TY - JOUR A1 - Caviezel, M. A1 - Aeschbach, A. P. A1 - Lutz, Werner K. A1 - Schlatter, C. T1 - Reduction of covalent binding of aflatoxin B1 to rabbit liver DNA after immunization against this carcinogen N2 - 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. KW - Krebs KW - DNA KW - Aflatoxin KW - Cancer prevention KW - Carcinogen KW - Covalent binding KW - DNA KW - Immunization Y1 - 1984 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-80116 ER - TY - CHAP A1 - Viviani, A. A1 - Lutz, Werner K. T1 - Modulation of the in vivo covalent binding of the carcinogen benzo(a)pyrene to rat liver DNA by selective induction of microsomal and nuclear aryl hydrocarbon hydroxylase activity N2 - The influence of microsomal (mAHH) and nuclear (nAHH) aryl hydrocarbon hydroxylase activity on the covalent binding of t:titiated benzo(a)pyrene to rat liver DNA was evaluated in vivo. Induction ofmAHH was obtained after phenobarbitone treatment (180% of control), which increased DNA binding to 210%, but left the nAHH unchanged. mAHH and nAHH were slightly indilced with dieldrin (130% and 120%), but the binding remairred unchanged. The increasing effect of mAHlt as weil as the possibly decreasing effect of nAHH induction on the binding became obvious when the data of 11 individual rats were used to solve the equation Binding = aX(mAHH) + bX(nAHH) + c. Multiple linear regression analysis resulted in positive values for a and c, a negative value for b, and a multiple correlation coefficient R = 0.82. An influence of other enzymes involved in the metabolism of benzo(a)pyrene cannot be excluded. The Study shows clearly that the binding of a foreign compound to DNA in vivo is not only dependent on microsomal enzyme activities but also on nuclear activities even if the latter are considerably lower than those of mic'rosomes. KW - DNA KW - Benzo(a)pyrene KW - DNA-Binding KW - Carcinogen KW - Enzyme KW - Induction KW - Aryl Hydrocarbon Hydroxylase KW - Rats KW - Phenobarbitone KW - Dieldrin Y1 - 1979 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-80132 ER - TY - CHAP A1 - Cantoreggi, S. A1 - Gupta, R. C. A1 - Lutz, Werner K. T1 - An improved 32P-postlabelling assay for detection and quantitation of styrene 7,8-oxide-DNA adducts N2 - Using DNA modified with [7-3H]styrene 7,8-oxide (SO) in vitro we have standardized the 32P-postlabelling assay for detecting SO-DNA adducts. Nuclease P 1-enriched adducts were 32P-labelled and purified by high-salt ( 4.0 M ammonium formate, pH 6.1} C1s reverse-phase TLC. After elution from the layer with 2-butoxyethanol:H20 (4:6), adducts were separated by two-dimensional PEI cellulose TLC in non-urea solvents (2.0 M ammonium formate, pH 3.5, and 2.7 M sodium phosphate, pH 5.6). One major, three minor and several trace adducts were detected. The efficiency of the kinase reaction depended on the ATP concentration. Use of standard labelling conditions (['Y· 32P]ATP, <3000 Ci/mmol; <2 Mikromol) resulted in poor ( 4-7%) adduct recovery. An ATP concentration of 40 Mikromol, however, increased the labeJling efficiency by a factor of 5-8 (35-55% based on 3H-SO labelied DNA). The results indicate that the new separation technique is suitable for the relatively polar SO-DNA adducts and that high labelling efficiency can be achieved. KW - Medizin Y1 - 1993 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-86305 ER - TY - CHAP A1 - Lutz, Werner K. A1 - Cantoreggi, S. A1 - Velic, I. T1 - DNA binding and stimulation of cell division in the carcinogenicity of styrene 7,8-oxide N2 - [7-3H)Styrene 7,8-oxide was administered by oral gavage to male CD rats at a dose of 1.3 mg/kg. After 4 h, the forestomach was excised, DNA was isolated, purified to constant specific radioactivity and degraded nzymatically to the 3 '-nucleotides. Highperformance liquid chromatography fractions with the normal nucleotides contained most of the radiolabel, but a minute level of adduct label was also detccted. Using the units of the covalent binding index (micromoles adduct per mole DNA nucleotide)/(millimole chemical administered per kilogram body weight), a DNA binding potency of 1.0 was derived. A comparison of the covalent binding indices and carcinogenic potencies of other genotoxic forestarnach carcinogens showed that the tumorigenic activity of styrene oxide is unlikely to be purely genotoxic. Therefore, styrene oxide was compared with 3-tbutylhydroxyanisole (BHA) with respect to stimulation of cell proliferation in the forestomach. Male Fischer 344 rats were treated for four weeks at three dose levels of styrene oxide (0, 137, 275 and 550 mg/kg, three times per week by oral gavage) and BHA (0, 0.5, 1 and 2% in the diet); the highest doses had been reported to result in 84% and 22% carcinomas in the forestomach, respectively. Cell proliferation was assessed by incorporation of bromodeoxyuridine into DNA and immunohistochemical analysis. An increase in the lablling indexwas found in a11 treated animals. In the prefundic region of the forestomach, the labeHing index increased significantly, from 42% (controls) to 54% with styrene oxide and from 41 to 55% with BHA. Rats treated with BHA also had severe hyperplastic lesions in the prefundic region, i.e., at the location of BHA-induced forestomach carcinomas. The number of cells per millimetre of section length was increased up to 19 fold. Hyperplastic lesions were not seen with styrene oxide, despite the higher tumour incidence reported with this compound. We conclude that the carcinogenicity of styrene oxide to the forestomach most probably involves a mechanism in which marginal genotoxicity is combined with promotion by increased cell proliferation. KW - Styrol KW - DNS-Bindung KW - Zellteilung KW - Carcinogenität Y1 - 1993 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-71597 ER - TY - JOUR A1 - Adami, Hans-Olov A1 - Dragsted, Lars A1 - Enig, Bent A1 - Hansen, Jens A1 - Haraldsdóttir, Jóhanna A1 - Hill, Michael J. A1 - Holm, Lars Erik A1 - Knudsen, Ib A1 - Larsen, Jens-Jorgen A1 - Lutz, Werner K. A1 - Osler, Merete A1 - Overvad, Kim A1 - Sabroe, Svend A1 - Sanner, Tore A1 - Strube, Michael A1 - Sorensen, Thorkild I. A. A1 - Thorling, Eivind B. T1 - Report from the working group on diet and cancer. N2 - No abstract available. KW - Krebs KW - Ernährung Y1 - 1993 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-71601 ER - TY - JOUR A1 - Lutz, Werner K. A1 - Schlatter, Josef T1 - The relative importance of mutagens and carcinogens in the diet. N2 - Known mutagens and carcinogens in the dict were compiled and the risk of cancer was estimated on the basis of average exposure Ievels in Switzerland and carcinogenic potencies from rodent bioassays. The analysis showed that, except for a1cohol, the sum of all known dietary carcinogens could only explain a few percent of the cancer deaths attributed by epidemiologists to dietary factors. The discrepancy was explained by a "carcinogenicity" of excess macronutrients. This hypothesis was based on an evaluation of dietary restriction experiments in rats and mice, where a dramatic reducing effect on spontaneaus tumour formation was seen. From these experiments, a "carcinogenic potency" was deduced for food in excess (TD50 approximately 16 g/kg per day). Ovemutrition in Switzerland was converted into excess food intake and the cancer risk estimated on the basis ofthe TD50 value. The resulting risk of60,000 cases per one million lives wou1d aJlow to explain by overnutrition almost all "diet-related" cancer deaths in humans. KW - Medizin Y1 - 1993 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-86311 ER - TY - CHAP A1 - Lutz, Werner K. T1 - Dose-response relationships in chemical carcinogenesis: from DNA adducts to tumor incidence N2 - Mechanistic possibilitles responsible for nonlinear shapes of the dose-response relationship in chemical carcinogenesis are discussed. (i) Induction and saturation of enzymatic activation and detoxification processes and of DNA repair affect the relationship between dose and steady-state DNA adduct Ievel; (ii) The fixation of DNA adducts in the form of mutations is accelerated by stimulation of the cell division, for Jnstance due to regenerative hyperplasia at cytotoxic dose Ievels; (iii) The rate of tumor formation results from a superposition of the rates of the individual steps. It can become exponential with dose if more than one step is accelerated by the DNA damage exerted by the genotoxic carcinogen. The strongly sigmoidal shapes often observed for dose-tumor incidence relationships in animal bioassays supports this analysis. A power of four for the dose in the su~linear part of the curve is the maximum observed (formaldehyde). In contrast to animal experiments, epidemiological data ln humans rarely show a slgnificant deviation from linearity. The discrepancy might be explained by the fact that a I arge nu mber of genes contribute to the overall sensitivity of an individual and to the respective heterogeneity within the human population. Mechanistic nonlinearities are flattened out in the presence of genetic and life-style factors which affect the sensitivity for the development of cancer. For a risk assessment, linear extrapolation from the high-dose lncidence to the spontaneaus rate can therefore be approprlate in a heterogeneous population even if the mechanism of action would result in a nonlinear shape of the dose-response curve in a homogeneaus population. KW - aflatoxin B1 KW - 2-acetylaminofluorene KW - DNA KW - adduct KW - covalent KW - binding KW - carcinogen KW - dose KW - extrapolation KW - individual KW - susceptibility KW - heterogeneous population KW - risk KW - tumour Y1 - 1991 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-71625 ER - TY - CHAP A1 - Shephard, S. E. A1 - Meier, I. A1 - Lutz, Werner K. T1 - Alkylating potency of nitrosated amino acids and peptides N2 - Tbe alkylating potency of unstable N-nitrosamino acids and N-nitrosopeptides was investigated in vitro using 4-(para-nitrobenzyl)pyridine (NBP) as nucleophile. Of the amino acids, Met and those with an aromatic side chain were the most potent. The relative overall alkylating potency was 23:10:5:4:2:1: for Trp, Met, His, 1)rr, Phe and Gly, respectively. The homo-dipeptides were much more potent than the amino acids, with relative potencies of 400:110:100:8:3:1, for Trp-Trp, l)T-'I)T, Met-Met, Asp-Asp, Phe-Phe and Gly, respectively. In the one-phase reaction system (in which NBP is already present durlog the nitrosation reaction at acidic pH), all amino acids tested showed a second-order reaction for nitrite. In the two-phase system (in which NBP is added only after bringing the nitrosation reaction mixture to neutrality), all amino acids tested except one again showed a second-order reaction for nitrite (Phe, His, Asp and the dipeptide artiticial sweetener aspartame); only Met under these conditions bad a reaction order of one for nitrite. This could mean that nitrosation of the side chain of Metproduces a second N-nitroso product which is relatively stable in acid but reacts with NBP under neutral conditions. In the human stomach, this side-chain nitrosation might become more important than the reactions at the primary amino group, firstly because of the greater stability of the product(s) in acid and secondly because of the tirst-order reaction rate for nitrite. A decrease in nitrite concentration from the millimolar concentrations ofthe in-vitro assay to the micromolar concentrations in the stomach reduces the reaction rate by a factor of 1000 for the side-chain nitrosation, whereas a million-fold reduction will be observed for nitrosation of the amino group. KW - Aminosäuren Y1 - 1991 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-86320 ER - TY - JOUR A1 - Min, Chul-Hee A1 - Goth, F. A1 - Lutz, P. A1 - Bentmann, H. A1 - Kang, B.Y. A1 - Cho, B.K. A1 - Werner, J. A1 - Chen, K.-S. A1 - Assaad, F. A1 - Reinert, F. T1 - Matching DMFT calculations with photoemission spectra of heavy fermion insulators: universal properties of the near-gap spectra of SmB\(_{6}\) JF - Scientific Reports N2 - Paramagnetic heavy fermion insulators consist of fully occupied quasiparticle bands inherent to Fermi liquid theory. The gap emergence below a characteristic temperature is the ultimate sign of coherence for a many-body system, which in addition can induce a non-trivial band topology. Here, we demonstrate a simple and efficient method to compare a model study and an experimental result for heavy fermion insulators. The temperature dependence of the gap formation in both local moment and mixed valence regimes is captured within the dynamical mean field (DMFT) approximation to the periodic Anderson model (PAM). Using the topological coherence temperature as the scaling factor and choosing the input parameter set within the mixed valence regime, we can unambiguously link the theoretical energy scales to the experimental ones. As a particularly important result, we find improved consistency between the scaled DMFT density of states and the photoemission near-gap spectra of samarium hexaboride (SmB\(_{6}\)). KW - SmB\(_{6}\) KW - heavy fermion insulators KW - dynamical mean field KW - samarium hexaboride KW - near-gap spectra Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170328 VL - 7 IS - 11980 ER -