Regulation of Drug Metabolizing Enzymes and Transporters in Infection, Inflammation, and Cancer

Under conditions of innate immune system activation (i.e., inflammation), the functions of specific cytochrome P450 enzymes, other drug metabolizing enzymes (DMEs), and drug transporters (DTs) are altered in the liver, small intestine, lung, kidney, and central nervous system (CNS). Many of these effects are primarily manifest at the transcriptional/RNA level, leading to corresponding changes in protein levels and function. This not only leads to altered drug and xenobiotic toxicity and action in diseased humans, but also has importance for disease therapy with biologic drugs that target inflammatory mediators or their receptors. Major roles for proinflammatory cytokines such as interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-α(TNFα) are inferred from the abilities of these agents to affect DMEs and DTs in cultured cells and in vivo, but the in vivo contributions of cytokines to regulation of these proteins in different inflammatory disease states is still poorly understood. Keywords: inflammation; infection; cytokines; toll-like receptors; biologics