Cytochrome P450 and Other Drug-Metabolizing Enzymes As Therapeutic Targets.

Abstract

Cytochrome P450 and other families of drug-metabolizing enzymes are commonly thought of and studied for their ability to metabolize xenobiotics and other foreign entities as they are eliminated from the body. Equally as important, however, is the homeostatic role that many of these enzymes play in maintaining the proper levels of endogenous signaling molecules such as lipids, steroids, and eicosanoids as well as their ability to modulate protein-protein interactions involved in downstream signaling cascades. Throughout the years, many of these endogenous ligands or protein partners of drug-metabolizing enzymes have been associated with a wide range of disease states from cancer to various cardiovascular, neurologic, or inflammatory diseases, prompting an interest in whether modulation of drug-metabolizing enzyme activity could have a subsequent pharmacological impact or lessening of disease severity. Beyond direct regulation of endogenous pathways, drug-metabolizing enzymes have also been proactively targeted for their ability to activate prodrugs with subsequent pharmacological activity or enhance the efficacy of a coadministered drug by inhibiting the metabolism of that drug through a rationally designed drug-drug interaction (i.e., ritonavir and human immunodeficiency virus antiretroviral therapy). The focus of this minireview will be to highlight research aimed at characterizing cytochrome P450 and other drug-metabolizing enzymes as therapeutic targets. Examples of successfully marketed drugs as well as early research efforts will be discussed. Finally, emerging areas of research utilizing typical drug-metabolizing enzymes to impact clinical outcomes will be discussed. SIGNIFICANCE STATEMENT: Although generally thought of for their drug-metabolizing capabilities, enzymes such as the cytochromes P450, glutathione S-transferases, soluble epoxide hydrolases, and others play a significant role in regulating key endogenous pathways, making them potential drug targets. This minireview will cover various efforts over the years to modulate drug-metabolizing enzyme activity toward pharmacological outcomes.