Toxicology of Industrial Compounds

6
Methods for the Determination of Reactive
Compounds
PETER SAGELSDORFF
CIBA-GEIGY Ltd, Basel
Introduction
It has well been recognised for a long time that adverse effects of chemicals
are associated with their reactivity whereby many unreactive chemicals are
metabolised in the cell to a reactive intermediate. Reactive intermediates
are generally electrophiles which undergo reactions with cellular
nucleophiles and the toxicological response is often the consequence of the
covalent binding of a chemical to cellular macromolecules. This chapter
will provide a brief survey of current methods for the determination of
protein and DNA adducts generated by reactive compounds, and will
discuss some useful applications of these technologies.
Source of reactive metabolites
Reactive chemicals are generally strong electrophilic agents. These
compounds can be reactive per se (direct electrophiles), such as methylmethanesulphonate,
epoxides or strained lactones. On the other hand,
unreactive chemicals can be enzymatically converted to electrophilic agents
(indirect electrophiles), such as aromatic amines and nitroarenes to the
corresponding nitrenium ions, polycyclic aromatic hydrocarbons to diol
epoxides or N-nitroso compounds to carbenium ions (Figure 6.1; Magee et
al., 1975; Weissburger and Williams, 1975; Lutz, 1979).
Interaction of reactive compounds with cellular
constituents
As electrophiles, these reactive compounds undergo reactions with
nucleophiles. The nature of the toxicological response is dependent on the
biological macromolecule affected. Reactions with water or glutathione,
two of the most abundant cellular nucleophiles, in most cases, lead to an
inactivation of the respective reactive compound.