Enzymatic activation of chemicals to toxic metabolites.

A variety of enzymes function in the oxygenation, oxidation-reduction, conjugation, and hydrolysis of drugs and other foreign chemicals. Often these enzymes detoxicate chemicals to prevent detrimental effects. In this review we will, however, concentrate on cases in which metabolism activates chemicals to reactive species which cause cellular damage. Particular attention will be given to mixed-function oxidases, which carry out a variety of oxygenations, as well as other reactions. (We will focus on cellular toxicity as opposed to initiation of tumorigenesis in this review.) In many cases, considerable circumstantial evidence exists linking these enzymes to enhanced toxicity of chemicals, although causal relationships have seldom been demonstrated. Further, in very few cases is the explicit cause of toxicity known. Modification of critical protein residues is suspected, although oxidative stress may also be involved in some cases. We discuss general aspects of mechanisms of toxic action, briefly list all cases in which metabolism is suspected to play a role in enhancing toxicity, and review a few examples in detail where substantial chemical and enzymatic information is available. The latter instances would involve knowledge of the enzymes involved, chemical evidence on the structures of the reactive metabolites, identification of adducts, and some inference into the biological processes which are effected to elicit toxicity. We consider, in this regard, vinyl halides (which have been a focus in our own laboratory), acetaminophen, pyrrolizidine alkaloids, and fluoroxene.