Glutathione isocyanate conjugates

Another type of activated double bond is found in isocyanates and isothiocyanates. Methylisocyanate was responsible for a disaster in Bhopal, India, in 1984 when approximately 40 tons of the gas were accidentally released leading to the death of thousands of people and injury to many more. Some have called this the worst industrial accident in history. Methylisocyanate reacts with nucleophiles as shown in Figure 8.18—in this case with a thiol. This reaction is reversible, and therefore a glutathione conjugate can act to... 

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. 

The toxicity of isocyanates is the distant consequence of their reactivity as electrophiles toward alcohols, phenols, amines, and thiols [112]. These are, indeed, the mechanisms by which isocyanates react with and modify proteins and nucleic acids [113][114], Isocyanates also react reversibly with the tripeptide glutathione (GSH), the resulting conjugates being considered to be transport forms as well as products of detoxification [115] [116]. 

Examples for GSH as a transporter of reversibly bound electrophiles are conjugates of isocyanates, isothiocyanates, alpha and beta unsaturated aldehydes, and aldehydes. These compounds form labile conjugates that may again disassociate to the parent electrophile and glutathione. The electrophile can then react with endogenous nucleophiles to form more thermodynamically favored adducts. 

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. 

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