Many drugs and phytochemicals can be activated to biological reactive intermediates

The metabolism of drugs and other xenobiotics is exemplified by cytochrome P450-mediated oxidation to more hydrophilic compounds. Enzymatic oxidation of some functional groups, however, can result in transient reactive intermediates--a transformation that is common in nature. Some drugs and many phytochemicals that contain, for example, a thiophene ring are oxidized by cytochrome P450 to reactive intermediates, such as sulfoxides, that can covalently bond to thiol nucleophiles in macromolecules, such as proteins. Many other functional groups can be oxidized to reactive intermediates--for instance, olefins, alkynes, alkylamines, furans, and p-aminophenols. Because any consequence of a biological reactive intermediate (BRI) is dependent on many factors a number of BRIs are benign. Toxicity is determined by complex and specific arrays of parallel and/or serial pathways and cellular states, not by entities or individual reactions. Because the formation of reactive intermediates can correlate with unacceptable toxicity, it is important to understand if or how a compound may undergo this type of transformation. Not all substances that form reactive intermediates are toxic; many are not. Therefore, it is critical to understand the mechanism of metabolism in considering any toxicity relevance and in evaluating animal models. Indeed, the complex nature of these many interactions and entities underscores the fact that the presence of a BRI is not an accurate indicator of human toxicity. A BRI is neither good nor a priori bad. It is a potential detoxication product and an incidental fate of the xenobiotic.