Insulin and Growth Factor Signaling: Effects on Drug-Metabolizing Enzymes

Expression of drug-metabolizing enzymes may be altered in response to development, aging, gender, genetics, nutrition, pregnancy, disease states such as diabetes, long-term alcohol consumption, and inflammation, and by xenobiotics. Although the mechanisms by which xenobiotics regulate drug-metabolizing enzymes have been intensively studied, relatively little is known regarding the cellular mechanisms by which drug-metabolizing enzymes are regulated in response to endogenous factors such as hormones and growth factors. The first major section of the chapter defines the major insulin- and growth factor-mediated signaling pathways implicated in regulating drug-metabolizing enzyme expression, including those involving mitogen-activated protein and phosphatidyl inositol 3-kinases, small G proteins, and phosphatases. The second major section of the chapter presents a summary and evaluation of methods for determination of the role and function of signaling pathways that are involved in the regulation of drug-metabolizing enzyme gene and protein expression, including methods for determination of kinase activity and phosphorylation, the use of kinase inhibitors and dominant-negative protein kinase constructs, and the application of new RNA interference methods.