@article{LutzSchlatter1979, author = {Lutz, Werner K. and Schlatter, C.}, title = {In vivo covalent binding of chemicals to DNA as a short-term test for carcinogenicity}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-80127}, year = {1979}, abstract = {The determination of a covalent binding of radioactive chemieals to DNA in intact mammalian organisms is proposedas a short-term test for carcinogenicity. The effectiveness of covalent binding to rat liver DNA correlates well with the hepatocarcinogenicity known from long-term bioassays. The binding indices range over more than five orders of rriagnitude between the strongest hepatocarcinogen aflatoxin B 1 and the limit of detection of a binding with 100 f-LCi 14C-labelled chemical. The order of magnitude of binding is therefore a surprisingly good quantitative measure for carcinogenicity. The pattern of DNA binding sites is important especially for small alkylating agents where the determination of total binding might indicate a higher carcinogenic potency than is actually observed.}, subject = {DNA}, language = {de} } @article{VivianiDaenikenSchlatteretal.1980, author = {Viviani, A. and D{\"a}niken, A. von and Schlatter, C. and Lutz, Werner K.}, title = {Effect of selected induction of microsomal and nuclear aryl hydrocarbon monooxygenase and epoxide hydrolase as well as cytoplasmic glutathione S-epoxide transferase on the covalent binding of the carcinogen benzo(a)pyrene to rat liver DNA in vivo}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-61114}, year = {1980}, abstract = {Groups of four adult male rats [ZUR:SIV -Z] were pretreated with corn oil (control; 2 ml/kg/day i. p. for 3 days), trans-stilbene-oxide (SO; 200 mg/kg/day i. p. for 2 days), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; 10 \(\mu\)g/kg i. p. once, 4 days before killing), phenobarbital (PB; 1 gjliter in the drinking water for 8 days), and dieldrin (20 mg/kg/day i. p. for 3 or 9 days). They received an injection of [G-\(^3\)H]benzo(a)pyrene (BaP, 31 \(\mu\)g/kg, 7.4. 10\(^9\) dpm/kg; i. v.) 16 h before killing. In the liver of each rat, five enzymatic activities and the covalent binding of BaP to DNA have been determined. The rnicrosomal aryl hydrocarbon monooxygenase activity (AHM) ranged frorn 75\% of control (SO) to 356\% (TCDD), the nuclear AHM from 63\% (SO) to 333\% (TCDD). Microsomal epoxide hydrolase activity (EH) was induced up to 238\% (PB), nuclear EH ranged from 86\% (TCDD) to 218\% (PB). A different extent of induction was observed in the two compartments. Highest induction of glutathione S-epoxide transferase activity (GST) was found with PB (202\%). The DNA binding of BaP was modulated within 79\% (dieldrin, 9 days) and 238\% of control (TCDD). An enzyme digest of control DNA was analysed by Sephadex LH-20 chromatography. Multiple linear regression analysis with all data expressedas o/o of control yielded the following equation: DNA Binding = 1.49 · Microsomal AHM- 1.07 · Nuclear AHM+ 0.33 · Microsomal EH- 0.52 · N uclear EH+ 0.11 · Cytoplasmic GST + 58.2. From this analysis it is concluded that (1) AHM located in the endoplasmic reticulum is most important in the formation of DNA-binding metabolites, (2) EH in the same compar.tment is not determinative in thls respect nor has it a protective effect, (3) both membrane-bound enzyme activities located in the nucleus may inactivate potential ultimate carcinogens, and ( 4) cytoplasmic GST probably cannot reduce DNA binding due to its subcellular localization.}, subject = {Toxikologie}, language = {en} } @article{CaviezelAeschbachLutzetal.1984, author = {Caviezel, M. and Aeschbach, A. P. and Lutz, Werner K. and Schlatter, C.}, title = {Reduction of covalent binding of aflatoxin B1 to rabbit liver DNA after immunization against this carcinogen}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-80116}, year = {1984}, abstract = {The covalent binding of [3H]aflatoxin B1 (AF) to liver DNA was determined, 6 h after oral administration to male rabbits. A Covalent Binding Index, CBI (flmol AF/mol DNA-P)/(mmol AF/kg b. w.) = 8,500 was found. Pretreatment of rabbits with AF coupled to bovine serum albumin in Freund's adjuvant led to the production of AF-directed antibodies. Administration of [3H]AF to such immunized rabbits resulted in a CJH of only 2,500, i.e., the iiDJ{.lUnization provided a protection by a factor of more than 3. Although this is encouraging evidence for the potential of active immunization against genotoxic carcinogens, a nurober of pointswill have to be clarified, such as the time course for the DNA binding and the question of a possible shift to other target cells.}, subject = {Krebs}, language = {en} } @incollection{ShephardSchlatterLutz1987, author = {Shephard, S. E. and Schlatter, C. and Lutz, Werner K.}, title = {Model risk analysis of nitrosatable compounds in the diet as precursors of potential endogenous carcinogens}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-86188}, publisher = {Universit{\"a}t W{\"u}rzburg}, year = {1987}, abstract = {The potential health risk posed by the endogenous formation of N-nitroso compounds (NOC) from nitrosation of dietary ureas, guanidines, amides, amino acids and amanes (primary, secondary and aromatic) was estimated according to the model: Risk = ( daily intake of precursor] X (gastric concentration of nitrite ]n X [nitrosatability rate constant] X [cilrcinogenicity of derivative]. The daily intakes ofthese compound classes span five orders ofmagnitude (100 g/day amides, top; 1-10 mg/day secondary amines, ureas, bottom); the nitrosation rate constants span seven orders of magnitude (aryl amines, ureas, top; amides, secondary amines, bottom); and the carcinogenicity estimates span a 10 000-fold range from 'very strong' to 'virtually noncarcinogenic'. The resulting risk estimates likewise span an enormous range (nine orders of magnitude ): dietary ureas and aromatic amines combined with high nitrite concentration could pose as great a risk as the intake of preformed N-nitrosodimethylamine in the diet. In contrast, the risk posed by the in-vivo nitrosation of primary and secondary amines is probably negligible. The risk contributed by amides (including protein), guanidines and primary amino acids is intermediate between these two extremes.}, subject = {Risikoanalyse}, language = {en} } @phdthesis{Tiedge2008, author = {Tiedge, Oliver}, title = {Kombinationswirkungen nicht linearer Dosis-Wirkungsbeziehungen}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-28522}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2008}, abstract = {Um realistische Risikoabsch{\"a}tzungen von karzinogenen und genotoxischen Expositionen besser bewerten zu k{\"o}nnen, bedarf es Untersuchungen von Kombinationen welche sich von der Einzellstoffbetrachtung losl{\"o}st. Die Zielsetzung der vorliegenden Arbeit bestand darin, herauszufinden, ob die Gentoxizit{\"a}t einer Kombination in ihrer St{\"a}rke vom erwarteten Effekt der normalen Additivit{\"a}t abweicht, wenn die Kurven der Dosis - Wirkungsbeziehung der Einzelkomponenten nicht lineare Verl{\"a}ufe zeigen. Dabei muss zwischen Dosisaddition und Wirkaddition der Kombinationen unterschieden werden, das heißt ob die Einzelkomponenten einen untereinander {\"a}hnlichen oder unabh{\"a}ngigen Wirkmechanismus verfolgen. F{\"u}r nicht lineare Dosis - Wirkungsbeziehungen differieren also die Kurvenverl{\"a}ufe zwischen Dosisaddition und Wirkaddition und bilden einen m{\"o}glichen Bereich der Additivit{\"a}t zwischen ihnen (auch: „H{\"u}lle der Additivit{\"a}t"). Nur Reaktionen welche außerhalb dieses Bereiches ablaufen, d{\"u}rfen als synergistische oder antagonistische Effekte bezeichnet werden. Diese {\"U}berlegungen wurden {\"u}berpr{\"u}ft mit der Analysierung von Mikrokernen, induziert in L5178Y Maus - Lymphom - Zellen durch die methylierenden Substanzen Methylmethansulfonat (MMS) und Methyl-Nitroso-Urea (MNU), sowie dem Topoisomerase II Inhibitor Genistein (GEN). Alle drei Chemikalien erzeugen reproduzierbare sublineare Dosis - Wirkungsbeziehungen. F{\"u}r die Analyse der Kombinationseffekte wurden diese Substanzen in drei bin{\"a}ren Mixturen miteinander gemischt. F{\"u}r MMS + MNU war der Effekt vereinbar mit Dosisaddition und lag signifikant h{\"o}her als der vorkalkulierte Effekt der Netto - Wirkung. F{\"u}r MMS + GEN lag der gemessene Effekt {\"u}ber der Wirkaddition, jedoch unter der Dosisaddition. F{\"u}r MNU + GEN lag der gemessene Effekt unterhalb der Wirkaddition und deutete damit auf einen echten Antagonismus hin. In Unkenntnis des sublinearen Dosis - Wirkungsverhaltens der Einzelsubstanzen w{\"a}re ein synergistischer Effekt von MMS mit beiden Substanzen MNU und GEN f{\"a}lschlicherweise vorausgesagt worden. Der beobachtete Unterschied zwischen MMS und MNU und deren jeweiligen Kombination mit GEN w{\"a}re mit einer stark vereinfachten Interpretation der DNA - Methylierung nicht vorausgesagt worden. Ursachen k{\"o}nnten eine doch zu unterschiedliche Form der DNA - Methylierung und / oder epigentische Faktoren sein. Zusammenfassend kann man sagen, dass Kenntnisse der Nichtlinearit{\"a}t von Dosis - Wirkungskurven der einzelnen Substanzen ausschlaggebend f{\"u}r die Analyse von Synergismus oder Antagonismus in deren Kombinationen ist. Weiterhin ist ein Vorwissen {\"u}ber tiefere mechanistische Vorg{\"a}nge hilfreich f{\"u}r eine Vorhersage von {\"a}hnlichen oder unabh{\"a}ngigen Wirkprozessen.}, subject = {Kleinkern}, language = {de} }