ABSTRACT
In contrast to the frequent binding of many xenobiotics to plasma proteins or intracellular macromolecules, which is a non-covalent and reversible effect (see section 1.2.1), other compounds, or their metabolites, can interact with macromolecules and bind to them in a covalent, and therefore irreversible, manner. For example, the ability of many xenobiotics to be metabolically converted to reactive metabolites which can covalently bind to DNA has been known for a long time. In fact, DNA adduct formation by a reactive intermediate (the ‘ultimate carcinogen’) has been recognized to be an important step in carcinogenesis. However, reactive metabolites can also attack proteins, lipids, or other macromolecules. The toxicological significance of covalent protein binding is less clear than that of DNA binding, except for a small number of well-studied examples. Recently, the role of covalent binding of reactive metabolites to cellular target molecules, which act as stress signal enhancers and are involved in signal transduction, has been emerging as an important mechanism in gene regulation.
