ABSTRACT
The history of bioactivation of chemicals predates cytochrome P450 (P450) research, beginning
with structure-activity studies of carcinogens by Fieser (1) and biochemical experiments by
Millers (2,3). The enzymatic activation of inert chemicals by oxidation or other processes can
generate electrophilic products that react with nucleophilic sites on DNA and proteins. The
concept was extended to drugs and other chemicals and can provide an explanation for toxicity,
following the classic studies of the Gillette and Brodie laboratories with acetaminophen and
bromobenzene in the 1970s (4,5). In the case of carcinogenesis, causality can be demonstrated at
least to the extent that mutagenicity can be demonstrated with defined DNA lesions (6). As
discussed later, the evidence linking toxicities with covalent binding is considerable but must
still be considered correlative (7,8).
