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OtherSymposium 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
Drug Metabolism and Disposition February 2008, 36 (2) 205-216; DOI: https://doi.org/10.1124/dmd.107.018747
Edward T. Morgan
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Kerry B. Goralski
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Micheline Piquette-Miller
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Kenneth W. Renton
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Graham R. Robertson
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Madhusudana R. Chaluvadi
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Kellie A. Charles
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Stephen J. Clarke
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Marina Kacevska
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Christopher Liddle
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Terrilyn A. Richardson
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Rohini Sharma
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Christopher J. Sinal
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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.

Footnotes

  • This work was supported in part by U.S. Public Health Service Grants GM069971 and DK072372 (E.T.M.), Canadian Institute of Health Research Operating 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, 17β-hydroxy-11β-[4-dimethylamino phenyl]-17α-[1-propynyl]estra-4,9-dien-3-one.

    • Received September 5, 2007.
    • Accepted October 29, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 36 (2)
Drug Metabolism and Disposition
Vol. 36, Issue 2
1 Feb 2008
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OtherSymposium 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
Drug Metabolism and Disposition February 1, 2008, 36 (2) 205-216; DOI: https://doi.org/10.1124/dmd.107.018747

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OtherSymposium 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
Drug Metabolism and Disposition February 1, 2008, 36 (2) 205-216; DOI: https://doi.org/10.1124/dmd.107.018747
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  • Article
    • Abstract
    • Dr. Kenneth W. Renton
    • Inflammation and Infection: Hazards for Drug Safety (K.W.R.)
    • Regulation of P450 Enzymes in Live and Sterile Models of Infection (E.T.M., M.R.C., and T.A.R.)
    • Transcriptional Repression of Hepatic CYP3A4 Gene in the Presence of Cancer (G.R.R., K.A.C., M.K., R.S., C.L., S.J.C.)
    • Regulation of P-Glycoprotein-Mediated Drug Transport and CYP3A Metabolism during CNS Inflammation (K.B.G., C.J.S., K.W.R.)
    • Regulation of Drug Transporters in Inflammation (M.P.-M.)
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  • Physiological Regulation of Drug Transport and Metabolism
  • P450 System Protein-Protein and Protein-Lipid Interactions
  • Interindividual Variability in P450s
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