metabolites. Chem. Res. Toxicol. 18 896. 

Guan X, Davis MR, Tang C, et al. Identification of S-(n-butylcarbamoyl)glutathione, a reactive carbamoylating metabolite of tolbutamide in the rat, and evaluation of its inhibitory effects on glutathione reductase in vitro. Chem Res Toxicol 1999 12(12) 1138-1143. 

However, the temptation to link glutathione (GSH) adducts to MBI must be avoided since the identification of metabolite adducts with GSH does not confirm MBI, albeit it may be an indicator of other adverse drug reactions (Walgren et al., 2005). By definition, exogenous nucleophiles such as GSH should offer no protection from MBI [161], and in principle, even when GSH adducts are formed from the same chemical entity responsible for MBI, the exogenous adducts themselves may not be related to the enzyme-inactivating species [174]. 

Figure 9. Identification of metabolites A through D in urine of rats treated with CDA led to the proposed hidden metabolites shown here in brackets. The reactive sulfate conjugate apparently undergoes glutathione conjugation, further metabolism via the mercapturic acid pathway and, finally, C-S cleavage, methylation and sulfur oxidation of C to yield D.

Methyl sulfones are ultimate mammalian metabolites of PCBs produced by a series of reactions involving arene oxides and glutathione conjugates and have been synthesized to enable their conclusive identification and quantification (Bergman and Wach-meister 1978 Haraguchi et al. 1987). This is discussed further in Section 7.5.2. 

Metabolites of the herbicides alachlor and metolachlor in which the chlorine of the -CO. CH2-C1 group is replaced by -S03- by glutathione conjugation and oxidation have been recovered from a number of water courses in the United States Two aspects are worth noting (a) the analytical problems of identification and (b) the fact that the sulfonate of alachlor has low bioconcentration potential and is nonmutagenic in contrast to its precursor (Field and Thurman 1996). 

MR Davis, K Kassahun, CM Jochheim, KM Brandt, TA Baillie. Glutathione and A-acetylcysteine conjugates of 2-chloroethyl isocyanate. Identification as metabolites of N,N -bis(2-chloroethyl)-A-nitrosourea in the rat and inhibitory properties toward glutathione reductase in vitro. Chem Res Toxicol 6 376, 1993. 

K Kassahun, K Farrell, F Abbott. Identification of characterization of the glutathione and N-acetylcysteine conjugates of (E)-2-propyl-2,4-pentadienoic acid, a toxic metabolite of valproic acid, in rats and humans. Drug Metab Dispos 19 525, 1991. 

Kassahun K, Davis M, Hu P, Martin B, BaUhe T. Biotransformation of the naturally occurring isothiocyanate sulforaphane in the rat identification of phase 1 metabolites and glutathione conjugates. Chem Res Toxicol 1997 10 1228-1233. 

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