@incollection{LohseKlotzSchwabeetal.1988, author = {Lohse, M. J. and Klotz, K.-N. and Schwabe, U. and Christalli, G. and Vittori, S. and Grifantini, M.}, title = {Pharmacology and Biochemistry of Adenosine Receptors}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-86251}, publisher = {Universit{\"a}t W{\"u}rzburg}, year = {1988}, abstract = {Adenosine modulates a variety of physiological functions via membrane-bound receptors. These receptors couple via G proteins to adenylate cyclase and K+channels. The A1 subtype mediates an inhibition of adenylate cyclase and an opening of K+-channels, and the A2 subtype a Stimulation of adenylate cyclase. Both subtypes have been characterized by radioligand binding. This has facilitated the development of agonists and antagonists with more than 1000-fold A1 selectivity. A1-selective photoaffinity labels have been used for the biochemical characterization of A1 receptors and the study of their coupling to adenylate cyclase. Such selective ligands allow the analysis of the involvement of adenosine receptors in physiological functions. Selective interference with adenosine receptors provides new pharmacological tools and eventually new therapeutic approaches to a number of pathophysiological states.}, subject = {Adenosinrezeptor}, language = {en} } @article{StopperZimmermannWecker1985, author = {Stopper, Helga and Zimmermann, U. and Wecker, E.}, title = {High yields of DNA-transfer into mouse L-cells by electropermeabilization}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-82408}, year = {1985}, abstract = {no abstracts available}, subject = {Toxikologie}, language = {en} } @article{StopperKirchnerSchiffmannetal.1994, author = {Stopper, Helga and Kirchner, S. and Schiffmann, D. and Poot, M.}, title = {Cell cycle disturbance in relation to micronucleus formation induced by the carcinogenic estrogen diethylstilbestrol}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-82250}, year = {1994}, abstract = {In addition to its tumor-promoting activity in honnone-receptive tissue, the carcinogenic estrogen diethylstilbestrol (DES) has been found to induce cell transformation, aneuploidy and micronucleus formation in mammalian cells. The majority of these micronuclei contained whole chromosomes and were fonned during mitosis. Here a possible relationship between a disturbance in cell cycle progression and micronucleus fonnation is investigated by exposing Syrian hamster embryo (SHE) cells to DES. Continuous bromodeoxyuridine labeling followed by bivariate Hoechst 33258/ethidium bromide flow cytometry was employed for analysis of cell cycle transit and related to the time course of micronucleus formation. Treatment of SHE cells with DES resulted in delayed and impaired cell activation (exit from the GO/G 1 phase), impaired S-phase transit and, mainly, G2-phase traverse. Cells forming micronuclei, on the other hand, were predominantly in G2 phase during DES treatment. These results suggest that impairment of Sand G2 transit may involve a process ultimately leading to micronucleus formation.}, subject = {Toxikologie}, language = {en} } @inproceedings{LutzSchlatter1978, author = {Lutz, Werner K. and Schlatter, C.}, title = {Extrapolation of carcinogenicity data to low doses with a dose-response study of the binding of benzo(a)pyrene to rat liver DNA}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-80157}, year = {1978}, abstract = {The binding of tritiated benzo(a)pyrene (BP) to liver DNA of 25 adult male rats (SIV 50) has been determined 50 h after a single intraperitoneal injection of doses between 40 ug/kg and 4; mg/kg. The dose-response relations~ ip is linear up to i mg/kg, shows a sigmoid step towards 2 mg/kg and a shallow linear. slope above that value. TlJe 0 bserved bin ding ranges from 1.7 to 180 nmoles BP per mole DNA phosphate. The non-linearity between 1 and 2 mg/kg could be explained 0):1 the basis of an induction of metabolizing enzymes. A pure1y mathematical extrapolation of therumour incidence from a carcinogenic dose (1 x 40mg/kg for a 20\% hepatoma incidence in newborn mice) to human exposure levels (aboilt 0.1 ug/kg per day) would never have followed a step like the on~ found in our experiments. Our dose-effect study therefore shows how carcinogenitity data could be extrapolated in a biologically founded way to low doses.}, subject = {Toxikologie}, language = {en} } @article{LutzSchlatter1978, author = {Lutz, Werner K. and Schlatter, C.}, title = {A closed inhalation system for pharmacokinetic and metabolism studies of volatile compounds with small laboratory animals}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-80145}, year = {1978}, abstract = {In the inhalation system described an animal can be kept in the same atmosphere of a 2-liter desiccator for up to 24 h. The expired carbon dioxide is adsorbed with soda lime and the resulting reduced pressure is balanced by a supply of oxygen also used for the inflow of the chemical to be investigated. Urine and faeces can be collected ~eparately and the system allows a periodical control of the concentration of the chemical by sampling the air with needle and syringe.}, subject = {Toxikologie}, language = {en} } @inproceedings{Lutz1984, author = {Lutz, Werner K.}, title = {Structural characteristics of compounds that can be activated to chemically reactive metabolites: use for a prediction of a carcinogenic potential}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-80105}, year = {1984}, abstract = {Many mutagens and carcinogens act via covalent interaction of metabolic intermediates with DNA in the target cell. This report groups those structural elements which are often found to form the basis for a metabolism to such chemically reactive metabolites. ~mpounds which are chemically reactive per se and which do not require metabolic activation form group 1. Group 2 compri~es of olefins and aromatic hydrocarbons where the oxidation via an epoxide can be responsible for the generation of reactive species. Aromatic amines, hydrazines, and nitrosamirres form group 3 requiring an oxidation of a nitrogen atom or of a carbon atom in alpha position to a nitrosated amine. Group 4 compounds are halogenated hydrocarbons which can either give rise to radicals or can form an ·olefin (group 2) upon dehydrohalogenation. Group 5 compounds depend upon some preceding enzymatic activity either not available in the target cell or acting on positions in the molecule which are not directly involved in the subsequent formation of electrophilic atoms. Examples for each group are taken from the "List of Chemieals and Irrdustrial Processes Associated with Cancer in Humans" as compiled by the International Agency for the Research on Cancer, and it is shown that 91\% of the organic carcinogens would have been detected on the basis of structural elements characteristic for group 1-5. As opposed to this very high sensitivity, the specificity ( the true negative fraction) of using this approach as a short-term test for carcinogenicity is shown to be bad because detoxification pathways have so far not been taken into account. These competing processes are so complex, however, that either only very extensive knowledge about pharmacokinetics, stability, and reactivity will be required or that in vivo systems have to be used to predict, on a quantitative basis, the darnage expected on the DNA. DNA-binding experiments in vivo are presented with benzene and toluene to demonstrate one possible way for an experimental assessment and it is shown that the detoxification reaction at the methyl group available only in toluene gives rise to a reduction by at least a factor of forty for the binding to rat liver DNA. This quantitative approach available with DNA-binding tests in vivo, also allows evaluation as to whether reactive metabolites and their DNA binding are always the most important single activities contributing to the overall carcinogenicity of a chemical. With the example of the livertumor inducing hexachlorocyclohexane isomers it is shown that situations will be found where reactive metabolites are formed and DNA binding in vivo is measurable but where this activity cannot be the decisive mode of carcinogenic action. It is concluded that the lack of structural elements known to become potentially reactive does not guarantee the lack of a carcinogenic potential.}, subject = {Toxikologie}, language = {en} } @inproceedings{Lutz1987, author = {Lutz, Werner K.}, title = {Quantitative evaluation of DNA-binding data in vivo for low-dose extrapolations}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-80079}, year = {1987}, abstract = {no abstract available}, subject = {Toxikologie}, language = {en} } @inproceedings{SagelsdorffLutz1987, author = {Sagelsdorff, P. and Lutz, Werner K.}, title = {Sensitivity of DNA and nucleotides to oxidation by permanganate and hydrogen peroxide}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-80062}, year = {1987}, abstract = {no abstract available}, subject = {Toxikologie}, language = {en} } @article{HintzscheJastrowKleineOstmannetal.2012, author = {Hintzsche, Henning and Jastrow, Christian and Kleine-Ostmann, Thomas and K{\"a}rst, Uwe and Schrader, Thorsten and Stopper, Helga}, title = {Terahertz electromagnetic fields (0.106 THz) do not induce manifest genomic damage in vitro}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-76268}, year = {2012}, abstract = {Terahertz electromagnetic fields are non-ionizing electromagnetic fields in the frequency range from 0.1 to 10 THz. Potential applications of these electromagnetic fields include the whole body scanners, which currently apply millimeter waves just below the terahertz range, but future scanners will use higher frequencies in the terahertz range. These and other applications will bring along human exposure to these fields. Up to now, only a limited number of investigations on biological effects of terahertz electromagnetic fields have been performed. Therefore, research is strongly needed to enable reliable risk assessment. Cells were exposed for 2 h, 8 h, and 24 h with different power intensities ranging from 0.04 mW/cm2 to 2 mW/cm2, representing levels below, at, and above current safety limits. Genomic damage on the chromosomal level was measured as micronucleus formation. DNA strand breaks and alkali-labile sites were quantified with the comet assay. No DNA strand breaks or alkali-labile sites were observed as a consequence of exposure to terahertz electromagnetic fields in the comet assay. The fields did not cause chromosomal damage in the form of micronucleus induction.}, subject = {Toxikologie}, language = {en} } @article{FoertschHuppMaetal.2011, author = {F{\"o}rtsch, Christina and Hupp, Sabrina and Ma, Jiangtao and Mitchell, Timothy J. and Maier, Elke and Benz, Roland and Iliev, Asparouh I.}, title = {Changes in Astrocyte Shape Induced by Sublytic Concentrations of the Cholesterol-Dependent Cytolysin Pneumolysin Still Require Pore-Forming Capacity}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-69084}, year = {2011}, abstract = {Streptococcus pneumoniae is a common pathogen that causes various infections, such as sepsis and meningitis. A major pathogenic factor of S. pneumoniae is the cholesterol-dependent cytolysin, pneumolysin. It produces cell lysis at high concentrations and apoptosis at lower concentrations. We have shown that sublytic amounts of pneumolysin induce small GTPase-dependent actin cytoskeleton reorganization and microtubule stabilization in human neuroblastoma cells that are manifested by cell retraction and changes in cell shape. In this study, we utilized a live imaging approach to analyze the role of pneumolysin's pore-forming capacity in the actin-dependent cell shape changes in primary astrocytes. After the initial challenge with the wild-type toxin, a permeabilized cell population was rapidly established within 20-40 minutes. After the initial rapid permeabilization, the size of the permeabilized population remained unchanged and reached a plateau. Thus, we analyzed the non-permeabilized (non-lytic) population, which demonstrated retraction and shape changes that were inhibited by actin depolymerization. Despite the non-lytic nature of pneumolysin treatment, the toxin's lytic capacity remained critical for the initiation of cell shape changes. The non-lytic pneumolysin mutants W433F-pneumolysin and delta6-pneumolysin, which bind the cell membrane with affinities similar to that of the wild-type toxin, were not able to induce shape changes. The initiation of cell shape changes and cell retraction by the wild-type toxin were independent of calcium and sodium influx and membrane depolarization, which are known to occur following cellular challenge and suggested to result from the ion channel-like properties of the pneumolysin pores. Excluding the major pore-related phenomena as the initiation mechanism of cell shape changes, the existence of a more complex relationship between the pore-forming capacity of pneumolysin and the actin cytoskeleton reorganization is suggested.}, subject = {Toxikologie}, language = {en} }