Rr

R = Alky I, Aryl, Benzylic, Allylic X - Br, CI, I, 0S03~ 0S02R, OPO(OR)2

Figure 3.15 • Formation of GSH conjugates of electrophilic xenobiotics or metabolites (E) and their conversion to mercapturic acids.

S-Substituted Cysteine Derivative

Figure 3.15 • Formation of GSH conjugates of electrophilic xenobiotics or metabolites (E) and their conversion to mercapturic acids.

The carbon center is rendered electrophilic as a result of the electron-withdrawing group (e.g., halide, sulfate, phosphate) attached to it. Nucleophilic displacement often is facilitated when the carbon atom is benzylic or allylic or when X is a good leaving group (e.g., halide, sulfate). Many industrial chemicals, such as benzyl chloride (C6H5CH2Cl), allyl chloride (CH2=CHCH2Cl), and methyl iodide, are known to be toxic and carcinogenic. The reactivity of these three halides toward GSH conjugation in mammalian systems is demonstrated by the formation of the corresponding mercapturic acid derivatives.424-428 Organophosphate insecticides, such as methyl parathion, are detoxified by two different GSH pathways.430,431 Pathway "a" involves aliphatic nucleophilic substitution and yields S-methylglu-

tathione. Pathway "b" involves aromatic nucleophilic substitution and produces S-p-nitrophenylglutathione. Aromatic or heteroaromatic nucleophilic substitution reactions with GSH occur only when the ring is rendered sufficiently electrondeficient by the presence of one or more strongly electron-withdrawing substituents (e.g., NO2, Cl). For example, 2,4-dichloronitrobenzene is susceptible to nucleophilic substitution by GSH, whereas chlorobenzene is not

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