Sitemap Contact Privacy Statement Imprint

Molecular mechanisms of ADME gene regulation

The interindividual variability of expression of genes encoding drug metabolizing enzymes and transporters contributes significantly to human drug disposition. Their expression is largely controlled by transcription factors at the level of transcription initiation. Improving our knowledge of variable drug disposition thus requires a well-founded and detailed understanding of the respective molecular mechanisms of transcriptional regulation. Members of the nuclear receptor (NR) family of transcription factors play a decisive role in transcriptional regulation of these genes, as they contribute both to constitutive and inducible expression. The xenosensing nuclear receptors PXR and CAR are here of special interest, as induction by xenobiotics, including many drugs, often results in drug-drug interactions with potential severe clinical consequences. Our research aims to elucidate the molecular mechanisms of ADME gene regulation by NRs, especially PXR and CAR, by identifying and characterizing the relevant cis-acting sequences in promoters and enhancers of regulated genes as well as identifying the trans-acting proteins (e.g. co-activators and co-repressors), which interact with the NRs in the regulation of their target genes. Furthermore, we are interested in the interplay of NRs and epigenetic modifications in the chromatin of the theses genes. In addition to molecular and biochemical approaches, we use comparative genomics to analyze the evolutionary conservation of gene-regulatory mechanisms. We currently focus on drug transporter genes and selected ABCB1, one of the most important human drug transporters, as the paradigm gene for our analyses.
Major Projects
  • Molecular mechanisms of the interindividual variability in expression and induction of ABCB1
  • Molecular mechanisms of gene regulation of drug transporters by NRs
  • Identification of proteins interacting with PXR/CAR
  • Comparative genomics of ADME gene regulation
  • Role of PXR/CAR in human non-alcoholic fatty liver disease
Dr. rer. nat. Oliver Burk

phone: ++49-711-8101 3753

Selected References
  • Burk O, Brenner SS, Hofmann U, Tegude H, Igel S, Schwab M, Eichelbaum M, Alscher MD. The impact of thyroid disease on the regulation, expression and function of MDR1/P-glycoprotein (ABCB1) and consequences for the disposition of digoxin. Clin Pharmacol Ther. 2010; 88:685-694
  • Istrate MA, Nussler AK, Eichelbaum M, Burk O. Regulation of CYP3A4 by pregnane X receptor: The role of nuclear receptors competing for response element binding. Biochem Biophys Res Commun. 2010; 393:688-693.
  • Burk O. Nuclear receptor-mediated regulation of drug transporters. In: Xie W (ed.) Nuclear receptors in drug metabolism. John Wiley & Sons, Hoboken 2008, pp 111-146.
  • Burk O, Arnold KA, Geick A, Tegude H, Eichelbaum M. A role for constitutive androstane receptor in the regulation of human intestinal MDR1 expression. Biol Chem. 2005; 386:503-513.
Major Networks and Collaborations
  • Prof. Leszek Wojnowski, Institute of Pharmacology, Johannes Gutenberg Universität, Mainz, Germany
  • José Pedro Gil, Karolinska Institute, Stockholm, Sweden

Curriculum Vitae Oliver Burk, PhD

Affiliation
Molecular Biologist
Deputy Head of the Cellular and Molecular Biology Department
Research Group Leader Molecular Mechanisms of ADME Gene Regulation

Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology
Auerbachstrasse 112
70376 Stuttgart, Germany
Phone: ++49-711-8101 3753
Fax: ++49-711-859295
e-mail: oliver.burk@ikp-stuttgart.de
Education and Professional Career
1981-1987 Study of Biology at the Justus-Liebig University Giessen, Germany.
1986-1987 Diploma thesis at the Institute of Genetics (Prof. Dr. Fritz Anders), Justus-Liebig University Giessen, Germany. Title of the thesis: “Conservation of homologues sequences of the nuclear protein-coding oncogenes v-fos, v-myc and v-myb in the animal kingdom”
1989-1993 PhD thesis in the laboratory of PD Dr. Karl-Heinz Klempnauer, first at the Center of Molecular Biology Heidelberg (ZMBH), since 1990 at the Max-Planck-Institute of Immunobiology, Freiburg, Germany. Title of the thesis: “Investigation of the regulation of myeloid-specific gene expression by the sequence-specific transcription factor v-myb”
1993 Dr. rer. nat. (PhD), Faculty of Biology, Justus-Liebig University Giessen, Germany
1993-1997 Postdoctoral research fellow in the laboratory of PD Dr. Karl-Heinz Klempnauer at the Max-Planck-Institute of Immunobiology, Freiburg, Germany, (within SFB 364: Molecular and cellular basis of tumor therapy); Research topic: “Identification of myb-regulated genes in haematopoiesis”
1997-1999 Postdoctoral research fellow in the research group of Prof. Dr. Hermann Wisser, Robert Bosch Hospital, Stuttgart, Germany. Research topic: “Age-dependent differential gene expression in the heart”
2000-2006 Reseach group leader in the research division “Pharmacogenomics” of Prof. Dr. Michel Eichelbaum at the Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany. Area of research: “Gene regulation of drug metabolizing enzymes and transporters by nuclear receptors”
2007-present Research group leader in the research division “Pharmacogenomics” of Prof. Dr. Matthias Schwab at the Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany. Area of research: “Molecular mechanisms of ADME gene regulation”
Professional Memberships
since 2000: International Society for the Study of Xenobiotics (ISSX)
since 2001: German Society for Biochemistry and Molecular Biology (Gesellschaft für Biochemie und Molekularbiologie (GBM))
since 2002: American Society for Biochemistry and Molecular Biology (ASBMB)
Scientific Journal Editorial Board Memberships
Frontiers in Pharmacogenetics