@misc{KruegerGengeKoehlerLaubeetal., author = {Kr{\"u}ger-Genge, Anne and K{\"o}hler, Susanne and Laube, Markus and Haileka, Vanessa and Lemm, Sandy and Majchrzak, Karolina and Kammerer, Sarah and Schulz, Christian and Storsberg, Joachim and Pietzsch, Jens and K{\"u}pper, Jan-Heiner and Jung, Friedrich}, title = {Anti-Cancer Prodrug Cyclophosphamide Exerts Thrombogenic Effects on Human Venous Endothelial Cells Independent of CYP450 Activation—Relevance to Thrombosis}, series = {Cells}, volume = {12}, journal = {Cells}, number = {15}, issn = {2073-4409}, doi = {10.3390/cells12151965}, abstract = {Cancer patients are at a very high risk of serious thrombotic events, often fatal. The causes discussed include the detachment of thrombogenic particles from tumor cells or the adverse effects of chemotherapeutic agents. Cytostatic agents can either act directly on their targets or, in the case of a prodrug approach, require metabolization for their action. Cyclophosphamide (CPA) is a widely used cytostatic drug that requires prodrug activation by cytochrome P450 enzymes (CYP) in the liver. We hypothesize that CPA could induce thrombosis in one of the following ways: (1) damage to endothelial cells (EC) after intra-endothelial metabolization; or (2) direct damage to EC without prior metabolization. In order to investigate this hypothesis, endothelial cells (HUVEC) were treated with CPA in clinically relevant concentrations for up to 8 days. HUVECs were chosen as a model representing the first place of action after intravenous CPA administration. No expression of CYP2B6, CYP3A4, CYP2C9 and CYP2C19 was found in HUVEC, but a weak expression of CYP2C18 was observed. CPA treatment of HUVEC induced DNA damage and a reduced formation of an EC monolayer and caused an increased release of prostacyclin (PGI2) and thromboxane (TXA) associated with a shift of the PGI2/TXA balance to a prothrombotic state. In an in vivo scenario, such processes would promote the risk of thrombus formation.}, language = {en} } @misc{PrillSinghSeeberetal., author = {Prill, Robert and Singh, Jasvinder A. and Seeber, Gesine H. and Mai Nielsen, Sabrina and Goodman, Susan and Michel, Sven and Kopkow, Christian and Schulz, Robert and Choong, Peter and Hommel, Hagen}, title = {Patient, physiotherapist and surgeon endorsement of the core domain set for total hip and total knee replacement in Germany: a study protocol for an OMERACT initiative}, series = {BMJ open}, volume = {10}, journal = {BMJ open}, number = {6}, issn = {2044-6055}, doi = {10.1136/bmjopen-2019-035207}, pages = {8}, language = {en} } @misc{PrillSinghSeeberetal., author = {Prill, Robert and Singh, Jasvinder A. and Seeber, Gesine H. and Mai Nielsen, Sabrina and Goodman, Susan and Michel, Sven and Kopkow, Christian and Schulz, Robert and Choong, Peter and Hommel, Hagen}, title = {Endorsement des OMERACT Core Domain Sets f{\"u}r H{\"u}ft- und Kniegelenkersatz: ein Survey unter Patienten, Physiotherapeuten und Orthop{\"a}den in Deutschland - ein Studienprotokoll}, series = {4. Forschungssymposium Physiotherapie, FSPT2019 Abstractband}, journal = {4. Forschungssymposium Physiotherapie, FSPT2019 Abstractband}, pages = {45 -- 46}, language = {de} } @misc{SchulzStegenJungetal., author = {Schulz, Christian and Stegen, Sarah and Jung, Friedrich and K{\"u}pper, Jan-Heiner}, title = {Mono-CYP CHO model : a recombinant Chinese hamster ovary cell platform for investigating CYP-specific tamoxifen metabolism}, series = {International journal of molecular sciences}, volume = {26}, journal = {International journal of molecular sciences}, number = {9}, editor = {Lamb, David and Syed, Khajamohiddin}, publisher = {MDPI}, address = {Basel}, issn = {1422-0067}, doi = {10.3390/ijms26093992}, pages = {1 -- 24}, abstract = {The metabolism of drugs and foreign substances in humans typically involves multiple enzymatic steps, particularly in phase-1 biotransformation in the liver, where various cytochrome P450 monooxygenases (CYPs) play crucial roles. This complexity can lead to a wide range of metabolites. Understanding the contributions of individual CYPs and their interactions within these intricate enzyme cascades can be challenging. We recently developed an in vitro biotransformation platform employing various Chinese Hamster Ovarian (CHO) cell clones. These clones express human cytochrome P450 oxidoreductase (CPR), and each is defined by a specific human CYP enzyme expression, thus exhibiting no detectable endogenous CYP enzyme activity (mono-CYP CHO platform). In this study, we investigated whether the mono-CYP CHO platform is a suitable tool for modeling complex drug metabolization reactions in vitro. Tamoxifen (TAM) was selected as a model substance due to its role as a prodrug widely used in breast cancer therapy, where its main active metabolite, endoxifen, arises from a two-step metabolism primarily involving the CYP system. Specifically, the combined activity of CYP3A4 and CYP2D6 is believed to be essential for efficient endoxifen production. However, the physiological metabolization pathway of TAM is more complex and interconnected, and the reasons for TAM's therapeutic success and variability among patients are not yet fully understood. Analogous to our recently introduced mono-CYP3A4 CHO cells, we generated a CHO cell line expressing human CPR and CYP2D6, including analysis of CYP2D6 expression and specific activity. Comparative studies on the metabolization of TAM were performed with both mono-CYP CHO models individually and in co-culture with intact cells as well as with isolated microsomes. Supernatants were analyzed by HPLC to calculate individual CYP activity for each metabolite. All the picked mono-CYP2D6 clones expressed similar CYP2D6 protein amounts but showed different enzyme activities. Mono-CYP2D6 clone 18 was selected as the most suitable for TAM metabolization based on microsomal activity assays. TAM conversion with mono-CYP2D6 and -3A4 clones, as well as the combination of both, resulted in the formation of the expected main metabolites. Mono-CYP2D6 cells and microsomes produced the highest detected amounts of 4-hydroxytamoxifen and endoxifen, along with N -desmethyltamoxifen and small amounts of N , N -didesmethyltamoxifen. N -desmethyltamoxifen was the only TAM metabolite detected in notable quantities in mono-CYP3A4, while 4-hydroxytamoxifen and endoxifen were present only in trace amounts. In CYP2D6/3A4 co-culture and equal mixtures of both CYP microsomes, all metabolites were detected at concentrations around 50\% of those in individual clones, indicating no significant synergistic effects. In conclusion, our mono-CYP CHO model confirmed the essential role of CYP2D6 in synthesizing the active TAM metabolite endoxifen and indicated that CYP2D6 is also involved in producing the by-metabolite N , N -didesmethyltamoxifen. The differences in metabolite spectra between the two mono-CYP models highlight the CYP specificity and sensitivity of our in vitro system.}, language = {en} } @misc{RammSchulzWalteretal., author = {Ramm, Franziska and Schulz, Christian and Walter, Ruben M. and Zemella, Anne}, title = {Wie CYPs Medikamente verarbeiten : Einblicke durch innovative Labortechniken}, series = {BIOspektrum}, volume = {30}, journal = {BIOspektrum}, number = {7}, publisher = {Springer Berlin Heidelberg}, address = {Berlin ; Heidelberg}, issn = {0947-0867}, doi = {10.1007/s12268-024-2307-6}, pages = {815 -- 818}, abstract = {Cytochrome-P450 enzymes (CYPs) represent a major class of enzymes responsible for the metabolism of xenobiotic substances. To assess the role of CYPs in drug metabolism, model systems such as liver cells are used but they harbor a variety of CYPs. Mono-CYP systems were established with a defined CYP activity to study the underlying mechanisms. We utilize a Mono-CYP system based with cell-free protein synthesis. We have shown that this combination enhances the understanding of CYP reactions.}, language = {de} } @incollection{ElmerHohbergRusselletal., author = {Elmer, Michael and Hohberg, Karin and Russell, D. and Christian, Axel and Schulz, H.- J. and Wanner, Manfred}, title = {Succession of the soil faunal community during initial ecosystem development}, series = {Initial development of the artificial catchment "Chicken Creek" : monitoring program and survey 2005-2008}, booktitle = {Initial development of the artificial catchment "Chicken Creek" : monitoring program and survey 2005-2008}, editor = {Schaaf, Wolfgang and Biemelt, Detlef and H{\"u}ttl, Reinhard F.}, publisher = {Univ. of Technology, Research Center Landscape Development and Mining Landscapes}, address = {Cottbus}, pages = {97 -- 118}, language = {en} } @incollection{HohbergElmerRusselletal., author = {Hohberg, Karin and Elmer, Michael and Russell, David J. and Christian, Axel and Schulz, Hans-J{\"u}rgen and Lehmitz, Ricarda and Wanner, Manfred}, title = {First five years of soil food-web development in Chicken Creek catchment}, series = {The artificial catchment Chicken Creek - initial ecosystem development 2005-2010}, booktitle = {The artificial catchment Chicken Creek - initial ecosystem development 2005-2010}, editor = {Elmer, Michael and Schaaf, Wolfgang and Biemelt, Detlef and Gerwin, Werner and H{\"u}ttl, Reinhard F.}, publisher = {FZLB}, address = {Cottbus}, pages = {93 -- 114}, language = {en} }