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    <title language="eng">OCT1-dependent uptake of structurally diverse pyrrolizidine alkaloids in human liver cells is crucial for their genotoxic and cytotoxic effects</title>
    <abstract language="eng">Pyrrolizidine alkaloids (PAs) are important plant hepatotoxins, which occur as contaminants in plant-based foods, feeds and phytomedicines. Numerous studies demonstrated that the genotoxicity and cytotoxicity of PAs depend on their chemical structure, allowing for potency ranking and grouping. Organic cation transporter-1 (OCT1) was previously shown to be involved in the cellular uptake of the cyclic PA diesters monocrotaline, retrorsine and senescionine. However, little is known about the structure-dependent transport of PAs. Therefore, we investigated the impact of OCT1 on the uptake and toxicity of three structurally diverse PAs (heliotrine, lasiocarpine and riddelliine) differing in their degree and type of esterification in metabolically competent human liver cell models and hamster fibroblasts. Human HepG2-CYP3A4 liver cells were exposed to the respective PA in the presence or absence of the OCT1-inhibitors D-THP and quinidine, revealing a strongly attenuated cytotoxicity upon OCT1 inhibition. The same experiments were repeated in V79-CYP3A4 hamster fibroblasts, confirming that OCT1 inhibition prevents the cytotoxic effects of all tested PAs. Interestingly, OCT1 protein levels were much lower in V79-CYP3A4 than in HepG2-CYP3A4 cells, which correlated with their lower susceptibility to PA-induced cytotoxicity. The cytoprotective effect of OCT1 inhibiton was also demonstrated in primary human hepatocytes following PA exposure. Our experiments further showed that the genotoxic effects triggered by the three PAs are blocked by OCT1 inhibition as evidenced by strongly reduced γH2AX and p53 levels. Consistently, inhibition of OCT1-mediated uptake suppressed the activation of the DNA damage response (DDR) as revealed by decreased phosphorylation of checkpoint kinases upon PA treatment. In conclusion, we demonstrated that PAs, independent of their degree of esterification, are substrates for OCT1-mediated uptake into human liver cells. We further provided evidence that OCT1 inhibition prevents PA-triggered genotoxicity, DDR activation and subsequent cytotoxicity. These findings highlight the crucial role of OCT1 together with CYP3A4-dependent metabolic activation for PA toxicity.</abstract>
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    <author>
      <firstName>Gabriel</firstName>
      <lastName>Ackermann</lastName>
    </author>
    <author>
      <firstName>Jan-Heiner</firstName>
      <lastName>Küpper</lastName>
    </author>
    <author>
      <firstName>Hansruedi</firstName>
      <lastName>Glatt</lastName>
    </author>
    <author>
      <firstName>Dieter</firstName>
      <lastName>Schrenk</lastName>
    </author>
    <author>
      <firstName>Jörg</firstName>
      <lastName>Fahrer</lastName>
    </author>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>Pyrrolizidine alkaloids</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>Cytotoxicity</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>Genotoxicity</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>OCT1</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>Transport</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>Primary human hepatocytes</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>γH2AX</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>p53</value>
    </subject>
    <collection role="institutes" number="2110">FG Molekulare Zellbiologie</collection>
  </doc>
  <doc>
    <id>32264</id>
    <completedYear/>
    <publishedYear>2023</publishedYear>
    <thesisYearAccepted/>
    <language>eng</language>
    <pageFirst/>
    <pageLast/>
    <pageNumber/>
    <edition/>
    <issue>17</issue>
    <volume>12</volume>
    <type>articler</type>
    <publisherName/>
    <publisherPlace/>
    <creatingCorporation/>
    <contributingCorporation/>
    <belongsToBibliography>0</belongsToBibliography>
    <completedDate>2024-01-04</completedDate>
    <publishedDate>--</publishedDate>
    <thesisDateAccepted>--</thesisDateAccepted>
    <title language="eng">Stable Chinese Hamster Ovary Suspension Cell Lines Harboring Recombinant Human Cytochrome P450 Oxidoreductase and Human Cytochrome P450 Monooxygenases as Platform for In Vitro Biotransformation Studies</title>
    <abstract language="eng">In the liver, phase-1 biotransformation of drugs and other xenobiotics is largely facilitated by enzyme complexes consisting of cytochrome P450 oxidoreductase (CPR) and cytochrome P450 monooxygenases (CYPs). Generated from human liver-derived cell lines, recombinant in vitro cell systems with overexpression of defined phase-1 enzymes are widely used for pharmacological and toxicological drug assessment and laboratory-scale production of drug-specific reference metabolites. Most, if not all, of these cell lines, however, display some background activity of several CYPs, making it difficult to attribute effects to defined CYPs. The aim of this study was to generate cell lines with stable overexpression of human phase-1 enzymes based on Chinese hamster ovary (CHO) suspension cells. Cells were sequentially modified with cDNAs for human CPR in combination with CYP1A2, CYP2B6, or CYP3A4, using lentiviral gene transfer. In parallel, CYP-overexpressing cell lines without recombinant CPR were generated. Successful recombinant expression was demonstrated by mRNA and protein analyses. Using prototypical CYP-substrates, generated cell lines proved to display specific enzyme activities of each overexpressed CYP while we did not find any endogenous activity of those CYPs in parental CHO cells. Interestingly, cell lines revealed some evidence that the dependence of CYP activity on CPR could vary between CYPs. This needs to be confirmed in further studies. Recombinant expression of CPR was also shown to enhance CYP3A4-independent metabolisation of testosterone to androstenedione in CHO cells. We propose the novel serum-free CHO suspension cell lines with enhanced CPR and/or defined CYP activity as a promising “humanised” in vitro model to study the specific effects of those human CYPs. This could be relevant for toxicology and/or pharmacology studies in the pharmaceutical industry or medicine.</abstract>
    <parentTitle language="eng">Cells</parentTitle>
    <identifier type="url">https://www.mdpi.com/2073-4409/12/17/2140#metrics</identifier>
    <identifier type="doi">10.3390/cells12172140</identifier>
    <identifier type="issn">2073-4409</identifier>
    <enrichment key="BTU">an der BTU erstellt / created at BTU</enrichment>
    <enrichment key="Artikelnummer">2140</enrichment>
    <enrichment key="Publikationsweg">Open Access</enrichment>
    <enrichment key="opus.source">publish</enrichment>
    <enrichment key="opus.doi.autoCreate">false</enrichment>
    <enrichment key="opus.urn.autoCreate">false</enrichment>
    <enrichment key="Fprofil">2 Gesundheit und Lifes Sciences / Health and Life Sciences</enrichment>
    <enrichment key="Fprofil">3 Globaler Wandel und Transformationsprozesse / Global Change and Transformation Processes</enrichment>
    <author>
      <firstName>Christian</firstName>
      <lastName>Schulz</lastName>
    </author>
    <submitter>
      <firstName>Christian</firstName>
      <lastName>Schulz</lastName>
    </submitter>
    <author>
      <firstName>Natalie</firstName>
      <lastName>Herzog</lastName>
    </author>
    <author>
      <firstName>Stefan</firstName>
      <lastName>Kubick</lastName>
    </author>
    <author>
      <firstName>Friedrich</firstName>
      <lastName>Jung</lastName>
    </author>
    <author>
      <firstName>Jan-Heiner</firstName>
      <lastName>Küpper</lastName>
    </author>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>Chinese hamster ovary cells</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>CHO-K1</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>CPR</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>CYP450</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>cytochrome P450 monooxygenase</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>liver</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>NADPH P450 oxidoreductase</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>phase-1 biotransformation</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>serum-free</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>suspension cells</value>
    </subject>
    <collection role="institutes" number="2110">FG Molekulare Zellbiologie</collection>
  </doc>
  <doc>
    <id>32265</id>
    <completedYear/>
    <publishedYear>2023</publishedYear>
    <thesisYearAccepted/>
    <language>eng</language>
    <pageFirst/>
    <pageLast/>
    <pageNumber/>
    <edition/>
    <issue>15</issue>
    <volume>12</volume>
    <type>articler</type>
    <publisherName/>
    <publisherPlace/>
    <creatingCorporation/>
    <contributingCorporation/>
    <belongsToBibliography>0</belongsToBibliography>
    <completedDate>2024-01-04</completedDate>
    <publishedDate>--</publishedDate>
    <thesisDateAccepted>--</thesisDateAccepted>
    <title language="eng">Anti-Cancer Prodrug Cyclophosphamide Exerts Thrombogenic Effects on Human Venous Endothelial Cells Independent of CYP450 Activation—Relevance to Thrombosis</title>
    <abstract language="eng">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.</abstract>
    <parentTitle language="eng">Cells</parentTitle>
    <identifier type="url">https://www.mdpi.com/2073-4409/12/15/1965</identifier>
    <identifier type="doi">10.3390/cells12151965</identifier>
    <identifier type="issn">2073-4409</identifier>
    <enrichment key="BTU">an der BTU erstellt / created at BTU</enrichment>
    <enrichment key="Artikelnummer">1965</enrichment>
    <enrichment key="Publikationsweg">Open Access</enrichment>
    <enrichment key="opus.source">publish</enrichment>
    <enrichment key="Fprofil">2 Gesundheit und Lifes Sciences / Health and Life Sciences</enrichment>
    <enrichment key="Fprofil">3 Globaler Wandel und Transformationsprozesse / Global Change and Transformation Processes</enrichment>
    <author>
      <firstName>Anne</firstName>
      <lastName>Krüger-Genge</lastName>
    </author>
    <submitter>
      <firstName>Christian</firstName>
      <lastName>Schulz</lastName>
    </submitter>
    <author>
      <firstName>Susanne</firstName>
      <lastName>Köhler</lastName>
    </author>
    <author>
      <firstName>Markus</firstName>
      <lastName>Laube</lastName>
    </author>
    <author>
      <firstName>Vanessa</firstName>
      <lastName>Haileka</lastName>
    </author>
    <author>
      <firstName>Sandy</firstName>
      <lastName>Lemm</lastName>
    </author>
    <author>
      <firstName>Karolina</firstName>
      <lastName>Majchrzak</lastName>
    </author>
    <author>
      <firstName>Sarah</firstName>
      <lastName>Kammerer</lastName>
    </author>
    <author>
      <firstName>Christian</firstName>
      <lastName>Schulz</lastName>
    </author>
    <author>
      <firstName>Joachim</firstName>
      <lastName>Storsberg</lastName>
    </author>
    <author>
      <firstName>Jens</firstName>
      <lastName>Pietzsch</lastName>
    </author>
    <author>
      <firstName>Jan-Heiner</firstName>
      <lastName>Küpper</lastName>
    </author>
    <author>
      <firstName>Friedrich</firstName>
      <lastName>Jung</lastName>
    </author>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>cancer</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>cyclophosphamide</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>human umbilical vein endothelial cells</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>HUVEC</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>liver</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>cytochrome P450 enzymes (CYP)</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>thrombosis</value>
    </subject>
    <collection role="institutes" number="2110">FG Molekulare Zellbiologie</collection>
  </doc>
  <doc>
    <id>32267</id>
    <completedYear/>
    <publishedYear>2023</publishedYear>
    <thesisYearAccepted/>
    <language>eng</language>
    <pageFirst>1413</pageFirst>
    <pageLast>1428</pageLast>
    <pageNumber/>
    <edition/>
    <issue>5</issue>
    <volume>97</volume>
    <type>articler</type>
    <publisherName/>
    <publisherPlace/>
    <creatingCorporation/>
    <contributingCorporation/>
    <belongsToBibliography>0</belongsToBibliography>
    <completedDate>2024-01-04</completedDate>
    <publishedDate>--</publishedDate>
    <thesisDateAccepted>--</thesisDateAccepted>
    <title language="eng">Potency ranking of pyrrolizidine alkaloids in metabolically competent human liver cancer cells and primary human hepatocytes using a genotoxicity test battery</title>
    <abstract language="eng">Pyrrolizidine alkaloids (PAs) occur as contaminants in plant-based foods and herbal medicines. Following metabolic activation by cytochrome P450 (CYP) enzymes, PAs induce DNA damage, hepatotoxicity and can cause liver cancer in rodents. There is ample evidence that the chemical structure of PAs determines their toxicity. However, more quantitative genotoxicity data are required, particularly in primary human hepatocytes (PHH). Here, the genotoxicity of eleven structurally different PAs was investigated in human HepG2 liver cells with CYP3A4 overexpression and PHH using an in vitro test battery. Furthermore, the data were subject to benchmark dose (BMD) modeling to derive the genotoxic potency of individual PAs. The cytotoxicity was initially determined in HepG2-CYP3A4 cells, revealing a clear structure–toxicity relationship for the PAs. Importantly, experiments in PHH confirmed the structure-dependent toxicity and cytotoxic potency ranking of the tested PAs. The genotoxicity markers γH2AX and p53 as well as the alkaline Comet assay consistently demonstrated a structure-dependent genotoxicity of PAs in HepG2-CYP3A4 cells, correlating well with their cytotoxic potency. BMD modeling yielded BMD values in the range of 0.1–10 µM for most cyclic and open diesters, followed by the monoesters. While retrorsine showed the highest genotoxic potency, monocrotaline and lycopsamine displayed the lowest genotoxicity. Finally, experiments in PHH corroborated the genotoxic potency ranking, and revealed genotoxic effects even in the absence of detectable cytotoxicity. In conclusion, our findings strongly support the concept of grouping PAs into potency classes and help to pave the way for a broader acceptance of relative potency factors in risk assessment.</abstract>
    <parentTitle language="eng">Archives of Toxicology</parentTitle>
    <identifier type="url">https://link.springer.com/article/10.1007/s00204-023-03482-8</identifier>
    <identifier type="doi">10.1007/s00204-023-03482-8</identifier>
    <identifier type="issn">0340-5761</identifier>
    <enrichment key="BTU">an der BTU erstellt / created at BTU</enrichment>
    <enrichment key="Publikationsweg">Open Access</enrichment>
    <enrichment key="opus.source">publish</enrichment>
    <enrichment key="Fprofil">2 Gesundheit und Lifes Sciences / Health and Life Sciences</enrichment>
    <enrichment key="Fprofil">3 Globaler Wandel und Transformationsprozesse / Global Change and Transformation Processes</enrichment>
    <author>
      <firstName>Manuel</firstName>
      <lastName>Haas</lastName>
    </author>
    <submitter>
      <firstName>Christian</firstName>
      <lastName>Schulz</lastName>
    </submitter>
    <author>
      <firstName>Karina</firstName>
      <lastName>Wirachowski</lastName>
    </author>
    <author>
      <firstName>Lea</firstName>
      <lastName>Thibol</lastName>
    </author>
    <author>
      <firstName>Jan-Heiner</firstName>
      <lastName>Küpper</lastName>
    </author>
    <author>
      <firstName>Dieter</firstName>
      <lastName>Schrenk</lastName>
    </author>
    <author>
      <firstName>Jörg</firstName>
      <lastName>Fahrer</lastName>
    </author>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>Cytotoxicity</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>Genotoxicity</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>Benchmark dose modeling</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>Pyrrolizidine alkaloids</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>Primary human hepatocytes</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>Potency ranking</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>γH2AX</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>p53</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>DNA damage</value>
    </subject>
    <collection role="institutes" number="2110">FG Molekulare Zellbiologie</collection>
  </doc>
  <doc>
    <id>32268</id>
    <completedYear/>
    <publishedYear>2023</publishedYear>
    <thesisYearAccepted/>
    <language>eng</language>
    <pageFirst>71</pageFirst>
    <pageLast>77</pageLast>
    <pageNumber/>
    <edition/>
    <issue>1</issue>
    <volume>9</volume>
    <type>articler</type>
    <publisherName/>
    <publisherPlace/>
    <creatingCorporation/>
    <contributingCorporation/>
    <belongsToBibliography>0</belongsToBibliography>
    <completedDate>2024-01-04</completedDate>
    <publishedDate>--</publishedDate>
    <thesisDateAccepted>--</thesisDateAccepted>
    <title language="eng">Light-induced changes in the morphology and fluorescence of Arthrospira platensis</title>
    <abstract language="eng">The cyanobacterium Arthrospira platensis is a well-known source of bioactive substances. Growth and the generation of bioactive ingredients of Arthrospira platensis depend mainly on the quantity of light in a controlled environment. Photoinhibition is a time, nutrient, and light intensity-dependent decrease in photosynthetic efficiency. However, too strong illumination can induce two harmful effects: (1) photoinhibition as a reduction in photosynthetic rate and (2) photooxidation which can have lethal effects on the cells, and which can lead to total loss of the culture. The results of this microscopical study demonstrate, that under the procedures described and very high photon flux den-sities, not only a decrease in the photosynthetic efficiency but beyond, also destruction of Arthrospira platensis can occur.</abstract>
    <parentTitle language="eng">Clinical Hemorheology and Microcirculation</parentTitle>
    <identifier type="url">https://content.iospress.com/articles/journal-of-cellular-biotechnology/jcb239001</identifier>
    <identifier type="doi">10.3233/JCB-239001</identifier>
    <identifier type="issn">1386-0291</identifier>
    <enrichment key="BTU">an der BTU erstellt / created at BTU</enrichment>
    <enrichment key="Publikationsweg">Open Access</enrichment>
    <enrichment key="opus.source">publish</enrichment>
    <enrichment key="opus.doi.autoCreate">false</enrichment>
    <enrichment key="opus.urn.autoCreate">false</enrichment>
    <enrichment key="Fprofil">2 Gesundheit und Lifes Sciences / Health and Life Sciences</enrichment>
    <enrichment key="Fprofil">3 Globaler Wandel und Transformationsprozesse / Global Change and Transformation Processes</enrichment>
    <author>
      <firstName>Conrad H. G.</firstName>
      <lastName>Jung</lastName>
    </author>
    <submitter>
      <firstName>Christian</firstName>
      <lastName>Schulz</lastName>
    </submitter>
    <author>
      <firstName>Peter</firstName>
      <lastName>Waldeck</lastName>
    </author>
    <author>
      <firstName>Ingolf</firstName>
      <lastName>Petrick</lastName>
    </author>
    <author>
      <firstName>Mosunmol</firstName>
      <lastName>Akinwunmi</lastName>
    </author>
    <author>
      <firstName>Steffen</firstName>
      <lastName>Braune</lastName>
    </author>
    <author>
      <firstName>Friedrich</firstName>
      <lastName>Jung</lastName>
    </author>
    <author>
      <firstName>Jan-Heiner</firstName>
      <lastName>Küpper</lastName>
    </author>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>Arthrospira platensis</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>light stress</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>photoinhibition</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>phototoxicity</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>morphology</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>fluorescence</value>
    </subject>
    <collection role="institutes" number="2110">FG Molekulare Zellbiologie</collection>
  </doc>
  <doc>
    <id>32258</id>
    <completedYear/>
    <publishedYear>2023</publishedYear>
    <thesisYearAccepted/>
    <language>eng</language>
    <pageFirst/>
    <pageLast/>
    <pageNumber/>
    <edition/>
    <issue>16</issue>
    <volume>28</volume>
    <type>articler</type>
    <publisherName/>
    <publisherPlace/>
    <creatingCorporation/>
    <contributingCorporation/>
    <belongsToBibliography>0</belongsToBibliography>
    <completedDate>2024-01-04</completedDate>
    <publishedDate>--</publishedDate>
    <thesisDateAccepted>--</thesisDateAccepted>
    <title language="eng">The effect of plastic-related compounds on transcriptome-wide gene expression on CYP2C19-overexpressing HepG2 cells</title>
    <abstract language="eng">In recent years, plastic and especially microplastic in the oceans have caused huge problems to marine flora and fauna. Recently, such particles have also been detected in blood, breast milk, and placenta, underlining their ability to enter the human body, presumably via the food chain and other yet-unknown mechanisms. In addition, plastic contains plasticizers, antioxidants, or lubricants, whose impact on human health is also under investigation. At the cellular level, the most important enzymes involved in the metabolism of xenobiotic compounds are the cytochrome P450 monooxygenases (CYPs). Despite their extensive characterization in the maintenance of cellular balance, their interactions with plastic and related products are unexplored. In this study, the possible interactions between several plastic-related compounds and one of the most important cytochromes, CYP2C19, were analyzed. By applying virtual compound screening and molecular docking to more than 1000 commercially available plastic-related compounds, we identified candidates that are likely to interact with this protein. A growth inhibition assay confirmed their cytotoxic activity on a CYP2C19-transfected hepatic cell line. Subsequently, we studied the effect of the selected compounds on the transcriptome-wide gene expression level by conducting RNA sequencing. Three candidate molecules were identified, i.e., 2,2′-methylene bis(6-tert-butyl-4-methylphenol), 1,1-bis(3,5-di-tert-butyl-2-hydroxyphenyl) ethane, and 2,2′-methylene bis(6-cyclohexyl-4-methylphenol)), which bound with a high affinity to CYP2C19 in silico. They exerted a profound cytotoxicity in vitro and interacted with several metabolic pathways, of which the ‘cholesterol biosynthesis process’ was the most affected. In addition, other affected pathways involved mitosis, DNA replication, and inflammation, suggesting an increase in hepatotoxicity. These results indicate that plastic-related compounds could damage the liver by affecting several molecular pathways.</abstract>
    <parentTitle language="eng">Molecules</parentTitle>
    <identifier type="url">https://www.mdpi.com/1420-3049/28/16/5952</identifier>
    <identifier type="doi">10.3390/molecules28165952</identifier>
    <identifier type="issn">1420-3049</identifier>
    <enrichment key="BTU">an der BTU erstellt / created at BTU</enrichment>
    <enrichment key="Artikelnummer">5952</enrichment>
    <enrichment key="Publikationsweg">Open Access</enrichment>
    <enrichment key="opus.source">publish</enrichment>
    <enrichment key="Fprofil">2 Gesundheit und Lifes Sciences / Health and Life Sciences</enrichment>
    <enrichment key="Fprofil">3 Globaler Wandel und Transformationsprozesse / Global Change and Transformation Processes</enrichment>
    <author>
      <firstName>Matteo</firstName>
      <lastName>Rosellini</lastName>
    </author>
    <submitter>
      <firstName>Christian</firstName>
      <lastName>Schulz</lastName>
    </submitter>
    <author>
      <firstName>Alicia</firstName>
      <lastName>Schulze</lastName>
    </author>
    <author>
      <firstName>Ejlal A.</firstName>
      <lastName>Omer</lastName>
    </author>
    <author>
      <firstName>Nadeen T.</firstName>
      <lastName>Ali</lastName>
    </author>
    <author>
      <firstName>Federico</firstName>
      <lastName>Marini</lastName>
    </author>
    <author>
      <firstName>Jan-Heiner</firstName>
      <lastName>Küpper</lastName>
    </author>
    <author>
      <firstName>Thomas</firstName>
      <lastName>Efferth</lastName>
    </author>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>cytotoxicity</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>ecotoxicity</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>hepatotoxicity</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>microplastic</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>RNA sequencing</value>
    </subject>
    <collection role="institutes" number="2110">FG Molekulare Zellbiologie</collection>
  </doc>
  <doc>
    <id>32259</id>
    <completedYear/>
    <publishedYear>2024</publishedYear>
    <thesisYearAccepted/>
    <language>eng</language>
    <pageFirst>159</pageFirst>
    <pageLast>168</pageLast>
    <pageNumber/>
    <edition/>
    <issue>1-2</issue>
    <volume>86</volume>
    <type>articler</type>
    <publisherName/>
    <publisherPlace/>
    <creatingCorporation/>
    <contributingCorporation/>
    <belongsToBibliography>0</belongsToBibliography>
    <completedDate>2024-01-04</completedDate>
    <publishedDate>--</publishedDate>
    <thesisDateAccepted>--</thesisDateAccepted>
    <title language="eng">In vitro simulation of the liver first-pass effect with biotransformation-competent HepG2 cells to study effects of MG-132 on liver and cancer cells</title>
    <abstract language="eng">BACKGROUND:&#13;
Liver biotransformation is the major route for drug metabolism in humans, often catalysed by cytochrome P450 (CYP) enzymes. This first-pass effect can lead to hepatotoxicity and influences the bioavailability of drugs.&#13;
&#13;
OBJECTIVE:&#13;
We aimed to establish in vitro culture systems simulating the liver first-pass to study effects of the proteasome inhibitor MG-132 simultaneously on hepatocytes and cancer cells.&#13;
&#13;
METHODS:&#13;
The first-pass effect was simulated by conditioned medium transfer (CMT) from pre-treated HepG2 CYP3A4-overexpressing cells to either pancreatic cancer cell line PANC-1 or primary colon cancer cells, and by indirect co-culture (CC) of liver and cancer cells in a shared medium compartment. Experimental proteasome inhibitor MG-132 was used as test substance as it is detoxified by CYP3A4.&#13;
&#13;
RESULTS:&#13;
Cancer cells showed higher viabilities in the first-pass simulation by CMT and CC formats when compared to monocultures indicating effective detoxification of MG-132 by HepG2 CYP3A4-overexpressing cells. HepG2-CYP3A4 cells showed reduced viabilites after treatment with MG-132.&#13;
&#13;
CONCLUSIONS:&#13;
We successfully established two different culture systems to simulate the liver first-pass effect in vitro. Such systems easily allow to study drug effects simultaneously on liver and on target cancer cells. They are of great value in pre-clinical cancer research, pharmaceutical research and drug development.</abstract>
    <parentTitle language="eng">Clinical Hemorheology and Microcirculation</parentTitle>
    <identifier type="url">https://content.iospress.com/articles/clinical-hemorheology-and-microcirculation/ch238108</identifier>
    <identifier type="doi">10.3233/CH-238108</identifier>
    <identifier type="issn">1386-0291</identifier>
    <enrichment key="BTU">an der BTU erstellt / created at BTU</enrichment>
    <enrichment key="Publikationsweg">Open Access</enrichment>
    <enrichment key="opus.source">publish</enrichment>
    <enrichment key="Fprofil">2 Gesundheit und Lifes Sciences / Health and Life Sciences</enrichment>
    <enrichment key="Fprofil">3 Globaler Wandel und Transformationsprozesse / Global Change and Transformation Processes</enrichment>
    <author>
      <firstName>Sarah</firstName>
      <lastName>Kammerer</lastName>
    </author>
    <submitter>
      <firstName>Christian</firstName>
      <lastName>Schulz</lastName>
    </submitter>
    <author>
      <firstName>Elisabeth</firstName>
      <lastName>Nowak</lastName>
    </author>
    <author>
      <firstName>René</firstName>
      <lastName>Mantke</lastName>
    </author>
    <author>
      <firstName>Friedrich</firstName>
      <lastName>Jung</lastName>
    </author>
    <author>
      <firstName>Jan-Heiner</firstName>
      <lastName>Küpper</lastName>
    </author>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>Liver biotransformation</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>first-pass effect</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>CYP3A4</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>MG-132</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>cancer cells</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>in vitro culture systems</value>
    </subject>
    <collection role="institutes" number="2110">FG Molekulare Zellbiologie</collection>
  </doc>
  <doc>
    <id>32261</id>
    <completedYear/>
    <publishedYear>2023</publishedYear>
    <thesisYearAccepted/>
    <language>eng</language>
    <pageFirst/>
    <pageLast/>
    <pageNumber/>
    <edition/>
    <issue/>
    <volume/>
    <type>articler</type>
    <publisherName/>
    <publisherPlace/>
    <creatingCorporation/>
    <contributingCorporation/>
    <belongsToBibliography>0</belongsToBibliography>
    <completedDate>2024-01-04</completedDate>
    <publishedDate>--</publishedDate>
    <thesisDateAccepted>--</thesisDateAccepted>
    <title language="eng">Decarbonization of Arthrospira platensis production by using  atmospheric CO2 as an exclusive carbon source: proof of principle</title>
    <abstract language="eng">There is an urgent need to develop technologies for removing CO2 from the atmosphere to combat climate change. Microalgae and cyanobacteria, such as Arthrospira platensis (AP), have shown promise due to their high photoautotrophic biomass production. Conventional AP culture media are supplemented with high concentrations of NaHCO3 since AP utilizes as a carbon source. These culture conditions result in significant amounts of CO2 escaping into the atmosphere, instead of being sequestered during cultivation. Here, we investigated whether ambient air (0.042% CO2) can be used for growing AP in a culture medium lacking a fossil-based carbon source. AP was cultured in 2 L glass bioreactors containing: (1) Zarrouk medium with 16.8 g/L NaHCO3 and aeration with 0.236 vvm air with 2% CO2 (“NaHCO3/CO2-based”) to compensate carbon loss due to CO2 outgassing, and (2) Zarrouk medium without NaHCO3 and a gas flow with ambient air (0.926 vvm) as the only carbon source (“air-based”). The air-based production resulted in the biofixation of 3.78 gCO2/L during the linear growth phase. With NaHCO3/CO2-based production, a comparable amount of 3.42 gCO2/L was obtained while 659.12 g of CO2 was released into the atmosphere. Total protein, phycocyanin, chlorophyll-a, and carotenoids were present in similar or increased amounts in AP produced by the air-based method. We concluded that cultivation of AP with Zarrouk medium lacking NaHCO3 but using ambient air with atmospheric CO2 as the only carbon source is possible without reducing productivity. These results improve our understanding of how atmospheric CO2 can be reduced by culturing AP.</abstract>
    <parentTitle language="eng">International Journal of Environmental Science and Technology</parentTitle>
    <identifier type="url">https://link.springer.com/article/10.1007/s13762-023-05215-x#citeas</identifier>
    <identifier type="doi">10.1007/s13762-023-05215-x</identifier>
    <identifier type="issn">1735-2630</identifier>
    <enrichment key="BTU">an der BTU erstellt / created at BTU</enrichment>
    <enrichment key="Publikationsweg">Open Access</enrichment>
    <enrichment key="opus.source">publish</enrichment>
    <enrichment key="opus.doi.autoCreate">false</enrichment>
    <enrichment key="opus.urn.autoCreate">false</enrichment>
    <enrichment key="Fprofil">2 Gesundheit und Lifes Sciences / Health and Life Sciences</enrichment>
    <enrichment key="Fprofil">3 Globaler Wandel und Transformationsprozesse / Global Change and Transformation Processes</enrichment>
    <author>
      <firstName>Conrad H. G.</firstName>
      <lastName>Jung</lastName>
    </author>
    <submitter>
      <firstName>Christian</firstName>
      <lastName>Schulz</lastName>
    </submitter>
    <author>
      <firstName>Theopolina</firstName>
      <lastName>Nghinaunye</lastName>
    </author>
    <author>
      <firstName>Peter</firstName>
      <lastName>Waldeck</lastName>
    </author>
    <author>
      <firstName>Steffen</firstName>
      <lastName>Braune</lastName>
    </author>
    <author>
      <firstName>Ingolf</firstName>
      <lastName>Petrick</lastName>
    </author>
    <author>
      <firstName>Jan-Heiner</firstName>
      <lastName>Küpper</lastName>
    </author>
    <author>
      <firstName>Friedrich</firstName>
      <lastName>Jung</lastName>
    </author>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>Arthrospira platensis</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>Atmospheric CO2</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>Biomass production</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>Climate change</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>Carbon capturing</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>Decarbonization</value>
    </subject>
    <collection role="institutes" number="2110">FG Molekulare Zellbiologie</collection>
  </doc>
  <doc>
    <id>34465</id>
    <completedYear/>
    <publishedYear/>
    <thesisYearAccepted/>
    <language>eng</language>
    <pageFirst/>
    <pageLast/>
    <pageNumber>19</pageNumber>
    <edition/>
    <issue>10</issue>
    <volume>14</volume>
    <type>articlenr</type>
    <publisherName>MDPI</publisherName>
    <publisherPlace/>
    <creatingCorporation/>
    <contributingCorporation/>
    <belongsToBibliography>0</belongsToBibliography>
    <completedDate>--</completedDate>
    <publishedDate>2024-10-01</publishedDate>
    <thesisDateAccepted>--</thesisDateAccepted>
    <title language="eng">Effects of arthrospira platensis on human Uumbilical vein endothelial cells</title>
    <abstract language="eng">Atherosclerosis is initiated by injury or damage to the vascular endothelial cell monolayer. Therefore, the early repair of the damaged vascular endothelium by a proliferation of neighbouring endothelial cells is important to prevent atherosclerosis and thrombotic events. Arthrospira platensis (AP) has been used as a dietary supplement, mainly due to its high content of vitamins, minerals, amino acids, and pigments such as chlorophylls, carotenoids, and phycocyanin, ingredients with antioxidant, anti-inflammatory, and anti-thrombotic properties. Therefore, in this prospective, placebo-controlled, data-driven, sample-size-estimated in vitro study, we tested whether an aqueous extract of AP at different concentrations (50, 100, and 200 µg/mL) had an effect on the different cellular parameters of human umbilical vein endothelial cells. Therefore, cell impedance measurement and cell proliferation were measured to investigate the monolayer formation. In addition, cell viability, integrity, and metabolism were analysed to evaluate singular cellular functions, especially the antithrombotic state. Furthermore, cell–cell and cell–substrate interactions were observed. The highest proliferation was achieved after the addition of 100 µg/mL. This was consistently confirmed by two independent optical experiments in cell cultures 48 h and 85 h after seeding and additionally by an indirect test. At this concentration, the activation or dysfunction of HUVECs was completely prevented, as confirmed by prostacyclin and interleukin-6 levels. In conclusion, in this study, AP induced a significant increase in HUVEC proliferation without inducing an inflammatory response but altered the hemostasiological balance in favour of prostacyclin over thromboxane, thereby creating an antithrombotic state. Thus, APE could be applied in the future as an accelerator of endothelial cell proliferation after, e.g., stent placement or atherosclerosis.</abstract>
    <parentTitle language="eng">Life</parentTitle>
    <identifier type="issn">2075-1729</identifier>
    <identifier type="doi">10.3390/life14101253</identifier>
    <enrichment key="opus.import.date">2024-11-07T21:07:53+00:00</enrichment>
    <enrichment key="opus.source">sword</enrichment>
    <enrichment key="opus.import.user">deepgreen</enrichment>
    <enrichment key="opus.import.file">attachment; filename=deposit.zip</enrichment>
    <enrichment key="opus.import.checksum">1d87aba67ffe29e41712641e38640242</enrichment>
    <enrichment key="BTU">an der BTU erstellt / created at BTU</enrichment>
    <enrichment key="Publikationsweg">Open Access</enrichment>
    <enrichment key="opus.doi.autoCreate">false</enrichment>
    <enrichment key="opus.urn.autoCreate">false</enrichment>
    <author>
      <firstName>Anne</firstName>
      <lastName>Krüger-Genge</lastName>
    </author>
    <editor>
      <firstName>Panagiotis</firstName>
      <lastName>Georgianos</lastName>
    </editor>
    <author>
      <firstName>Kudor</firstName>
      <lastName>Harb</lastName>
    </author>
    <author>
      <firstName>Steffen</firstName>
      <lastName>Braune</lastName>
    </author>
    <author>
      <firstName>Conrad H. G.</firstName>
      <lastName>Jung</lastName>
    </author>
    <author>
      <firstName>Sophia</firstName>
      <lastName>Westphal</lastName>
    </author>
    <author>
      <firstName>Stefanie</firstName>
      <lastName>Bär</lastName>
    </author>
    <author>
      <firstName>Olivia</firstName>
      <lastName>Mauger</lastName>
    </author>
    <author>
      <firstName>Jan-Heiner</firstName>
      <lastName>Küpper</lastName>
    </author>
    <author>
      <firstName>Friedrich</firstName>
      <lastName>Jung</lastName>
    </author>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>human umbilical vein endothelial cells</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>HUVEC</value>
    </subject>
    <collection role="institutes" number="2110">FG Molekulare Zellbiologie</collection>
    <collection role="Import" number="import">Import</collection>
  </doc>
  <doc>
    <id>34471</id>
    <completedYear/>
    <publishedYear/>
    <thesisYearAccepted/>
    <language>eng</language>
    <pageFirst>525</pageFirst>
    <pageLast>536</pageLast>
    <pageNumber/>
    <edition/>
    <issue>2</issue>
    <volume>98</volume>
    <type>articlenr</type>
    <publisherName>Springer Berlin Heidelberg</publisherName>
    <publisherPlace/>
    <creatingCorporation/>
    <contributingCorporation/>
    <belongsToBibliography>0</belongsToBibliography>
    <completedDate>--</completedDate>
    <publishedDate>2024-02-01</publishedDate>
    <thesisDateAccepted>--</thesisDateAccepted>
    <title language="eng">Impact of plastic-related compounds on the gene expression signature of HepG2 cells transfected with CYP3A4</title>
    <abstract language="eng">The presence of plastic and microplastic within the oceans as well as in marine flora and fauna have caused a multitude of problems that have been the topic of numerous investigations for many years. However, their impact on human health remains largely unknown. Such plastic and microplastic particles have been detected in blood and placenta, underlining their ability to enter the human body. Plastics also contain other compounds, such as plasticizers, antioxidants, or dyes, whose impact on human health is currently being studied. Critical enzymes within the metabolism of endogenous molecules, especially of xenobiotics, are the cytochrome P450 monooxygenases (CYPs). Although their importance in maintaining cellular balance has been confirmed, their interactions with plastics and related products are poorly understood. In this study, the possible relationship between different plastic-related compounds and CYP3A4 as one of the most important CYPs was analyzed using hepatic cells overexpressing this enzyme. Beginning with virtual compound screening and molecular docking of more than 1000 plastic-related compounds, several candidates were identified to interact with CYP3A4. In a second step, RNA-sequencing was used to study in detail the transcriptome-wide gene expression levels affected by the selected compounds. Three candidate molecules ((2,2′-methylenebis(6- tert -butyl-4-methylphenol), 1,1-bis(3,5-di- tert -butyl-2-hydroxyphenyl)ethane, and 2,2′-methylenebis(6-cyclohexyl-4-methylphenol)) had an excellent binding affinity to CYP3A4 in-silico as well as cytotoxic effects and interactions with several metabolic pathways in-vitro. We identified common pathways influenced by all three selected plastic-related compounds. In particular, the suppression of pathways related to mitosis and ‘DNA-templated DNA replication’ which were confirmed by cell cycle analysis and single-cell gel electrophoresis. Furthermore, several mis-regulated metabolic and inflammation-related pathways were identified, suggesting the induction of hepatotoxicity at different levels. These findings imply that these compounds may cause liver problems subsequently affecting the entire organism.</abstract>
    <parentTitle language="eng">Archives of Toxicology</parentTitle>
    <identifier type="issn">0340-5761</identifier>
    <identifier type="issn">1432-0738</identifier>
    <identifier type="doi">10.1007/s00204-023-03648-4</identifier>
    <enrichment key="opus.import.date">2024-11-08T08:47:08+00:00</enrichment>
    <enrichment key="opus.source">sword</enrichment>
    <enrichment key="opus.import.user">deepgreen</enrichment>
    <enrichment key="opus.import.file">attachment; filename=deposit.zip</enrichment>
    <enrichment key="opus.import.checksum">37a08bb579ad0c34197e9f9982288a0e</enrichment>
    <enrichment key="BTU">an der BTU erstellt / created at BTU</enrichment>
    <enrichment key="Publikationsweg">Open Access</enrichment>
    <enrichment key="opus.doi.autoCreate">false</enrichment>
    <enrichment key="opus.urn.autoCreate">false</enrichment>
    <author>
      <firstName>Matteo</firstName>
      <lastName>Rosellini</lastName>
    </author>
    <author>
      <firstName>Ejlal A.</firstName>
      <lastName>Omer</lastName>
    </author>
    <author>
      <firstName>Alicia</firstName>
      <lastName>Schulze</lastName>
    </author>
    <author>
      <firstName>Nadeen T.</firstName>
      <lastName>Ali</lastName>
    </author>
    <author>
      <firstName>Joelle C.</firstName>
      <lastName>Boulos</lastName>
    </author>
    <author>
      <firstName>Federico</firstName>
      <lastName>Marini</lastName>
    </author>
    <author>
      <firstName>Jan-Heiner</firstName>
      <lastName>Küpper</lastName>
    </author>
    <author>
      <firstName>Thomas</firstName>
      <lastName>Efferth</lastName>
    </author>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>Cytotoxicity</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>Ecotoxicity</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>Environmental pollution</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>Hepatotoxicity</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>Marine pollution</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>Microplastic</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>RNA-sequencing</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>Biological Sciences</value>
    </subject>
    <collection role="institutes" number="2110">FG Molekulare Zellbiologie</collection>
    <collection role="Import" number="import">Import</collection>
  </doc>
  <doc>
    <id>36847</id>
    <completedYear/>
    <publishedYear>2025</publishedYear>
    <thesisYearAccepted/>
    <language>eng</language>
    <pageFirst>3769</pageFirst>
    <pageLast>3785</pageLast>
    <pageNumber>17</pageNumber>
    <edition/>
    <issue>9</issue>
    <volume>99</volume>
    <type>articler</type>
    <publisherName>Springer</publisherName>
    <publisherPlace>Berlin ; Heidelberg</publisherPlace>
    <creatingCorporation/>
    <contributingCorporation/>
    <belongsToBibliography>0</belongsToBibliography>
    <completedDate>2025-05-21</completedDate>
    <publishedDate>2025-09-01</publishedDate>
    <thesisDateAccepted>--</thesisDateAccepted>
    <title language="eng">Molecular dosimetry of estragole and 1′-hydroxyestragole-induced DNA adduct formation, clastogenicity and cytotoxicity in human liver cell models</title>
    <abstract language="eng">The phenylpropene estragole (ES) is found in essential oils of herbs and spices, such as bitter fennel and basil. Humans are exposed to ES through the diet and phytomedicines. After its absorption, ES undergoes metabolic activation by CYP1A2 and SULT1A1 in the liver, which can give rise to DNA adducts and hepatocarcinogenesis. Until now, quantitative genotoxicity data for ES in human liver cells are scarce, correlating DNA adduct levels with critical effects such as clastogenicity. Here, we used human HepG2 and HepG2-CYP1A2 cells as well as primary human hepatocytes (PHH) to study the genotoxic, clastogenic and cytotoxic potential of ES and its crucial metabolite 1′-hydroxyestragole (1′OH-ES). In addition, primary rat hepatocytes (PRH) were used for selected endpoints. Treatment of HepG2-CYP1A2 cells with ES (0–2 mM) led to the concentration-dependent formation of E3′- N 2 -dG adducts. Apart from a moderate γH2AX induction, neither p53 accumulation nor cytotoxicity was observed. However, clastogenicity was demonstrated at ES concentrations ≥ 1 mM. Incubation of HepG2 cells with 1′OH-ES (0—35 µM) led to 10–50-fold higher E3′- N 2 -dG adduct levels compared to equimolar ES concentrations. Furthermore, 1′OH-ES caused γH2AX formation, p53 accumulation and cytotoxicity, which was confirmed in PHH. In agreement, 1′OH-ES induced clastogenicity at concentrations ≥ 25 µM. Molecular dosimetry revealed that a certain E3′- N 2 -dG adduct level is required to trigger clastogenicity and cytotoxicity. This was confirmed by Benchmark Concentration (BMC) modelling, showing that the BMC for clastogenicity is 12–17-fold higher than the respective BMC for DNA adduct formation. Our data indicate that a threshold level of DNA adducts is required, both in rat and human liver cells, to trigger markers of clastogenicity. These levels are unlikely to be reached in humans following chronic ES exposure through phytomedicines or the diet.</abstract>
    <parentTitle language="eng">Archives of toxicology</parentTitle>
    <identifier type="issn">0340-5761</identifier>
    <identifier type="issn">1432-0738</identifier>
    <identifier type="doi">10.1007/s00204-025-04084-2</identifier>
    <enrichment key="opus.import.date">2025-11-29T10:06:06+00:00</enrichment>
    <enrichment key="opus.source">sword</enrichment>
    <enrichment key="opus.import.user">deepgreen</enrichment>
    <enrichment key="opus.import.file">attachment; filename=deposit.zip</enrichment>
    <enrichment key="opus.import.checksum">f4c19ab2ffe09ecbeb3f189f6dad3ae3</enrichment>
    <enrichment key="BTU">an der BTU erstellt / created at BTU</enrichment>
    <enrichment key="Publikationsweg">Open Access</enrichment>
    <licence>Creative Commons - CC BY - Namensnennung 4.0 International</licence>
    <author>
      <firstName>G.</firstName>
      <lastName>Ackermann</lastName>
    </author>
    <author>
      <firstName>M.</firstName>
      <lastName>Peil</lastName>
    </author>
    <author>
      <firstName>C.</firstName>
      <lastName>Quarz</lastName>
    </author>
    <author>
      <firstName>A.</firstName>
      <lastName>Schmidt</lastName>
    </author>
    <author>
      <firstName>M.</firstName>
      <lastName>Halaczkiewicz</lastName>
    </author>
    <author>
      <firstName>A. D.</firstName>
      <lastName>Thomas</lastName>
    </author>
    <author>
      <firstName>S.</firstName>
      <lastName>Stegmüller</lastName>
    </author>
    <author>
      <firstName>E.</firstName>
      <lastName>Richling</lastName>
    </author>
    <author>
      <firstName>G.</firstName>
      <lastName>Manolikakes</lastName>
    </author>
    <author>
      <firstName>M.</firstName>
      <lastName>Christmann</lastName>
    </author>
    <author>
      <firstName>Jan-Heiner</firstName>
      <lastName>Küpper</lastName>
    </author>
    <author>
      <firstName>D.</firstName>
      <lastName>Schrenk</lastName>
    </author>
    <author>
      <firstName>J.</firstName>
      <lastName>Fahrer</lastName>
    </author>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>Plant toxin</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>Phenylpropanoids</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>Estragole</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>Human hepatocytes</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>Liver damage</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>Cytotoxicity</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>Genotoxicity</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>Clastogenicity</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>Concentration–response modelling</value>
    </subject>
    <collection role="institutes" number="2110">FG Molekulare Zellbiologie</collection>
  </doc>
</export-example>
