microflora may also lead to the formation of reactive toxic products. With some chemicals only one enzymatic reaction is involved, whereas with other compounds, several reactions, often involving multiple pathways, are necessary for the production of the ultimate reactive metabolite.

8.3NATURE AND STABILITY OF REACTIVE METABOLITES

Reactive metabolites include such diverse groups as epoxides, quinones, free radicals, reactive oxygen species, and unstable conjugates. Figure 8.2 gives some examples of activation reactions, the reactive metabolites formed, and the enzymes catalyzing their bioactivation.

As a result of their high reactivity, reactive metabolites are often considered to be short-lived. This is not always true, however, because reactive intermediates can be transported from one tissue to another, where they may exert their deleterious effects. Thus reactive intermediates can be divided into several categories depending on their half-life under physiological conditions and how far they may be transported from the site of activation.

8.3.1Ultra-short-lived Metabolites

These are metabolites that bind primarily to the parent enzyme. This category includes substrates that form enzyme-bound intermediates that react with the active site of the enzyme. Such chemicals are known as “suicide substrates.” A number of compounds are known to react in this manner with CYP, and such compounds are often used experimentally as CYP inhibitors (see the discussion of piperonyl butoxide, Section 7.2.2). Other compounds, although not true suicide substrates, produce reactive metabolites that bind primarily to the activating enzyme or adjacent proteins altering the function of the protein.

Figure 8.2 Examples of some activation reactions.

8.3.2Short-lived Metabolites

These metabolites remain in the cell or travel only to nearby cells. In this case covalent binding is restricted to the cell of origin and to adjacent cells. Many xenobiotics fall into this group and give rise to localized tissue damage occurring at the sites of activation. For example, in the lung, the Clara cells contain high concentrations of CYP and several lung toxicants that require activation often result in damage primarily to Clara cells.

8.3.3Longer-lived Metabolites

These metabolites may be transported to other cells and tissues so that although the site of activation may be the liver, the target site may be in a distant organ. Reactive intermediates may also be transported to other tissues, not in their original form but as conjugates, which then release the reactive intermediate under the specific conditions in the target tissue. For example, carcinogenic aromatic amines are metabolized in the liver to the N -hydroxylated derivatives that, following glucuronide conjugation, are transported to the bladder, where the N -hydroxy derivative is released under the acidic conditions of urine.