Toxicology of Industrial Compounds

74 METHODS FOR THE DETERMINATION OF REACTIVE COMPOUNDS
Figure 6.2 Nucleophilic centres in nucleobases and DNA ‘adduct library’ indicating
the preferential binding sites on guanine for several classes of chemicals. The most
reactive targets are indicated by an arrow (from Lutz, 1979; Beach and Gupta,
1992).
The most important nucleophilic centres in proteins are the side chains
of the amino acids cysteine, methionine, histidine and tyrosine, and the
amino group of the N-terminal amino acid. Reactions of electrophiles with
proteins lead to the formation of protein adducts. This results in general or
specific cytotoxicity depending on whether the function of a particular
protein is disturbed (Lawley, 1976; Brooks, 1977). Adduct formation with
blood proteins can result in the formation of immunogens and subsequent
allergenic responses.
Finally, reactions with DNA predominantly occur with the nucleobases
adenine, cytosine, thymine and guanine, whereby the most important
nucleophile in DNA is guanine (Figure 6.2). Adduct formation with
nucleobases in DNA is recognised as a crucial step in the formation of
mutations and cancer (Lutz, 1979).