HOME > セミナー案内 > 詳細ページ
セミナー案内 | 詳細ページ
タイトル Ulrich Zanger博士 特別講演会
講演者 Ulrich Zanger博士
所属 Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology. University of Tübingen, Germany
開催日 2017-12-13 14:00
終了日 2017-12-13 15:00
Ulrich Zanger博士 特別講演会のお知らせ

演題:Role of (epi)genetic and (patho)physiological factors for variability 
of human drug metabolism
講師:Dr. Ulrich M. Zanger
Dr. Margarete Fischer-Bosch-Institut für Klinische Pharmakologie, 
Auerbachstr. 112, D - 70376 Stuttgart, and Eberhard-Karls-University, 
Tübingen, Germany
日時: 2017年12月13日(水) 14時00分〜15時00分
場所:九州大学大学院薬学研究院2号館5階 第4講堂(福岡市東区馬出3丁目1番1号)

Ulrich Zanger先生は、Dr. Margarete Fischer-Bosch Institute of Clinical 
Pharmacologyの副研究所長であり、University of Tübingen, Germanyのextraordinary 
(absorption, distribution, metabolism, excretion) 


Dr. Ulrich M. Zanger
Dr. Margarete Fischer-Bosch-Institut für Klinische Pharmakologie, 
Auerbachstr. 112, D - 70376 Stuttgart, and Eberhard-Karls-University, 
Tübingen, Germany

Role of (epi)genetic and (patho)physiological factors for variability of 
human drug metabolism

Regulation of genes involved in absorption, distribution, metabolism and excretion (ADME) is influenced by genetic and nongenetic factors but a large fraction of intra- and interindividual variability remains unexplained. I will present new aspects of the influence of genetic polymorphisms on various CYPs and other ADME genes, including single nucleotide polymorphisms and copy number variation. For some genes, e.g. CYP3A4, the contribution by genetic factors has been unclear. Recent studies using the classical twin approach assessed the global impact of genetic factors. On the other hand, the role of nongenetic factors is exemplified by inflammation, which has a strong negative impact on most ADME genes in parallel to the positive acute phase response to battle the inflammation. Human liver genome wide mRNA expression data suggest a broad reprogramming during inflammatory conditions. Systems biology modeling and experimental data from human primary hepatocytes indicate a 
central role for the orphan nuclear receptor RXRα, as well as heterodimerization partners CAR and PXR for the cytokine-induced 
downregulation of ADME genes. Mechanistically the downregulation appears to involve various signaling pathways and may also include microRNAs. We found that miR-130b, which was upregulated in inflammation, has the capability to downregulate the enzyme activity of several cytochromes P450 (CYPs 1A2, 2B6, 2C8, 2C9, 3A4). Direct interactions of miR130b include the target genes CYP2C9 and RXRα. A closer understanding of these interaction networks is expected to allow better prediction of drug metabolism capacity in various pathophysiological conditions.

Some References:

Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther. 2013 Apr;138(1):103-41. doi: 10.1016/j.pharmthera.2012.12.007. Epub 2013 Jan 16. Review. PMID: 23333322 Free Article

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.

Rieger JK, Reutter S, Hofmann U, Schwab M, Zanger UM (2015): Inflammation-Associated microRNA-130b downregulates cytochrome P450 activities and directly targets CYP2C9. Drug Metab Dispos 43:884-8.

Meyer UA, Zanger UM, Schwab M. Omics and drug response. Annu Rev Pharmacol Toxicol. 2013;53:475-502. doi: 10.1146/annurev-pharmtox-010510-100502. Epub 2012 Nov 5. Review. PMID: 23140244

Kandel BA, Thomas M, Winter S, Damm G, Seehofer D, Burk O, Schwab M, Zanger UM. Genomewide comparison of the inducible transcriptomes of nuclear receptors CAR, PXR and PPARα in primary human hepatocytes. Biochim Biophys Acta. 2016 Sep;1859(9):1218-27. doi: 10.1016/j.bbagrm.2016.03.007. Epub 2016 Mar 17. PMID:   26994748

Keller R, Klein M, Thomas M, Dräger A, Metzger U, Templin MF, Joos TO, Thasler WE, Zell A, Zanger UM. Coordinating Role of RXRα in Downregulating Hepatic Detoxification during Inflammation Revealed by Fuzzy-Logic Modeling. PLoS Comput Biol. 2016 Jan 4;12(1):e1004431. doi: 10.1371/journal.pcbi.1004431. eCollection 2016 Jan. PMID:    26727233 Free PMC Article

Ryu CS, Klein K, Zanger UM. Membrane Associated Progesterone Receptors: Promiscuous Proteins with Pleiotropic Functions - Focus on Interactions with Cytochromes P450. Front Pharmacol. 2017 Mar 27;8:159. doi: 10.3389/fphar.2017.00159. eCollection 2017. Review.

Tremmel R, Herrmann K, Engst W, Meinl W, Klein K, Glatt H, Zanger UM. Methyleugenol DNA adducts in human liver are associated with SULT1A1 copy number variations and expression levels. Arch Toxicol. 2017 Oct;91(10):3329-3339. doi: 10.1007/s00204-017-1955-4. Epub 2017 Mar 22. PMID:   28326452

石井祐次 九州大学大学院薬学研究院分子衛生薬学分野
電話: 092-642-6586
E-mail: ishii@phar.kyushu-u.ac.jp