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

Abstract

ABSTRACT:This article is a report on a symposium sponsored by the American Society for Pharmacology and Experimental Therapeutics and held at the Experimental Biology 07 meeting in Washington, DC. The presentations discussed the phenomenology, clinical consequences, and underlying mechanisms of cytochrome P450 and drug transporter regulation by inflammatory and infectious stimuli. Although considerable insights into the links between inflammatory mediators and altered hepatic drug clearance pathways have been gained from previous studies with acute inflammatory stimuli, this symposium highlighted recent advances in understanding how these processes operate in other organs and chronic inflammatory states relevant to human diseases. The development of mouse models of live bacterial infection provides excellent opportunities to explore the impact of infection on drug metabolism beyond the well characterized effects of bacterial endotoxin. Altered levels of cytochromes P450 and especially drug transporters due to inflammation in brain, intestine, and placenta have significant implications for the use of many drugs in diverse clinical settings. The consequences of inflammatory cytokine production by tumors for drug safety and efficacy in cancer patients were outlined. Repression of drug clearance pathways by tumor-derived cytokines may result in extreme toxicity to chemotherapy, compromising treatment of many cancers. It is fitting that, in honoring the career contributions and achievements of Dr. Kenneth W. Renton, this symposium reinforced the clinical relevance of this field.Inflammation regulates the expression, activity, and functions of many drug-metabolizing enzymes and drug transporters. Although impairment of drug-metabolizing enzyme activities during inflammation has been known to occur for half a century, regulation of transporters by inflammation was recognized relatively recently, in the last decade. Although the regulation of both cytochrome P450s (P450s) and drug transporters has profound implications for clinical drug therapy in disease states, research on inflammation in drug metabolism and transporters has tended to proceed in parallel. This symposium was organized to bring the areas together to identify commonalities and differences in the regulation of transporters and drug-metabolizing enzymes and to promote cross-fertilization of knowledge. It is appropriate then, that this symposium also recognized the career and contributions of Dr. Kenneth W. Renton on the occasion of his retirement.The diverse presentations on regulation of both P450 enzymes and drug transporters revealed that the regulation of both systems in inflammation, infection, and cancer have much in common. In the face of a global inflammatory stimulus such as bacterial endotoxin

Intertissue Flow of Glutathione (GSH) as a Tumor Growth-promoting Mechanism

“…This has been linked to changes in liver expression of drug-metabolizing enzymes, such as cytochromes P450 (59) and more recently to that of drug transporters (60). In this sense, it has been suggested that proinflammatory cytokines, such as IL-1␤, TNF␣, and IL-6, may contribute to altered expression of hepatic drug transporters occurring during inflammation (61).…”

Oxidative stress and breast cancer biomarkers: the case of the cytochrome P450 2E1

“…[14][15][16][17] CYP2E1 overexpression in cancer is attributed to the inflammatory conditions present in the tumor microenvironment characterised by increased inflammatory cytokine production which affects CYP2E1 gene expression. [18][19][20] Several CYP2E1 dependent mechanisms contributing to tumorigenesis have been suggested including formation of toxic intermediate derivatives and activated carcinogens. [21][22][23] CYP2E1 mediated ROS generation could also contribute to tumor development through pathways in which ROS play vital role such as DNA damage, enhanced angiogenic responses [24] autophagy [4,25,26] ER stress [27] and unfolded protein response (UPR).…”

Effect of Lipopolysaccharide on the Xenobiotic-Induced Expression and Activity of Hepatic Cytochrome P450 in Mice

“…2) This particular incident was probably owing to the decreased theophylline clearance by hepatic CYP enzymes in children infected with influenza, 3) caused by the influenza-infection-related downregulation of CYP gene expression. This incident alerted clinicians to the potential for adverse effects of an otherwise beneficial medicine in patients suffering from another disease.…”