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Prof. Dr. Ulrich Michael Zanger

Affiliation

Dr. Margarete Fischer-Bosch-Institue of Clinical Pharmacology
Deputy Head of the IKP
Section Head of the Department Molecular and Cell Biology
Auerbachstr. 112
70376 Stuttgart
Germany

Phone: +49 (0) 711 - 8101 3704
Fax: +49 (0) 711 - 859 295
e-mail: uli.zanger@ikp-stuttgart.de

Originally a chemist, Dr. Zanger began to work on drug metabolism in the laboratory of Prof. Urs A. Meyer at the Biocenter of the University of Basel, Switzerland, where he obtained a Dr. phil. nat. (PhD) degree in biochemistry in 1988 for his work on biochemistry of liver cytochromes P450. He then spent three years of postdoctoral training on transcriptional regulation of steroid hydroxylases with Prof. Michael R. Waterman at the Southwestern Medical Center at Dallas, Texas, USA. After further two years as an independent postdoctoral researcher at the Biocenter Basel he moved to Stuttgart in 1994, where he established his own pharmacogenetics research group. Major research interests are in drug metabolism, molecular genetics of drug metabolizing enzymes, and pharmacogenetics/genomics with a strong mission towards translating his basic research into clinical applications like new diagnostic assays or improved drug therapy. Towards these goals Dr. Zanger has established a number of national and international research cooperations in clinical pharmacology, pharmacogenomics, ansd systems biology. Scientific work amounts to more than 120 original research articles and numerous review articles. As an extraordinary professor he is lecturing in Pharmacology and Toxicology at the University of Tübingen.

Academic Education and Professional Career

  • 1974 – 1981
    Study of Chemistry, Albert-Ludwigs-University Freiburg i.Br., Germany
  • 1982 – 1984
    Study of Medicine (Physikum), Albert-Ludwigs-University Freiburg i.Br., Medical School, Germany
  • 1984 – 1989
    Dissertation, Biocenter of University of Basel, Dept. of Pharmacology (Urs A. Meyer), on biochemistry of cytochrome P450
  • 1989 – 1992
    Postdocteral fellow, Southwestern Medical Center, Dallas, TX, USA (Michael R. Waterman), on transcriptional regulation of steroid hydroxylases
  • 1992 – 1994
    Independent Postdoctoral scientist at the Biocenter, University of Basel
  • 1994 –
    Senior research scientist at the Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart
  • 1995 –
    Head of the Department of Molecular and Cell Biology 2001 Habilitation and Venia Legendi in Biochemical Pharmacology, University of Tübingen Medical School
  • 2004 –
    Member of the scientific board of the Robert-Bosch Hospital and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology
  • Since 2008
    Extraordinary Professor of the University of Tübingen Medical School; Deputy Head of the IKP

Fellowship

  • 1989
    PhD Fellowship from the Boehringer Ingelheim Fonds for a 2-year visit at the Southwestern Medical Center, Dallas, TX, USA

Contents and Research Group

How do variations in genes contribute to altered pharmacokinetics and drug response?

We are interested in the basic factors that lead to variable drug metabolism and drug response and in translating our findings into clinical diagnostics and therapeutic application. To this end we study both genetic and nongenetic mechanisms that lead to inter- and intraindividual differences in drug biotransformation. Because most of this takes place in the liver, our preferred working tools are a large human liver bank, now consisting of about 300 clinically well documented surgical samples, as well as human hepatocytes in primary culture, which we receive from several clinical partners of our scientific networks. In the liver samples we study the molecular genetics and biochemistry of drug metabolizing enzymes, their population variability, and genotype-phenotype relationships. Hepatocytes allow us to investigate dynamic processes such as the induction or repression of genes by drugs. Based on such in vitro studies we conduct volunteer studies to validate our results, and we try to assess the clinical value of our findings in clinical studies. We recently extended our strategies to include genome-wide technologies, aiming at a more comprehensive and systems level analysis of the so-called ADME genes.

Major projects

  • Pharmacogenomics of drug metabolizing cytochromes P450 in human liver
  • Regulation of ADME genes
  • Sex differences in human drug metabolism
  • Systems biology approaches to drug metabolism in human hepatocytes
  • Exploitation of genome-wide technologies for interindividual variability

Group Members

Research Scientists

  • Kathrin Klein, PhD
  • Maria Thomas, PhD
  • Jessica Rieger, PhD

PhD Students

  • Tarek Magdy
  • Benjamin Kandel
  • Marcus Klein
  • Roman Tremmel

Technicians

  • Britta Klumpp
  • Igor Liedermann

Professional memberships

Societies

European Society of Pharmacogenomics and Theranostics (ESPT)
German Association of Pharmacology and Toxicology (DGPT)
International Society for the Study of Xenobiotics (ISSX)
American Society for Pharmacology and Experimental Therapeutics (ASPET)

Editorial Board

Pharmacogenomics (Associate Editor)
PLoS One (Associate Editor)
Frontiers in Pharmacology (Chief Editor Section Pharmacogenetics and Pharmacogenomics)
Pharmacogenomics (Associate Editor)
Drug Metabolism and Drug Interactions (Associate Editor) Editorial Board
Frontiers in Pharmacogenetics (Chief Editor Section Pharmacogenetics)
Pharmacogenomics (Associate Editor)
PLoS One (Associate Editor)

Extramural Funding

HepatoSys and Virtual Liver, Bundesministerium für Bildung und Forschung (BMBF)
European Union (7 FP)

Selected original publications

  • Ulrich M. Zanger and and Kathrin Klein. Pharmacogenetics of cytochrome P450 2B6 (CYP2B6): advances on polymorphisms, mechanisms, and clinical relevance. Front Genet. 2013; 4: 24.
  • Magdy T, Arlanov R, Winter S, Lang T, Klein K, Toyoda Y, Ishikawa T, Schwab M, Zanger UM. ABCC11/MRP8 polymorphisms affect 5-fluorouracil-induced severe toxicity and hepatic expression. Pharmacogenomics. 2013 Sep;14(12):1433-48.
  • Klein K, Thomas M, Winter S, Nussler AK, Niemi M, Schwab M, Zanger UM. PPARA: A Novel Genetic Determinant of CYP3A4 In Vitro and In Vivo. Clin Pharmacol Ther. 2012 Jun;91(6):1044-52
  • Schröder A, Klein K, Winter S, Schwab M, Bonin M, Zell A, Zanger UM. Genomics of ADME gene expression: mapping expression quantitative trait loci relevant for absorption, distribution, metabolism and excretion of drugs in human liver. Pharmacogenomics J. doi: 10.1038/tpj.2011.44. [Epub ahead of print](2011)
  • Zhang Y, Klein K, Sugathan A, Nassery N, Dombkowski A, Zanger UM, Waxman DJ. Transcriptional profiling of human liver identifies sex-biased genes associated with polygenic dyslipidemia and coronary artery disease. PLoS One. 6(8):e23506 (2011)
  • Riedmaier S, Klein K, Winter S, Hofmann U, Schwab M, Zanger UM. Paraoxonase (PON1 and PON3) Polymorphisms: Impact on Liver Expression and Atorvastatin-Lactone Hydrolysis. Front Pharmacol. 2:41 (2011)
  • Bucher J, Riedmaier S, Schnabel A, Marcus K, Vacun G, Weiss TS, Thasler WE, Nüssler AK, Zanger UM, Reuss M. A systems biology approach to dynamic modeling and inter-subject variability of statin pharmacokinetics in human hepatocytes. BMC Syst Biol.May 6;5:66. doi: 10.1186/1752-0509-5-66 (2011).
  • Klein K, Winter S, Turpeinen M, Schwab M, Zanger UM. Pathway-Targeted Pharmacogenomics of CYP1A2 in Human Liver. Front Pharmacol. 1:129 (2010)
  • Riedmaier S, Klein K, Hofmann U, Keskitalo JE, Neuvonen PJ, Schwab M, Niemi M, Zanger UM. UDP-glucuronosyltransferase (UGT) polymorphisms affect atorvastatin lactonization in vitro and in vivo. Clin Pharmacol Ther. 87:65-73 (2010).
  • Ana M. Gomes, Stefan Winter, Kathrin Klein, Miia Turpeinen, Elke Schaeffeler, Matthias Schwab, Ulrich M. Zanger: Multifactorial Analysis of NADPH:Cytochrome P450 Oxidoreductase in Human Liver: Polymorphisms, Haplotype Structures, and Impact on Microsomal Drug Oxidation Activities. Pharmacogenomics 10:579-599 (2009).
  • Elmar Langenfeld, Ulrich M. Zanger, Klaus Jung, Helmut E. Meyer, Katrin Marcus: Mass spectrometry-based absolute quantification of microsomal cytochrome P450 2D6 in human liver. Proteomics 9:2313-2323 (2009).
  • Redlich G, Zanger UM, Riedmaier S, Bache N, Giessing ABM, Eisenacher M, Stephan C, Meyer HE, Jensen ON, Marcus K: Distinction between human Cytochrome P450 (CYP) isoforms and identification of new phosphorylation sites by mass spectrometry. J Proteome Res 7:4678-4688 (2008).
  • Hofmann MH, Blievernicht JK, Klein K, Saussele T, Schaeffeler E, Schwab M, Zanger UM: Aberrant Splicing Caused by Single Nucleotide Polymorphism c.516G>T [Q172H], a Marker of CYP2B6*6, Is Responsible for Decreased Expression and Activity of CYP2B6 in Liver. J Pharmacol Exp Ther 325:284–292 (2008).
  • Schwab M, Zanger UM, Marx C, Schaeffeler E, Klein K, Dippon J, Kerb R, Blievernicht J, Fischer J, Hofmann U, Bokemeyer C, Eichelbaum M; German 5-FU Toxicity Study Group: Role of genetic and nongenetic factors for fluorouracil treatment-related severe toxicity: a prospective clinical trial by the German 5-FU Toxicity Study Group. J Clin Oncol 26:2131-2138 (2008).
  • Rotger M, Tegude H, Colombo S, Cavassini M, Furrer H, Decosterd L, Blievernicht J, Saussele T, Gunthard HF, Schwab M, Eichelbaum M, Telenti A, Zanger UM: Predictive value of known and novel alleles of CYP2B6 for efavirenz plasma concentrations in HIV-infected individuals. Clin Pharmacol Ther 81:557-566 (2007)
  • Toscano C, Klein C, Blievernicht J, Schaeffeler E, Saussele T, Raimundo S, Eichelbaum M, Schwab M, Zanger UM: Impaired expression of CYP2D6 in intermediate metabolizers carrying the *41 allele caused by the intronic SNP 2988G>A: evidence for modulation of splicing events. Pharmacogenet Genomics. 16:755-766 (2006).
  • Zukunft J, Lang T, Richter T, Hirsch-Ernst KI, Nussler AK, Klein K, Schwab M, Eichelbaum M, Zanger UM: A natural CYP2B6 TATA box-polymorphism (-82T>C) leading to enhanced transcription and relocation of the transcriptional start site. Mol Pharmacol 67(5):1772-1782 (2006).
  • Schaeffeler E, Schwab M, Eichelbaum M, Zanger UM: CYP2D6 Genotyping Strategy Based on Gene Copy Number Determination by TaqMan Real-Time PCR. Human Mutation 22:476-485 (2003).
  • Wolbold R, Klein K, Burk O, Nüssler AK, Neuhaus P, Eichelbaum M, Schwab M, Zanger UM: Sex is a Major Determinant of CYP3A4 Expression in Human Liver. Hepatology 38:978-988 (2003).
  • Lang T, Klein K, Fischer J, Nüssler AK, Neuhaus P, Hofmann U, Eichelbaum M, Schwab M, Zanger UM: Extensive Genetic Polymorphism in the Human CYP2B6 Gene with Impact on Expression and Function in Human Liver. Pharmacogenetics 11: 399-415 (2001).

 

Selected reviews

  •  Zanger UM, Schwab M: Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther. 138:103-141 (2013).
  • Zanger U, Klein K, Thomas M, Rieger J, Tremmel R, Kandel B, Klein M, Magdy T: Genetics, Epigenetics, and Regulation of Drug-Metabolizing Cytochrome P450 Enzymes. Clin Pharmacol Ther. 2013 Nov 6. [Epub ahead of print]
  • Zanger UM, Klein K: Pharmacogenetics of cytochrome P450 2B6 (CYP2B6): advances on polymorphisms, mechanisms, and clinical relevance. Front Genet. 2013 Mar 5;4:24. doi: 10.3389/fgene.2013.00024. eCollection 2013.
  • Klein K, Zanger UM: Pharmacogenomics of Cytochrome P450 3A4: Recent Progress Toward the "Missing Heritability" Problem. Front Genet. 2013 Feb 25;4:12. doi: 10.3389/fgene.2013.00012. eCollection 2013.
  • Zanger UM. Pharmacogenetics - challenges and opportunities ahead. Front. Pharmacol.: Aug 20;1:112 (2010)
  • Telenti A, Zanger UM: Pharmacogenetics of anti-HIV drugs. Annu Rev Pharmacol Toxicol 48:227-256 (2008).
  • Zanger UM, Turpeinen M, Klein K, Schwab M: Functional pharmacogenetics/genomics of human cytochromes P450 involved in drug biotransformation (Review). Anal Bioanal Chem 392(6):1093-1108 (2008).
  • Zanger UM, Klein K, Saussele T, Blievernicht J, Hofmann M, Schwab M: Polymorphic CYP2B6: Molecular Mechanisms and Emerging Clinical Significance (Review). Pharmacogenomics 8:743-759 (2007).
  • Zanger UM, Eichelbaum M: Cytochrome P450 2D6: Overview and Update on Pharmacology, Genetics, Biochemistry (Review). Naunyn - Schmiedebergs Arch Pharmacol 369: 23-37 (2004).