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Biomedical subjects

H Bartsch

Publications and source records attributed to H Bartsch.

At least 307 records · Page 17Linked to original sources
PubMed1987

Formation of reactive oxygen species and of 8-hydroxydeoxyguanosine in DNA in vitro with betel quid ingredients.

The formation of reactive oxygen species (ROS) from betel quid ingredients, namely areca nut, catechu and tobacco, was studied using a chemiluminescence (CL) technique. Aqueous extracts of areca nut and catechu were capable of generating superoxide anion and hydrogen peroxide at pH greater than 9.5. The formation of O2 was enhanced by Fe2+, Fe3+ and Cu2+ but inhibited by Mn2+. Tobacco extract failed to generate ROS under similar conditions. Saliva was found to inhibit both O2 and H2O2 formation from betel quid ingredients. Upon incubation of DNA at alkaline pH with areca nut extract and Fe3+ or catechu, 8-hydroxydeoxyguanosine was formed as quantified by high performance liquid chromatography (HPLC)/electrochemical detection. The data suggest a possible role of reactive oxygen species in the etiology of oral cancer in betel quid chewers.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1987

Synthesis, structure-activity relationships and a reaction mechanism for mutagenic N-nitroso derivatives of glycosylamines and Amadori compounds--model substances for N-nitrosated early Maillard reaction products.

A series of nine glycosylamines and an Amadori compound were synthesized, together with their N-nitroso derivatives. Their structures were established by physico-chemical and spectroscopic data and elemental analyses. The N-nitroso compounds were further characterized by denitrosation with hydrogen bromide-acetic acid, followed by detection of the liberated NO by a chemiluminescence detector. N-Nitroso derivatives of N-p-nitrophenyl/p-methylphenyl/p-carboxyphenyl pentopyranosylamines, N-p-methylphenyl-1-deoxy-D-fructosylamine (the Amadori compound) and N-3-ethylindole-D-xylopyranosylamine were shown to be direct-acting mutagens in Salmonella typhimurium TA100. The activity of some of the compounds was similar to that of N-ethyl-N-nitrosourea. Their mutagenic activity was shown to depend on the structure of the amine and the sugar moieties and to require the presence of free hydroxyl groups in the sugar. The mutagenicity of N-nitrosoglycosylamines was attributed to their hydrolysis to arenediazonium cations. The formation of these compounds was detected by azo-coupling with N-ethyl-1-naphthylamine, using spectrophotometric and mass spectrometric analyses. These data implicate arene(alkyl)diazonium cations as the ultimate mutagens of N-nitrosoglycosylamines (and possibly of N-nitroso Amadori compounds), a little-explored class of N-nitroso compounds that may be formed in vivo.

Amino Sugars↗
PubMed1987

Magnetic polyethyleneimine (PEI) microcapsules as retrievable traps for carcinogen electrophiles formed in the gastrointestinal tract.

Semi-permeable magnetic microcapsules containing polyethyleneimine (PEI) have been developed as retrievable carcinogen traps. In vitro, the soluble core PEI and membrane both bound reactive substances of limited aqueous stability, such as from [14C]N-methyl-N-nitrosourea ([14C]NMU), and aqueous stable dyes of molecular weight up to 1000. The core/membrane location ratio of binding was dependent upon membrane characteristics of the microcapsule batch used. Microcapsules administered intragastrically to rats bound up to 0.006% of [14C]dimethylhydrazine ([14C]DMH) and 1.4% of [14C]NMU administered i.p. or intrarectally, respectively. Time-dependency of [14C]DMH binding was consistent with labelling of microcapsules within the small intestine. There were no detectable metabolites from [14C]DMH trapped within the colon, whereas binding of [14C]NMU indicated that microcapsules could bind transient species present within the colon in competition with the faecal bulk. These results indicate that this approach could be used to detect highly unstable and possibly genotoxic substances in situ, hitherto unknown, formed within the intestinal lumen.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1987

Substituted hydroxyphenanthrenes in opium pyrolysates implicated in oesophageal cancer in Iran: structures and in vitro metabolic activation of a novel class of mutagens.

Previous epidemiological and laboratory studies have indicated an association between the ingestion of opium pyrolysates, dietary deficiencies and the high incidence of oesophageal cancer in subjects in north-east Iran. Pyrolysates of opium, and particularly of morphine, a major opium alkaloid, were both shown to contain similar highly mutagenic substances that were also clastogenic in mammalian cells and which transformed hamster embryo cells in culture. We now report the isolation and characterization of nine of the most abundant mutagenic compounds present in morphine pyrolysates, using h.p.l.c, GC-MS and n.m.r. spectroscopy. The hitherto unknown compounds, all containing a hydroxyphenanthrene moiety, were identified as: I, 3-methyl-3H-naphth[1,2-e]indol-10-ol; II, 1,2-dihydro-3-methyl-3H-naphth[1,2-e]indol-10-ol; III, 1-methyl-1H-naphth[2,1-g]indol-10-ol; IV, 2-methylphenanthro[3,4-d]-[1,3]oxazol-10-ol; V, 6-methylaminophenanthren-3-ol; VI, 2-methyl-3H-phenanthro[3,4-d]imidazol-10-ol; VII, 1,2-dimethyl-1H-phenanthro[3,4-d]imidazol-10-ol; VIII, 2,5-dimethyl-3H-phenanthro[3,4-d]imidazol-10-ol; and IX, 2-ethyl-3H-phenanthro[3,4-d]imidazol-10-ol. Structures for the heterocyclic rings of compounds IV and VI to IX are tentative. Mutagenicity in Salmonella typhimurium TA98 in the presence of rat liver homogenates increased in the order listed and ranged over four orders of magnitude, IX being 1000 times more active than benzo[a]pyrene. Compounds I and VII were converted by rat liver 9000 g supernatant into phenols and dihydrodiols, implicating arene oxides as ultimate mutagens. The formation and reaction of these arene oxides was shown by trapping experiments in vitro with ethanethiol and subsequent characterization of the ethyl sulfide reaction products. The order of biological activity of compounds I-IX, dependent on the structure of the heterocyclic ring, suggests that carbocations, resonance-stabilized as quinone methides, are their ultimate reactive metabolites. Our results lend additional support to the role of opium pyrolysates as an etiological factor in oesophageal cancer in north-east Iran.

Biotransformation↗
PubMed1987

A monoclonal antibody against cytochrome P-450 enhances mutagen activation of N-nitrosodimethylamine by mouse liver S9: studies on the mode of action.

The effect of the monoclonal antibody MAb 2-66-3, directed against the major rat liver phenobarbital (PB)-induced cytochrome P-450 (P-450), on the S9-mediated mutagenicity of N-nitrosodimethylamine (DMN) in Salmonella typhimurium strain TA1530 was studied using liver S9 from PB-treated mice. This MAb enhanced approximately 2-fold S9-mediated mutagenicity of DMN but inhibited both its N-demethylation and N-denitrosation by 50%. Thus MAb-mediated enhancement of DMN mutagenesis does not result from altered activation/inactivation pathways, both known to involve P-450 isozymes. DMSO, a hydroxyl radical (HO.) scavenger and desferrioxamine, an inhibitor of HO.-dependent reactions, quenched the MAb-mediated enhancement of DMN mutagenesis, implicating the HO.-dependent activation of DMN to mutagenic species. As a mechanism, we propose that the binding of this MAb to P-450 isozyme implicated in DMN metabolism decreases the functional coupling between the reductase and the P-450 complex, leading to an increased electron flow from the reductase towards molecular oxygen to form reduced oxygen species (HO.) at the expense of the monooxygenase functions.

Animals↗
PubMed1987

Tumorigenicity study in Syrian hamsters fed areca nut together with nitrite.

In order to evaluate the effect of concurrent administration of areca nut and sodium nitrite, a long-term feeding study was conducted with 120 Syrian hamsters. The animals were divided into four treatment groups, each consisting of 15 males and 15 females, and received 2 g/kg diet of sodium nitrite (group I), 20 g/kg diet of powdered areca nut (group II), 2 g/kg diet of sodium nitrite plus 20 g/kg diet of areca nut (group III) or powdered diet only (group IV) throughout their lifetime. Urine samples from all groups were analysed for N-nitrosonipecotic acid (NNIP), a major urinary metabolite of areca-nut-derived nitrosamines. NNIP was only detected in the urine of hamsters fed nitrite plus areca nut (concentration: 1.9 +/- 0.9 ng/ml urine), indicating that areca nut alkaloids underwent in vivo nitrosation to form areca-nut-specific nitrosamines. The total tumour response was not significantly elevated in groups II and III. Hamsters of group III had a markedly, but also insignificantly higher frequency of malignant tumours than those of the other groups, with a statistically significant increase in malignant lymphomas in the males. Although limited by the low number of animals per group, these results indicate that exposure to nitrite together with areca nut constituents appears to enhance the risk of developing malignancies.

Animals↗
PubMed1987

Binding of benzo[a]pyrene metabolites in the rat intestinal lumen by magnetic polyethyleneimine microcapsules following an intragastric dose of [14C]benzo[a]pyrene.

Semi-permeable magnetic polyethyleneimine (PEI) microcapsules have been developed to trap carcinogens and their metabolites in vivo and their time-dependent binding of a model carcinogen, [14C]benzo[a]pyrene [( 14C]BaP), is studied within the intestinal lumen. Overall, approximately 0.5% of an intragastric BaP dose was bound by these microcapsules recovered from faeces with specific binding of metabolites (nmol/10(6) recovered microcapsules) being similar in the 0-24-h and 24-48-h periods, but approximately 10-fold lower in the 48-72-h period. Successive extractions of microcapsules with ammoniacal methanol, 2.5 N HCl, methanol and dimethylsulfoxide released approximately 60% of bound radiolabeled and the unextracted radiolabel was presumed to have been bound covalently. By contrast, greater than 90% of bound radiolabel was extractable from the faeces of the treated animals and from microcapsules treated in vitro with [14C]7,8-dihydroxy-9,10-epoxytetrahydrobenzo[a]pyrene (BaPDE), indicating that the in vivo microcapsule-bound metabolites were not derived either from adsorbed faecal material or from [14C]BaPDE formed in situ. A time-dependent appearance of BaP 3,6-dione was found. Also the qualitative and quantitative patterns of metabolites trapped by microcapsules, as assayed by h.p.l.c., were consistent only with a unique set of BaP metabolites being bound within the intestinal lumen. Hence these carcinogen-binding microcapsules can be used to investigate the in situ formation of carcinogen metabolites within the intestinal tract.

Animals↗
PubMed1987

Biochemical studies on the catalysis of nitrosation by bacteria.

Biochemical and microbiological studies were conducted to characterize the mechanism of bacterial formation of N-nitrosomorpholine from morpholine and nitrite at neutral pH. Nitrosating activity was markedly induced when bacteria were cultured anaerobically in minimal culture medium containing nitrate, while the presence of cysteine or tungsten in the medium inhibited induction. Of various metals, coenzymes and inhibitors tested for their effects on in vitro nitrosation of morpholine, potassium cyanide, sodium azide, NAD(P)H and nitrate strongly inhibited nitrosation. Several mutants of Escherichia coli A10 strain were prepared in order to examine whether nitrosation activity is linked to specific loci. Niridazole-resistant mutants, which lack nitroreductase, had as much nitrosating activity as the original E. coli A10, but chlorate-resistant mutants had completely lost this activity. A good correlation was observed between nitrate reductase activity and nitrosating activity in these mutants. These results indicate that bacterial nitrosation is an enzyme-mediated reaction closely associated with molybdenoenzymes such as the nitrate reductase/formate hydrogenlyase system.

Azides↗
PubMed1987

Elevated lipid peroxidation in rats induced by dietary lipids and N-nitrosodimethylamine and its inhibition by indomethacin monitored via ethane exhalation.

The effect of dietary lipids alone or in combination with an administered carcinogen, N-nitrosodimethylamine (NDMA), on whole body lipid peroxidation was studied in rats in vivo. Groups of rats were fed diets containing 2%, 12.5%, or 25% of either saturated or polyunsaturated fat. Lipid peroxidation in individual animals was determined by measuring the concentration of ethane in exhaled air. Increased ethane exhalation was found in rats when the amount of dietary fat was increased from 2% to 12.5%, but animals receiving 12.5% or 25% fat in the diet exhaled ethane at similar rates. Rats consuming polyunsaturated fat exhaled more ethane than those eating saturated fat. In all groups, NDMA administration drastically increased ethane exhalation. Indomethacin completely blocked the increase in ethane exhalation caused by dietary lipids.

Animals↗
PubMed1987

Lipid peroxidation induced by N-nitrosodimethylamine (NDMA) in rats in vivo and in isolated hepatocytes.

To investigate the role of carcinogenic chemicals as a possible cause for oxidative damage, rats were treated with N-nitrosodimethylamine (NDMA) and various measures of lipid peroxidation were followed. As an indication of enhanced peroxidative processes in vivo, NMDA treatment produced rapidly an increase in the rate of ethane exhalation. A single i.p. or p.o. injection of 10 mg/kg b.w. elevated ethane exhalation by 13-14 fold; a single dose of 0.5 mg/kg of NDMA (the smallest dose tested) increased 5-fold the amount of ethane exhaled. Similarly, lipid peroxidation in the liver of NDMA-treated rats (measured by diene conjugation, chemiluminescence, the production of fluorescent and TBA-reactive material) was found to be increased rapidly showing a peak already 20 min after dosing. Simultaneously, NDMA-treatment slightly decreased antioxidant enzyme activities and GSH contents in the liver. In isolated rat hepatocytes the lucigenin-dependent chemiluminescence, as well as H2O2 release, were increased by micromolar concentrations of NDMA. Finally, it was shown that the rate of NADPH-stimulated ethane production by hepatic microsomes, prepared from untreated rats, was increased in the presence of NDMA. Thus, our results demonstrate that the alkylating NDMA can induce oxidative stress in rodents. Whether the same is true for other classes of carcinogens and processes known to affect tumor initiation/progression is presently under investigation.

Animals↗
PubMed1987

Specific membrane receptors for human interferon-gamma (IFN-gamma).

IFN-gamma is a T-cell derived lymphokine which possesses antitumoral activity for a variety of malignant cells by virtue of its direct effect on cell growth and by its immunomodulatory activity. All IFN-gamma actions are initiated by binding to high affinity cell surface receptors, which are constitutively expressed in virtually all cell lines from various tissues. Although the detailed structure of the IFN-gamma receptor is still elusive, the available data suggest that the high affinity IFN-gamma binding site is a heterodimeric molecule of 128 kDa comprised of two subunits of 53 and 75 kDa, which is invariantly expressed in distinct tumor cells, differing in their response to IFN-gamma. Thus, the capability and type of cellular response to IFN-gamma appears to be largely determined at a post-receptor level. Nevertheless, in sensitive cell lines, the magnitude of response is proportional to the quantity of receptor ligand interactions. This could be important for the definition of effective doses in clinical applications of IFN-gamma, as distinct tumor cells are heterogeneous with respect to quantity of IFN-gamma receptors, with greater 20-fold differences of the number of receptors per cell.

Affinity Labels↗
PubMed1987

N-nitrosamine formation by microorganisms isolated from human gastric juice and urine: biochemical studies on bacteria-catalysed nitrosation.

Twelve out of 14 bacterial strains isolated from patients with urinary infections and nine out of 30 microorganisms isolated from gastric juice from patients with gastric achlorhydria were shown to catalyse the formation of N-nitrosomorpholine (NMOR) from nitrite and morpholine at neutral pH. The effects of various metal ions and cofactors on the bacterial nitrosation reaction was investigated. The presence of nitrate in the culture medium was required to induce nitrosating activity in bacteria, but low nitrate concentrations inhibited the nitrosation reaction.

Escherichia coli↗
PubMed1987

An improved method for analysis of total N-nitroso compounds in gastric juice.

An improved procedure for the analysis of total N-nitroso compounds (NOC) in human gastric juice was developed by modifying previous methods. The gastric juice sample, treated with sulfamic acid to remove nitrite, is injected directly into refluxing ethyl acetate containing either acetic acid for determining thermo/acetic acid-labile-thermal energy analyser (TEA)-responsive compounds (TAC), or into hydrogen bromide for the analysis of TAC and NOC. The nitric oxide (NO) levels released are measured by chemiluminescence by TEA, and the difference between the two determinations represents the concentrations of NOC in gastric juice. This method also allows the determination of nitrite and is not affected by nitrate concentrations up to 1,000 mumol/l. The method was found to be reproducible and sensitive (detection limit, 0.02 mumol NOC/l), requiring only small volumes of gastric juice and no prior extraction. Because the difficulties arising from the 'system response' to the denitrosating agent and variability of NO release by acetic acid from nitrite were eliminated, this improved method can more accurately distinguish NOC from most other TEA-responsive species. Suitable techniques for stabilizing gastric juice samples from duodenal ulcer/atrophic gastritis patients and the influence of the time and storage conditions on NOC concentrations have been studied.

Gastric Juice↗
PubMed1987

Synthesis, analysis and mutagenic activity of N-nitroso derivatives of glycosylamines and Amadori compounds: nitrosated model substances for the early Maillard reaction products.

A series of nine glycosylamines and an Amadori compound and their N-nitroso derivatives were synthesized. The structures were ascertained by spectroscopy and elemental analysis. The N-nitroso compounds were further characterized by denitrosation with hydrogen bromide-acetic acid, followed by detection of the liberated NO by a chemiluminescence detector. N-Nitroso derivatives of N-p-nitrophenyl/p-methylphenyl/p-carboxyphenyl pentosylamines, N-p-methylphenyl-1-deoxy-D-fructosylamine (Amadori compound) and N-3-ethylindole-D-xylosylamine were shown to be directly-acting mutagens in Salmonella typhimurium TA100. The activity of some of the compounds was similar to that of N-ethyl-N-nitrosourea. Their mutagenic activity was shown to be dependent on the structure of the amine and the sugar moieties and requires the presence of free hydroxyl groups in the sugar. The mutagenicity of N-nitrosoglycosylamines was attributed to their hydrolysis to arene diazonium cations. Their formation was detected via azo-coupling with N-ethyl-1-naphthylamine, using spectrophotometric and mass-spectrometric analyses. Our data implicate arene (alkyl) diazonium cations as the ultimate mutagens of N-nitrosoglycosylamines and N-nitroso Amadori compounds, a little explored class of N-nitroso compounds which may be formed in vivo.

Amino Sugars↗
PubMed1987

N-nitrosamine formation in urinary-tract infections.

Urine samples from 31 patients with urinary-tract infections and from 31 controls were analysed for volatile nitrosamines, N-nitrosamino acids, total N-nitroso compounds as a group, and nitrite/nitrate. The concentration of N-nitrosodimethylamine was significantly elevated in urines infected with Escherichia coli, Proteus mirabilis and Klebsiella pneumoniae. The levels of nitrite, N-nitrosoproline and total N-nitroso compounds, when expressed as the amount per mol creatinine, were also significantly increased in patients with bacteriuria. Several bacterial strains were capable of catalysing nitrosation of morpholine at neutral pH. These results suggest that N-nitroso compounds can be formed in vivo in the infected bladder, which could explain the association between urinary-tract infections and increased risk for bladder cancer.

Adolescent↗
PubMed1987

Occurrence of volatile nitrosamines in food samples collected in three high-risk areas for nasopharyngeal carcinoma.

Fifty-four samples of foods consumed frequently in Tunisia, southern China and Greenland, all high-risk areas for nasopharyngeal carcinoma (NPC), were analysed for the presence of volatile nitrosamines by gas chromatography (GC) combined with a thermal energy analyser (TEA). Relatively high levels of N-nitrosodimethylamine (NDMA), N-nitrosopiperidine (NPIP) and N-nitrosopyrrolidine (NPYR) were found in Tunisian stewing base (touklia) and dried mutton preserved in olive oil (qaddid). In one Chinese salted and dried fish sample, a high level of NDMA (133 micrograms/kg) was detected, but for the 14 others the levels ranged from undetectable to 14 micrograms/kg, with a mean of 3 micrograms/kg. Similarly high levels of NDMA, were found in Eskimo dried, unsalted fish samples. NDMA, NPIP and NPYR at various levels were present in Chinese vegetables fermented in brine. The possible role of nitrosamines in the etiology of NPC is discussed.

China↗
PubMed1987

Endogenous nitrosation in the oral cavity of chewers while chewing betel quid with or without tobacco.

In order to evaluate endogenous nitrosation in the oral cavity of chewers of betel quid with tobacco (BQT) or without tobacco (BQ), saliva samples were collected from healthy male volunteers after chewing sequentially (i) unmodified BQT or BQ, (ii) BQT or BQ to which proline has been added, and (iii) BQT or BQ to which proline and ascorbic acid had been added. Samples were collected over 20 min and analysed for N-nitrosoproline (NPRO), tobacco-specific nitrosamines (TSNA) and areca nut-specific nitrosamines using gas chromatography-thermal energy analysis, arecoline and nicotine using gas chromatography-nitrogen phosphorus-specific detector, and for nitrite and thiocyanate. When results were expressed as a ratio of NPRO (ng/ml) to nicotine (micrograms/ml), all BQT chewers had increased NPRO contents after chewing BQT with proline. For BQ chewers, when the results were expressed as a ratio of NPRO (ng/ml) to arecoline (micrograms/ml), a similar increase in NPRO content was observed. However, the presence of ascorbic acid inhibited the increased nitrosation in only four out of ten BQT chewers and in five out of ten BQ chewers; in the rest of the samples, its presence enhanced the levels of NPRO. N'-Nitrosoanatabine (NAT) and N-nitrosoguvacoline (NGCO) levels decreased significantly in saliva of chewers of BQT in the presence of ascorbic acid, suggesting inhibition of their formation. In-vitro nitrosation of BQT/BQ with proline and proline plus ascorbic acid showed a similar pattern of nitrosation at salivary pH. The study confirmed previous results that certain nitrosamines are formed during the chewing of BQT/BQ.

Areca↗