Reactive metabolites hard electrophiles

It therefore is necessary to identify targets for these reactive metabolites (i.e., covalently modified macromolecules) that are critical to the toxicological process. Hard electrophiles generally react with hard nucleophiles, such as the basic groups in DNA and lysine u-amino residues in proteins. Soft electrophiles react with soft nucleophiles, which include cysteine residues in proteins and in glutathione. Unfortunately, no simple rules predict the target macromolecules tor a particular chemically reactive metabolite or the biological consequences of a particular modification. Furthermore, noncovalent interactions also ... 

In contrast, soft electrophiles react with nucleophilic SH groups in GSH and proteins. Soft electrophiles are typically cytotoxic, such as the metabolite of paracetamol, N-acetyl-p-benzoquinoneimine (Fig. 4.73) (see also chap. 7). So reactivity with GSH depends on the hardness/softness of the electrophile. 

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