Visual Universitätsmedizin Mainz

Research and Publications

The inter-individual differences in the expression and activity of CYP3A

The CYP3A enzymes play a central role in the metabolism of drugs and environmental toxins due to their abundance in the liver and gut combined with their wide substrate spectrum. Drugs metabolized by CYP3A exhibit great pharmacokinetic variability, which has been attributed to significant differences in hepatic and intestinal CYP3A expression observed in the general population. The same variability has been postulated to affect an individual’s predisposition to cancers caused by toxins that are CYP3A substrates. Most of the inter-individual differences in CYP3A expression are presumably caused by genetic factors, but their identity remains unknown. In addition to CYP3A, we investigate the functional relevance of genetic variants in other drug metabolizing cytochrome P450s.

Optimization of therapies with anthracyclines

Anthracyclines are well established as highly efficacious antineoplastic agents for various haematopoietic and solid tumours. The wide variation in the individual sensitivity to anthracyclines suggests the presence of a genetic component. We recently identified risk genes for anthracycline-induced heart failure. Current work focuses on the verification of these findings in animal studies and on the elecidation of the apoptotic mechanisms of anthracyclines.

Publications

2015

Reichwagen A, Ziepert M, Kreuz M, Gödtel-Armbrust U, Rixecker T, Poeschel V, Reza Toliat M, Nürnberg P, Tzvetkov M, Deng S, Trümper L, Hasenfuss G, Pfreundschuh M, Wojnowski L: Association of NADPH oxidase polymorphisms with anthracycline-induced cardiotoxicity in the RICOVER-60 trial of patients with aggressive CD20(+) B-cell lymphoma. Pharmacogenomics. 16(4):361-72. doi: 10.2217/pgs.14.179.

Deng S, Yan T, Nikolova T, Fuhrmann D, Nemecek A, Gödtel-Armbrust U, Kaina B, Wojnowski L: The catalytic topoisomerase II inhibitor dexrazoxane induces DNA breaks, ATF3 and the DNA damage response in cancer cells. Br J Pharmacol. 172(9):2246-57. doi: 10.1111/bph.13046

2014

Deng S, Yan T, Jendrny C, Nemecek A, Vincetic M, Gödtel-Armbrust U, Wojnowski L: Dexrazoxane may prevent doxorubicin-induced DNA damage via depleting both topoisomerase II isoforms. BMC Cancer. 18;14:842. doi: 10.1186/1471-2407-14-842.  

Kräenbring J, Monzon Penza T, Gutmann J, Muehlich S, Zolk O, Wojnowski L, Maas R, Engelhardt S, Sarikas A. Accuracy and completeness of drug information in wikipedia: a comparison with standard textbooks of pharmacology. PLoS One. 2014 Sep 24;9(9):e106930. doi: 10.1371/journal.pone.0106930. eCollection 2014.

Laspas P, Goloborodko E, Sniatecki JJ, Kordasz ML, Manicam C, Wojnowski L, Li H, Patzak A, Pfeiffer N, Gericke A. Role of nitric oxide synthase isoforms for ophthalmic artery reactivity in mice. Exp Eye Res. 2014 Oct;127:1-8. doi: 10.1016/j.exer.2014.06.018. Epub 2014 Jul 10.

Ewer M, Gianni L, Pane F, Sandri MT, Steiner RK, Wojnowski L, Yeh ET, Carver JR, Lipshultz SE, Minotti G, Armstrong GT, Cardinale D, Colan SD, Darby SC, Force TL, Kremer LC, Lenihan DJ, Sallan SE, Sawyer DB, Suter TM, Swain SM, van Leeuwen FE. Report on the international colloquium on cardio-oncology (rome, 12-14 march 2014). Ecancermedicalscience. 2014 May 29;8:433. doi: 10.3332/ecancer.2014.433. eCollection 2014.

Baranyai D, Muro E, Gödtel-Armbrust U, Schirmer MA, Kisanga E, Diczfalusy U, Fillekes Q, Schuurman R, Burger D, Wojnowski L. Reduction of nevirapine-driven HIV mutations by carbamazepine is modulated by CYP3A activity. J Antimicrob Chemother. 2014 Jul;69(7):1933-7. doi: 10.1093/jac/dku086. Epub 2014 Apr 2.

Mathäs M, Nußhag C, Burk O, Gödtel-Armbrust U, Herlyn H, Wojnowski L, Windshügel B. Structural and functional similarity of amphibian constitutive androstane receptor with mammalian pregnane X receptor. PLoS One. 2014 May 5;9(5):e96263. doi: 10.1371/journal.pone.0096263. eCollection 2014.

2013

Qiu H, Gołas A, Grzmil P, Wojnowski L. Lineage-specific duplications of Muroidea Faim and Spag6 genes and atypical accelerated evolution of the parental Spag6 gene. J Mol Evol. 2013 Sep;77(3):119-29. doi: 10.1007/s00239-013-9585-9. Epub 2013 Sep 27

Gericke A, Goloborodko E, Sniatecki JJ, Steege A, Wojnowski L, Pfeiffer N. Contribution of nitric oxide synthase isoforms to cholinergic vasodilation in murine retinal arterioles. Exp Eye Res. Epub 2013 Feb 19

2012

Marklein D, Graab U, Naumann I, Yan T, Ridzewski R, Nitzki F, Rosenberger A, Dittmann K, Wienands J, Wojnowski L, Fulda S, Hahn H: PI3K Inhibition Enhances Doxorubicin-Induced Apoptosis in Sarcoma Cells. PlosOne Epub 2012 Dec 31

Pelczar P, Zibat A, van Dop WA, Heijmans J, Bleckmann A, Gruber W, Nitzki F, Uhmann A, Guijarro MV, Hernando E, Dittmann K, Wienands J, Dressel R, Wojnowski L, Binder C, Taguchi T, Beissbarth T, Hogendoorn PC, Antonescu CR, Rubin BP, Schulz-Schaeffer W, Aberger F, van den Brink GR, Hahn H. Inactivation of Patched1 in mice leads to development of gastrointestinal stromal-like tumors that express Pdgfrα but not kit. Gastroenterology Epub 2012 Oct 3

Domagala TB, Szeffler A, Dobrucki LW, Dropinski J, Polanski S, Leszczynska-Wiloch M, Kotula-Horowitz K, Wojciechowski J, Wojnowski L, Szczeklik A, Kalinowski L: Nitric oxide production and endothelium-dependent vasorelaxation ameliorated by n1-methylnicotinamide in human blood vessels. Hypertension, 59:825-32

Nem D, Baranyai D, Qiu H, Gödtel-Armbrust U, Nestler S, Wojnowski L: Pregnane X Receptor and Yin Yang 1 contribute to the Differential Tissue Expression and Induction of CYP3A5 and CYP3A4. PlosOne Epub Jan 23, 2012

Arlanov R,Porter A, Strand D, Brough R, Karpova D, Kerb R, Wojnowski L, Schwab M, Lang T.: Functional Characterization of Protein Variants of the Human Multidrug Transporter ABCC2 by a Novel Targeted Expression System in Fibrosarcoma Cells.  Hum Mutat, 33:750-62

2011

Mathäs M, Burk O, Qiu H, Nußhag C, Gödtel-Armbrust U, Baranyai D, Deng S, Römer K, Nem D, Windshügel B, Wojnowski L: Evolutionary History and Functional Characterization of the Amphibian Xenosensor CAR. Mol Endocrinol Epub Nov 10, 2011

2010

Qiu H, Mathäs M, Nestler S, Bengel C, Nem D, Gödtel-Armbrust U, Lang T, Taudien S, Burk O, Wojnowski L: The unique complexity of the CYP3A4 upstream region suggests a nongenetic explanation of its expression variability. Pharmacogenetics and Genomics, 20:167-78

Hoffmann M, Schirmer M, Tzvetkov M, Kreuz M, Ziepert M, Wojnowski L, Kube D, Pfreundschuh M, Trümper L, Loeffler M, Brockmöller J. A functional polymorphism in the NAD(P)H oxidase subunit CYBA is related with gene expression, enzyme activity and outcome in Non-Hodgkin lymphoma. Cancer Res, 70: 2328-38

2009

Yan T, Deng S, Metzger A, Gödtel-Armbrust U, Porter A, Wojnowski L. Topoisomerase II alpha-dependent and -independent apoptotic effects of dexrazoxane and doxorubicin. Mol Cancer Ther 8: 1075-85

Deng S, Kruger A, Schmidt A, Metzger A, Yan T, Gödtel-Armbrust U, Hasenfuss G, Brunner F, Wojnowski L. Differential roles of NOS isozymes in cardiotoxicity and mortality following chronic doxorubicin treatment in mice. Arch Pharmacol 380: 25-34

Kumar S, Qiu H, Oezguen N, Herlyn H, Halpert JR, Wojnowski L Expression, protein stability, and ligand diversity of human and chimpanzee CYP3A4 and their putative common ancestor. Drug Metab Dispos 37: 1328-33

Zibat A, Uhmann A, Nitzki F, Wijgerde M, Frommhold A, Heller T, Armstrong V, Wojnowski L, Quintanilla-Martinez L, Reifenberger J, Schulz-Schaeffer W, Hahn H. Time-point and dosage of gene inactivation determine the tumor spectrum in conditional Ptch knockouts. Carcinogenesis. 2009 Mar 25. [Epub ahead of print]

Spanier G, Xu H, Xia N, Tobias S, Deng S, Wojnowski L, Forstermann U, Li H. Resveratrol reduces endothelial oxidative stress by modulating the gene expression of superoxide dismutase 1 (sod1), glutathione peroxidase 1 (gpx1) and nadph oxidase subunit (nox4). J Physiol Pharmacol 60 (Suppl 4): 111-116

Ecke I, Petry F, Rosenberger A, Tauber S, Mönkemeyer S, Hess I, Dullin C, Kimmina S, Pirngruber J, Johnsen S, Uhmann A, Nitzki F, Wojnowski L, Schulz-Schaeffer W, Witt O, Hahn H. Antitumor effects of a combined 5-aza-2'deoxycytidine and valproic acid treatment on rhabdomyosarcoma and medulloblastoma in Ptch mutant mice. Cancer Res 69: 887-95

2008

Holden M, Deng S, Wojnowski L, Kulle B: GSEA-SNP: Applying Gene Set Enrichment Analysis to SNP data from genome-wide association studies. Bioinformatics 24: 2784-85

Kassner N, Huse K, Martin HJ, Gödtel-Armbrust U, Metzger A, Meineke I, Brockmöller J, Klein K, Zanger UM, Maser E, Wojnowski L: CBR1 is a predominant doxorubicin reductase in the human liver. Drug Metab Dispos 36: 2113-20

Kulle B, Frigessi A, Edvardsen H, Kristensen V, Wojnowski L: Accounting for haplotype phase uncertainty in LD estimation. Genet Epidemiol, 32: 168-178

Tsukamoto H, Irie A, Senju S, Hatzopoulos AK, Wojnowski L, Nishimura Y: B-Raf-mediated signaling pathway regulates T cell development. Eur J Immunol, 38: 518-27.

Qiu H, Taudien S, Herlyn H, Schmitz J, Zhou Y, Chen G, Roberto R, Rocchi M, Platzer M, Wojnowski L: CYP3 phylogenomics: evidence for positive selection of CYP3A4 and CYP3A7. Pharmacogenetics and Genomics, 18: 53-66

Wenzel P, Müller J, Zurmeyer S, Schuhmacher S, Schulz E, Oelze M, Pautz A, Kawamoto T, Wojnowski L, Kleinert H, Münzel T, Daier A: ALDH-2 deficiency increases cardiovascular oxidative stress--evidence for indirect antioxidative properties. Biochem Biophys Res Commun, 367: 137-43

Janke D, Mehralivand S, Strand D, Gödtel-Armbrust U, Habermeier A, Gradhand U, Fischer C, Toliat MR, Fritz P, Zanger UM, Schwab M, Fromm MF, Nürnberg P, Wojnowski L, Closs EI, Lang T: 6-mercaptopurine and 9-(2-phosphonyl-methoxyethyl) adenine (PMEA) transport altered by two missense mutations in the drug transporter gene ABCC4. Hum Mutat, 29: 659.69

2007

Kube D, Hua T-D, Klöss M, Kulle B, Brockmöller J, Wojnowski L, Löffler M, Pfreundschuh M, Trümper L: The Interleukin-10 gene promoter polymorphism -1087AG does not correlate with clinical outcome in Non-Hodgkin lymphoma. Genes and Immunity, 8: 164-7

Deng S, Kruger A, Kleschyov AL, Kalinowski L, Daiber A, Wojnowski L: Gp91phox-containing NAD(P)H oxidase increases superoxide formation by doxorubicin and NADPH. Free Radic Biol Med, 42: 466-73

Nitzki F , Kruger A , Reifenberg K, Wojnowski L , Hahn H: Identification of a genetic contamination in a commercial mouse strain using two panels of polymorphic markers. Lab Animals, 41: 218-28


Schirmer M, Rosenberger A, Klein K, Kulle B, Toliat MR, Nürnberg P, Zanger UM, Wojnowski L: Sex-dependent genetic markers of CYP3A4 expression and activity in human liver microsomes. Pharmacogenomics, 8: 443-453

Gödtel-Armbrust U, Metzger A, Kroll U, Kelber O, Wojnowski L: Variability in PXR-mediated induction of CYP3A4 by commercial preparations and dry extracts of St. John's wort. Arch Pharmacol, 375: 377-82

Deng S, Wojnowski L: Genotyping the risk of anthracycline-induced cardiotoxicity. Cardiovasc Toxicol, 7: 129-34

Paulides M, Wojnowski L: Chemotherapeutics-induced drug failure. Med Klin, 102: 574-8

Deng S, Kulle B, Hosseini M, Schlüter G, Hasenfuss G, Wojnowski L, Schmidt A: Dystrophin-deficiency increases the susceptibility to doxorubicin-induced cardiotoxicity. Eur J Heart Failure, 9: 986-94

2006

Schirmer M, Toliat MR, Haberl M, Suk A, Kamdem LK, Klein K, Brockmöller J, Nürnberg P, Zanger UM, Wojnowski L: Genetic signature consistent with selection against the CYP3A4*1B allele in non-African populations. Pharmacogenetics  and Genomics  16: 59-71

Wojnowski L, Kamdem L: Clinical implications of CYP3A polymorphisms. Expert Opin Drug Metab Toxicol 2: 1-12

Kamdem L, Meineke I, Gödtel-Armbrust U, Brockmöller J, Wojnowski L: Dominant contribution of P450 3A4 to the hepatic carcinogenic activation of aflatoxin B1. Chem Res Toxicol 19: 577-86

Wojnowski L: ADHD drugs and cardiovascular risk. N Engl J Med 354: 2296-8


Kersting G, Tzvetkov MV, Huse K, Kulle B, Hafner V, Brockmöller J, Wojnowski L: Topoisomerase II beta expression level correlates with doxorubicin-induced apoptosis in peripheral blood cells. Arch Pharmacol, 374: 21-30

Kruger A, Wojnowski L: Kardiotoxizität von Anthrazyklinen – ein ungelöstes Problem. Deutsches Ärzteblatt 103: 2393–7


Niemi M, Arnold K, Backman J, Pasanen M, Gödtel-Armbrust U, Wojnowski L, Zanger U, Neuvonen P, Eichelbaum M, Kivistö K, Lang T: Association of genetic polymorphism in ABCC2 with hepatic MRP2 expression and pravastatin pharmacokinetics. Pharmacogenetics and Genomics, 16: 801-808.

Köhler S, von Ahsen N, Schlumbohm C, Gödtel-Armbrust U, Oellerich M, Wojnowski L, Armstrong VM: Marmoset CYP3A21, a model for human CYP3A4: transcriptional control and functional characterization of the promoter. Xenobiotica, 36: 1210-26

2005

Tzvetkov MV, Becker Ch, Kulle B, Nürnberg, Brockmöller J, Wojnowski L: Genome-wide single-nucleotide polymorphism arrays demonstrate high fidelity of multiple displacement-based whole-genome amplification. Electrophoresis 26: 710–715

Kulle B, Schirmer M, Toliat MR, Suk A, Becker Ch, Tzvetkov MV, Brockmöller J, Bickeböller H, Hasenfuss G, Nürnberg P, Wojnowski L: Application of genome-wide SNP arrays for detection of simulated susceptibility loci. Human Mutation 25:557-565

Kamdem L, Streit F, Zanger U, Brockmöller J, Oellerich M, Armstrong V, Wojnowski L: Contribution od CYP3A5 to the in vitro hepatic clearance of tacrolimus. Clin Chem 51: 1374-81

Kamata T, Kang J, Lee T-H, Wojnowski L, Pritchard C, Leavitt A: A critical function of B-Raf at multiple stages of myelopoiesis. Blood 106: 833-840

Haberl M, Anwald B, Klein K, Weil R, Fuß C, Gepdiremen A, Zanger U, Meyer U, Wojnowski L: Three haplotypes  associated  with CYP2A6 phenotypes in Caucasians. Pharmacogenetics  and Genomics  15: 609-624

Uhmann A, Ferch U, Bauer R, Tauber S, Arziman Z, Chen C, Hemmerlein B, Wojnowski L, Hahn H. A model for PTCH1/Ptch1-associated tumors comprising mutational inactivation and gene silencing. Int J Oncol. 27: 1567-75    

Wojnowski L, Kulle B, Schirmer M, Schluter G, Schmidt A, Rosenberger A, Vonhof S, Bickeboller H, Toliat MR, Suk EK, Tzvetkov M, Kruger A, Seifert S, Kloess M, Hahn H, Loeffler M, Nurnberg P, Pfreundschuh M, Trumper L, Brockmoller J, Hasenfuss G: NAD(P)H oxidase and multidrug resistance protein genetic polymorphisms are associated with doxorubicin-induced cardiotoxicity. Circulation 112: 3754-62

2004

Burk O, Koch I, Raucy J, Hustert E, Eichelbaum M, Brockmöller J, Zanger UM, Wojnowski L: The induction of CYP3A5 in human liver and intestine is mediated by the xenobiotic sensors PXR and CAR. J Biol Chem 279:38379-38385

Kamdem LK, Meineke I, Koch I, Zanger UM, Brockmöller, Wojnowski L: Limited contribution of CYP3A5 to the hepatic 6beta-hydroxylation of testosterone. Naunyn Schmiedebergs Arch Pharmacol 370:71-7

Wojnowski L, Brockmoller J: Single nucleotide polymorphism characterization by mRNA expression imbalance assessment. Pharmacogenetics 14:267-9

Burk O, Wojnowski L: Cytochrome P450 3A and their regulation. Naunyn Schmiedebergs Arch Pharmacol 369:105-24

Wojnowski L: Genetics of the variable expression of CYP3A in humans. Ther Drug Monit 26:192-9

Lang T, Klein K, Richter T, Zibat A, Kerb R, Eichelbaum M, Schwab M, Zanger UM: Multiple Novel Nonsynonymous CYP2B6 Gene Polymorphisms in Caucasians: Demonstration of Phenotypic Null Alleles. J Pharmacol Exp Ther 311:34-43

Lang T, Hitzl M, Burk O, Mornhinweg E, Keil A, Kerb R, Klein K, Zanger UM, Eichelbaum M, Fromm MF: Genetic polymorphisms in the multidrug resistance-associated protein 3 (ABCC3, MRP3) gene and relationship to its mRNA and protein expression in human liver. Pharmacogenetics 14:155-64

Wojnowski L, Turner PC, Pedersen B, Hustert E, Brockmoller J, Mendy M, Whittle HC, Kirk G, Wild PC: Increased levels of aflatoxin-albumin adducts are associated with CYP3A5 polymorphisms in The Gambia, West Africa. Pharmacogenetics 14: 691-700

Pritchard C, Hayes L, Wojnowski L, Zimmer A, Marais R, Norman J: B-Raf acts via the ROCKII/LIMK/Cofilin Pathway to maintain actin stress fibers in fibroblasts. Mol Cell Biol 24:5937-5952

2003


Vormfelde S, Burckhardt G, Zirk A, Wojnowski L, Brockmöller J: Pharmacogenomics of diuretic drugs: data on rare monogenic disorders and on polymorphisms and requirements for further research. Pharmacogenomics 4:701-734

2002


Wojnowski L, Hustert E, Klein K, Goldammer M, Haberl M, Kirchheiner J, Koch I, Klattig J, Zanger UM, Brockmöller J: Re: Modification of Clinical Presentation of Prostate Tumors by a Novel Genetic Variant in CYP3A4. J Natl Cancer Inst 94:630-631

Burk O, Tegude H, Koch I, Hustert E, Wolbold R, Glaeser H, Klein K, Fromm MF, Nuessler AK, Neuhaus P, Zanger UM, Eichelbaum M, Wojnowski L: Molecular mechanisms of polymorphic CYP3A7 expression in adult human liver and intestine. J Biol Chem 277:24280-8

Koch I, Weil R, Wolbold R, Brockmöller J, Hustert E, Burk O, Nuessler A, Neuhaus P, Eichelbaum M, Zanger UM, Wojnowski L: Interindividual Variability and Tissue-Specificity in the Expression of Cytochrome P450 3A mRNA. Drug Metab Dispos 30:1108-1114

2001


Gellner K, Eiselt R, Hustert E, Arnold H, Koch I, Haberl M, Deglmann CJ, Burk O, Buntefuss D, Escher S, Bishop C, Koebe H-G, Brinkmann U, Klenk H-P, Kleine K, Meyer UA, Wojnowski L: Genomic organization of the human CYP3A locus: identification of a new, inducible CYP3A gene. Pharmacogenetics 11:111-21

Eiselt R, Domanski TL, Zibat A, Mueller R, Presecan-Siedel E, Hustert E, Zanger UM, Brockmöller J, Klenk H-P, Meyer UA, Khan KK, He YA, Halpert JR, Wojnowski L: Identification and functional characterization of eight CYP3A4 protein variants. Pharmacogenetics 11:447-58

Hustert E, Haberl M, Burk O, Wolbold R, He YQ, Klein K, Neussler A, Neuhaus P, Klattig J, Eiselt R, Koch I, Zibat A, Brockmöller J, Halpert JR, Zanger UM, Wojnowski L: The genetic determinants of the CYP3A5 polymorphism. Pharmacogenetics 11:773-779

Hustert E, Zibat A, Presecan-Siedel E, Eiselt R, Mueller R, Fuß C, Brehm I, Brinkmann U, Eichelbaum M, Wojnowski L, Burk O: Natural protein variants of pregnane x receptor with altered transactivation activity toward cyp3a4. Drug Metab Dispos 29:1454-9