Reactive metabolites other peptides

With few exceptions, such as peptides and hormones, drugs and their precursors are typically low-molecular-weight compounds and, therefore, haptens. To build a complete antigen, they must bind to macromolecules e.g. human tissue or serum proteins. Some drugs are primarily reactive while, in others, reactive metabolites are only generated in vivo. Oral administration is usually better tolerated and may even induce tolerance. However, intermittent exposure by epi- or intradermal application or by inhalation, as it typically occurs in occupational settings, carries the highest risk of sensitization (Bircher 1996). 

In contrast to the lability of certain dN adducts formed by the BHT metabolite above, amino acid and protein adducts formed by this metabolite were relatively stable.28,29 The thiol of cysteine reacted most rapidly in accord with its nucleophilic strength and was followed in reactivity by the a-amine common to all amino acids. This type of amine even reacted preferentially over the e-amine of lysine.28 In proteins, however, the e-amine of lysine and thiol of cysteine dominate reaction since the vast majority of a-amino groups are involved in peptide bonds. Other nucleophilic side chains such as the carboxylate of aspartate and glutamate and the imidazole of histidine may react as well, but their adducts are likely to be too labile to detect as suggested by the relative stability of QMs and the leaving group ability of the carboxylate and imidazole groups (see Section 9.2.3). 

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