September 16-20, 2001 – Copenhagen, Denmark
Organizing committee: Henrik Enghusen Poulsen, Kim Brøsen, Steffen Loft, Urs Meyer, F.F. Kadlubar, P.F. Guengerich, Sven Frøkjær, Arne Svejgaard
Synopsis: Drug metabolism is the enzymatic mechanisms by which the body eliminates unwanted substances. These enzymes have attracted particular interest not only from pharmacologists, but also from toxicologists because they can activate pro-carcinogens.
Benzon Symposium No. 48 is devoted to important aspects of drug metabolism. The sessions will include enzymology, transformation, enzyme induction, and the prediction of drug metabolism in man. The huge intra-individual variation in drug-metabolising enzyme activity has clinical implications, particularly for drugs with narrow therapeutic intervals. The symposium includes presentations on ethnic variation as well as genetic and environmental influence on the activity of drug-metabolising enzymes. Furthermore, the symposium will cover the relation between drug-metabolising enzymes and environmental toxicology, their relation to disease development, and clinical relevance. One session deals with the tissue-specific drug transport.
There is a particular focus on the important cytochrome P450 super family of drug-metabolising enzymes which are of utmost importance for the elimination of drugs, but also of great importance for toxicology. During metabolism of many xenobiotics reactive intermediates may be formed, e.g. disease causing nucleophiles.
Invited speakers: Urs A. MEYER, Franz OESCH, Frank GONZALEZ, Joyce A. GOLDSTEIN, Magnus INGELMAN-SUNDBERG, Denis GRANT, Jan-Åke GUSTAVSSON, Poul TALAHAY, Brian BURCHELL, Philippe BEAUNE, Paul B. WATKINS, Geoffrey TUCKER, Peter F. GUENGERICH, Fred F. KADLUBAR, Pierre HAINAUT, Sergei RODIN, M. EICHELBAUM, Neil CAPORASO, Daniel W. NEBERT, Keld DANØ, W.N. KONINGS, Heyo KROEMER, Leif BERTILSSON, David GREENBLATT, Jack A. HINSON
Scientific Programme:
Henrik Enghusen Poulsen: Introduction
Session I – Enzymology of drug-metabolising enzymes
Chairmen: Fred Guengerich & Henrik E. Poulsen
Urs-A. Meyer: The biology and clinical importance of the CYP-gene superfamily
Franz Oesch: Metabolism of CYP-generated reactive intermediates by epoxide hydrolases
Frank J. Gonzalez: Analyzing the function of genes encoding human drug metabolizing enzymes using humanized transgenic mice
Selected oral presentations:
Wendela A. Kappers: Investigation of diazinon activation by P450 enzymes in human liver (Poster No. I-5)
Ivan Gut: CYP 2D6 and 2E1 expression in human individuals: stability, effect of genotype, disulfiram and alcohol pretreatment (Poster No. II-4)
Vibeke Breinholt: In vitro identification of the cytochrome P450 enzymes responsible for the metabolism of dietary flavonoids (Poster No. VI-3)
Ulla Grove Sidelmann: Directly coupled HPLC-NMR-MS approaches for the rapid characterization of drug metabolites: application to the human metabolism of naproxen (Poster No. I-11)
Session II: Polymorphism in biotransformation
Chairmen: Urs A. Meyer & Kim Brøsen
Joyce A. Goldstein: Genetic polymorphisms in the human CYP2C subfamily
Magnus Ingelman-Sundberg: Polymorphism in biotransformation: CYP2D6
Dennis Grant: NAT
Poster session (Posters Nos. I-1-11; II-1-10).
Session III: Mechanisms of induction
Chairmen: Jan Åke Gustavsson & Steffen Loft
Jan Åke Gustafsson: Molecular mechanisms of CYP induction
Paul Talalay: Phase II enzymes: regulation, chemistry of inducers, protective functions
Brian Burchell: Induction of glucuronidation
Selected oral presentations:
Jukka Hakkola: Characterisation of factors affecting CYP2E1 transcription (Poster No. III-4)
G. Arold: The Influence of St. John’s Wort Extract (SJW, Esbericum® capsules) on the pharmacokinetics of alprazolam, caffeine, tolbutamide and digoxin in human (Poster No. IV-1)
Olavi Pelkonen: EUROCYP: In Vitro approaches to predict drug metabolism and interactions in man in drug development (Poster No. IV-9)
Lisbeth Knudsen: The importance of genetic polymorphisms (GSTM1 & NAT2) in urban air exposure and chromosomal aberrations (Poster No. VI-5)
Session IV: Prediction of drug metabolism in man
Chairmen: Daniel W. Nebert & Kim Brøsen
Philippe Beaune: In vitro techniques
Paul B. Watkins: In vivo assessment of CYP3A4
Geoffrey T. Tucker: From enzyme kinetics to pharmacokinetics
Poster session (Posters Nos. III-1-4; IV-1-12).
Session V: Drug-metabolising enzymes and environmental toxicology
Chairmen: Fred Kadlubar & Steffen Loft
Peter F. Guengerich: Enzymatic activation of carcinogens
Fred Kadlubar: Drug metabolising enzymes and carcinogen-DNA adduct formation in man
Sergei N. Rodin: On the origin of p53 mutations in lung cancer
Pierre Hainaut: Mutation spectra in human cancer: lessons from TP53 mutation analysis
Session VI: Drug-metabolising enzymes, relation to disease
Chairmen: Paul Talalay & Henrik E. Poulsen
Michael Eichelbaum: Is there a relation between drug metabolism and disease?
Neil Caporaso: Susceptibility factors for lung cancer
Daniel W. Nebert: Ethnic and genetic differences in susceptibility genes that affect individual risk of toxicity and cancer
Poster session (Posters Nos. V-1-10; VI-1-7).
Session VII: Tissue-specific drug transport
Chairmen: Kim Brøsen & Sven Frøkjær
Keld Danø: The discovery of the MDR-pump. A rationale for selecting extracellular targets for cancer chemotherapy
W. N. Konings: Multidrug transporters in bacteria
Heyo Kroemer: The functional coupling of P-glycoprotein and drug metabolism
Selected oral presentations:
Sebastian Härtter: CYP1A2 phenotyping using orally given melatonin (Poster No. VIII-1)
Sune Laugesen: The impact of paroxetine on tramadol analgesia (Poster No. VIII-10)
Kim Dalhoff: Alcohol in relation to other risk factors in paracetamol-induced hepatotoxicity (Poster No. VIII-9)
Maria Gabriella Scordo: CYP2D6 and CYP2C9 genetic polymorphisms and psychoactive-drug treatment outcome (Poster No. VIII-6)
Session VIII: Clinical relevance of drug metabolism
Chairmen: Geoffrey T. Tucker & Henrik E. Poulsen
Leif Bertilsson: Ethnic variations in drug metabolism and effects
David J. Greenblatt: Drug Interactions: mechanisms and consequences
Jack A. Hinson: Acetaminophen hepatotoxicity: role of reactive oxygen and nitrogen species
Poster session (Posters Nos. VII-1-2; VIII-1-10).