Symposium Report Regulation of Drug-Metabolizing Enzymes and Transporters in Infection, Inflammation, and Cancer Edward T. Morgan, Kerry B. Goralski, Micheline Piquette-Miller, Kenneth W. Renton, Graham R. Robertson, Madhusudana R. Chaluvadi, Kellie A. Charles, Stephen J. Clarke, Marina Kacevska, Christopher Liddle, Terrilyn A. Richardson, Rohini Sharma, and Christopher J. Sinal Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia (E.T.M., M.R.C., T.A.R.) Department of Pharmacology (K.B.G., K.W.R., C.J.S.) and College of Pharmacy (K.B.G.), Dalhousie University, Halifax, Nova Scotia, Canada; Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada (M.P.-M.); Cancer Pharmacology Unit, ANZAC Research Institute, Concord, Australia (G.R.R, S.J.C., M.K.); Storr Liver Unit, Westmead Millennium Institute, Westmead, Australia (K.A.C., C.L., R.S.) Received September 5, 2007; accepted October 29, 2007 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 con- sequences, 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 ad- vances in understanding how these processes operate in other organs and chronic inflammatory states relevant to human dis- eases. The development of mouse models of live bacterial in- fection 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 conse- quences 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 treat- ment 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 inflamma- tion 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 occa- sion 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 This work was supported in part by U.S. Public Health Service Grants GM069971 and DK072372 (E.T.M.), Canadian Institute of Health Research Op- erating Grants (M.P.-M. and K.W.R), Australian National Health and Medical Research Council Grant 352419 (G.R.R.), and the Dalhousie University Pharmacy Endowment Fund (K.B.G.). E.T.M., K.B.G., M.P.-M., K.W.R., and G.R.R. contributed equally to this work. Article, publication date, and citation information can be found at http://dmd.aspetjournals.org. doi:10.1124/dmd.107.018747. ABBREVIATIONS: P450, cytochrome P450; LPS, lipopolysaccharide; IL, interleukin; CNS, central nervous system; PGP, P-glycoprotein; M3G, morphine 3-glucuronide; M6G, morphine 6-glucuronide; CSF, cerebrospinal fluid; TNF, tumor necrosis factor; TLR, toll-like receptor; PXR, pregnane X receptor; EHS, Engelbreth-Holm-Schwarm; SAP, serum amyloid P; STAT, signal transducer and activator of transcription; Mdr/MDR, multidrug resistance protein; Mrp/MRP, multidrug resistance-associated protein; Oatp, organic anion transporting polypeptide; CAR, constitutive androstane receptor; i.c.v., intracerebroventricular; ABC, ATP-binding cassette; RU486, 17-hydroxy-11-[4-dimethylamino phenyl]-17- [1-propynyl]estra-4,9-dien-3-one. 0090-9556/08/3602-205–216$20.00 DRUG METABOLISM AND DISPOSITION Vol. 36, No. 2 Copyright © 2008 by The American Society for Pharmacology and Experimental Therapeutics 18747/3294090 DMD 36:205–216, 2008 Printed in U.S.A. 205 at ASPET Journals on April 1, 2016 dmd.aspetjournals.org Downloaded from