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H Bartsch

Publications and source records attributed to H Bartsch.

At least 361 records · Page 20Linked to original sources
PubMed1984

Nitrosating properties of bis-methylthio-diiron-tetranitrosyl (Roussin's red methyl ester), a nitroso compound isolated from pickled vegetables consumed in northern China.

Bis-methylthio-diiron-tetranitrosyl (Roussin's red methyl ester, RRME), recently identified in pickled vegetables consumed in a high incidence area of oesophageal cancer in Northern China, was examined for its activity as a nitrosating agent in vivo and in vitro. Freshly synthesized RRME nitrosated secondary amines (morpholine and pyrrolidine) slowly in the presence of air; it failed to nitrosate these amines under strictly anaerobic conditions. In experiments in rats, a fresh sample of RRME was found to be a weak nitrosating agent, whereas partially decomposed RRME showed a strong nitrosating activity comparable to that of nitrite. Possible mechanisms for nitrosation by RRME are discussed.

Animals↗
PubMed1984

Presence in human urine of new sulfur-containing N-nitrosamino acids: N-nitrosothiazolidine 4-carboxylic acid and N-nitroso 2-methylthiazolidine 4-carboxylic acid.

A new type of sulfur-containing N-nitrosamino acid, N-nitrosothiazolidine 4-carboxylic acid (NTCA) and N-nitroso 2-methylthiazolidine 4-carboxylic acid (NMTCA), was isolated and identified in the urine of human subjects. Identification was based on identical chromatographic and mass spectral data for the purified urine sample and the synthesized authentic compounds. The amounts of NTCA and NMTCA excreted in 24-h urines of 15 volunteers varied from 0.9 to 35.9 micrograms/day and from 0.4 to 19.8 micrograms/day, respectively. These amounts were 2.4 and 1.6 times greater than that of N-nitrosoproline (NPRO) detected in the same urine samples. Thiazolidine 4-carboxylic acid and its 2-methyl derivative were found to be nitrosated in vitro about 250-500 and 60-300 times more rapidly than proline, respectively. In addition, NTCA and NMTCA were also readily formed by reaction of a mixture of nitrite and L-cysteine, with formaldehyde and acetaldehyde, respectively. Although their origin in human urine is unknown, preliminary results in one human volunteer have shown that some of these compounds are formed endogenously. Thus, measurement of these new sulfur-containing N-nitrosamino acids in the urine may (i) provide another index for endogenous nitrosation reactions in the human body and (ii) allow monitoring of exposure of humans to precursors such as aldehydes and nitrate/nitrite.

Chemical Phenomena↗
PubMed1984

Recent studies on N-nitroso compounds as possible etiological factors in oesophageal cancer.

Possible etiological factors involved in oesophageal cancer in various parts of the world and in certain provinces in Northern China are summarized. Evidence is accumulating that N-nitroso compounds and their precursors are involved in the disease in Northern China, as shown in a recent study: excretion of urinary N-nitrosamino acids by inhabitants living in a high- (Linxian) and in a low-risk area (Fanxian) for oesophageal cancer was compared. Linxian subjects excreted significantly more nitrate and nitrosamino acids (N-nitrosoproline, N-nitrosothiazolidine-4-carboxylic acid, N-nitrososarcosine) than those in Fanxian. When Linxian subjects were given 100 mg vitamin C three times a day (after each meal) together with proline, the level of urinary N-nitrosamino acids was reduced to that found in Fanxian. Thus, vitamin C, an efficient inhibitor of endogenous nitrosation, should now be examined in intervention trials in subjects in whom endogenous formation of N-nitroso compounds is elevated.

Africa↗
PubMed1984

Monitoring endogenous nitrosamine formation in man.

Results from animal experiments and studies in human subjects indicated that the amount of nitrosoproline (NPRO) excreted in the 24-h urine, following ingestion of precursors, is an index for the rate of endogenous nitrosation; this method was found to be sensitive, reproducible and could be satisfactorily applied to human subjects in clinical and field studies. N-Nitrosothiazolidine 4-carboxylic acid (NTCA) and its 2-methyl derivative (NMTCA) were also identified in the urine of human subjects. As the respective amino precursors (thiazolidine 4-carboxylic acids) can be formed by reaction of formaldehyde or acetaldehyde with cysteine, measurement of NTCA and NMTCA in urine may provide a further index for endogenous nitrosation in the human body and may also allow monitoring of exposure of human subjects to aldehydes, nitrate and nitrite. The yield of nitroso compounds formed endogenously in the human body was shown to be linked to the intake of precursors, but several inhibitors and catalysts, either as pure substances or occurring in complex mixtures, were shown to modify the nitrosation reaction in vivo. In particular, ingestion of ascorbic acid after nitrate-rich meals was efficient in lowering human exposure to endogenously formed N-nitroso compounds. A dose-response relationship was established for the formation of NPRO in rats in vivo, after concurrent administration of various concentrations of the precursors, L-proline and sodium nitrite. The logarithm of the amount of NPRO formed was found to be proportional to the logarithm of the product of the proline dose and the square of the nitrite dose. On the basis of these results, a kinetic model was formulated allowing the estimation of the daily precursor dose quantity, ([amine][nitrite]2), required to give 50% tumour incidence in rats after two years of feeding. The potential application of this model, for the estimation of carcinogenic risk from endogenously formed N-nitrosamines in humans, is discussed. Our results demonstrate unequivocally the endogenous formation of N-nitroso compounds in the human body, the significance of which in human carcinogenesis remains to be established.

Animals↗
PubMed1983

Interrelationships in mice of antipyrine half-life, hepatic monooxygenase activities and liver S9-mediated mutagenicity of aflatoxin B1, benzo[alpha]pyrene 7,8-dihydrodiol, 2-acetylaminofluorene and N-nitrosomorpholine.

To evaluate the predictive value of serum antipyrine half-life AP(T1/2) as an index of hepatic carcinogen metabolism, groups of C57BL/6 and DBA/2 mice were treated with various inducers and inhibitors of cytochrome P-450-dependent monooxygenases (pregnenolone-16 alpha-carbonitrile (PCN), phenobarbital (PB), 5,6-benzoflavone (5,6-BF), 3-methylcholanthrene (MC), disulfiram (DIS), 7,8-BF). Groups of mice were also given ethanol (3% in drinking water) for 12 days. Within each group, mean serum AP-(T1/2) was compared with (i) the in vitro activity of hepatic microsomal benzo[alpha]pyrene (BP) 3-hydroxylase, 2-acetylaminofluorene (AAF)-N-hydroxylase and aldrin monooxygenase, and (ii) the liver S9-mediated mutagenicity of aflatoxin B1 (AFB), trans-7,8-dihydro-7,8-dihydroxybenzo[alpha]pyrene (BP 7,8-diol), 2-acetylaminofluorene and N-nitrosomorpholine (NMOR) in Salmonella typhimurium strains. Serum AP(T1/2) was only correlated negatively with the activity of BP 3-hydroxylase (P less than 0.001) and aldrin monooxygenase (P less than 0.001). No statistically significant correlation was found between serum AP(T1/2) and liver S9-mediated mutagenicity for any of the four carcinogens. On the basis of these results, we conclude that serum AP(T1/2) may not be a reliable index of the capacity of liver to convert carcinogens into reactive intermediates.

2-Acetylaminofluorene↗
PubMed1983

Quantitative comparison of carcinogenicity, mutagenicity and electrophilicity of 10 direct-acting alkylating agents and of the initial O6:7-alkylguanine ratio in DNA with carcinogenic potency in rodents.

The quantitative relationship between carcinogenicity in rodents and mutagenicity in Salmonella typhimurium was examined, by using 10 monofunctional alkylating agents, including N-nitrosamides, alkyl methanesulfonates, epoxides, beta-propiolactone and 1,3-propane sultone. The compounds were assayed for mutagenicity in two S. typhimurium strains (TA1535 and TA100) and in plate and liquid assays. The mutagenic activity of the agents was compared with their alkylating activity towards 4-(4'-nitrobenzyl)pyridine and with their half-lives (solvolysis constants) in an aqueous medium. No correlations between these variables were found, nor was mutagenic activity correlated with estimates of carcinogenicity in rodents. There was a positive relationship between carcinogenicity and the initial ratios of 7-:O6-alkylguanine formed or expected after their reaction with double-stranded DNA in vitro. The results suggest that alkylation of guanine at position O6 (or at other O atoms of DNA bases) may be a critical DNA-base modification that determines the overall carcinogenicity of these alkylating agents in rodents.

Alkylating Agents↗
PubMed1983

Presence in human urine of a new N-nitroso compound, N-nitrosothiazolidine 4-carboxylic acid.

Urine samples collected in several countries from human subjects showed the presence of a number of N-nitroso compounds not previously identified. By several separative procedures and by comparison with authentic material, the major unknown N-nitroso compound was shown to be N-nitrosothiazolidine 4-carboxylic acid (NTCA). Although its origin in human urine is unknown, thiazolidine 4-carboxylic acid, the easily nitrosatable amine precursor, can be formed by reaction of formaldehyde with cysteine in vivo and in vitro. Thus measuring NTCA excreted in the urine may allow monitoring exposure of human subjects to precursors like formaldehyde and NO-3/NO-2.

Chromatography, Gas↗
PubMed1983

Hydroxylation and nitroreduction are required to activate dimethylnitramine into alkylating and mutagenic agents.

Dimethylnitramine (DMNO) was shown to undergo hydroxylation in the presence of 9000 g supernatant from rat liver (S9) to yield hydroxymethyl-methylnitramine (OH-MNO). OH-MNO displayed a 100-fold higher mutagenic activity in Salmonella typhimurium TA100 strain than DMNO, when compared on a molar basis. The mutagenicity of DMNO in TA100 strain in the presence of S9 paralleled the production of OH-MNO. Acetoxymethyl-methylnitramine (Ac-MNO) and methylnitramine (MNO), two synthetic derivatives of DMNO, were also investigated. Ac-MNO was found to be mutagenic in TA100 strain only in the presence of S9, probably through the release of OH-MNO catalysed by esterase(s); under similar conditions, MNO showed no mutagenicity or toxicity to TA100 strain. OH-MNO showed no alkylating activity towards nicotinamide. These findings implicate OH-MNO as a proximate mutagenic metabolite of DMNO. DMNO and Ac-MNO were found to be more mutagenic in a nitroreductase(s)-proficient (TA100) than in a deficient (TA100 NR) strain. After reduction of OH-MNO with Zn/NH4Cl, it yielded an agent(s) which alkylated nicotinamide. The latter results imply a reduction of the nitro group in OH-MNO to yield a hydroxylamino derivative as the ultimate (or penultimate) mutagenic metabolite. The enzymes and reactive intermediates that may be involved in the activation of DMNO are discussed.

Alkylating Agents↗
PubMed1983

Induction of SCE by opium pyrolysates in CHO cells and human peripheral blood lymphocytes.

The induction of sister chromatid exchange (SCE) by opium pipe scrapings (sukhteh, Su) and the pyrolysis products of opium (Op) and of its major alkaloids, morphine (Mo), have been compared with that of cigarette smoke condensate (CSC). All pyrolysates induced SCE and the frequency was further increased by the inclusion of S9-mix in the protocol. The pyrolysates of Op induced considerably more SCE than CSC when the same concentrations were compared on a weight basis, and the rank in order of potency in CHO cells was MO greater than Op greater than CSC greater than Su. The Op pyrolysates may therefore contribute a significant risk factor to the observed high incidence of oesophageal cancer in areas of Iran where heavy Op usage occurs.

Animals↗
PubMed1983

Studies on the efficiency of the Salmonella/rat hepatocyte assay for the detection of carcinogens as mutagens: activation of 1,2-dimethyl-hydrazine and procarbazine into bacterial mutagens.

Aflatoxin B1, benzo[a]pyrene, N-nitrosomorpholine, procarbazine (PC) and 1,2-dimethylhydrazine (DMH) were used to investigate the efficiency of the Salmonella/rat hepatocyte assay for detecting carcinogens as mutagens. In this assay, bacteria and the test compound were co-incubated with freshly isolated rat hepatocytes and then plated onto minimal glucose agar. Factors for optimal mutagenicity, including the number of hepatocytes and the number of bacteria, the type of assay medium and the length of incubation in liquid medium were investigated. All the compounds were metabolized into bacterial mutagens. Mediation of the mutagenicity of PC and DMH by rat hepatocytes indicates that freshly isolated cells of this type are a useful alternative metabolic activation system for use in screening chemicals found to be non-mutagenic in the Salmonella/microsome assay.

1,2-Dimethylhydrazine↗
PubMed1983

Inhibition of endogenous nitrosation of proline in rats by lyophilized beer constituents.

Various amounts of lyophilized beer were administered to rats dosed with proline and sodium nitrite. N-Nitrosoproline (NPRO) excreted in the 24-h urine was monitored as an index of endogenous nitrosation. In vitro formation of NPRO was determined after 15-min incubation of the same precursor solutions. Both in vivo and in vitro nitrosation of proline was inhibited in a dose-dependent fashion by lyophilized beers of different brands; the effects in vitro were most pronounced at pH below 4. The highest inhibitory effect was with beers with a high total polyphenolic content. Our results demonstrate that ingredients present in this widely consumed beverage inhibit endogenous nitrosation.

Animals↗
PubMed1983

Evaluation of DNA damage by the alkaline elution technique in liver, kidneys and lungs of rats and hamsters treated with N-nitrosodialkylamines.

Induction of single-strand breaks in the DNA of three organs of BD-VI rats and Syrian golden hamsters was examined 4 h after a single i.p. dose of N-nitrosodimethylamine (DMN) or N-nitrosodiethylamine (DEN). Damage was monitored in vivo by the alkaline elution method, in which DNA is dosed fluorometrically. DNA damage was induced by DMN in the liver and kidneys of rats and in the liver and lungs of hamsters, and by DEN in rat and hamster liver. High doses of the hepatocarcinogen and hepatotoxic compound carbon tetrachloride, did not induce DNA damage in rat liver. A correspondence between DNA fragmentation (our study) and tumour induction (reported in the literature) was found in the following organs: rat and hamster liver (DMN, DEN), rat kidney (DMN), rat lung (DMN, DEN), hamster kidney (DMN, DEN). In contrast, no such correlation was observed in rat kidney and hamster lung following DEN-treatment and in hamster lung following DMN-treatment. Thus, the in vivo alkaline elution assay would appear to be most useful for detecting DNA damage by chemicals that are activated metabolically in the liver and that bind to hepatic DNA.

Animals↗
PubMed1983

Bacterial-mammalian mutagenesis correlations: mechanistic significance for carcinogenesis.

Chemicals evaluated for their carcinogenic potential in the IARC Monographs (Supplement 4 to volumes 1-29)2 are used to compare their response in bacterial and mammalian cell mutagenicity assays in vitro. Simultaneous positive and negative test results in both systems showed a high degree of parallelism. Several carcinogens active in animals/humans, however, were not detected in either assay. The possibility of a quantitative extrapolation of bacterial mutagenesis data to processes occurring in intact mammals was further examined. Published covalent binding indices in rat liver DNA for 36 compounds were found to be correlated with their mutagenic effects in the Salmonella/liver-microsome test; several compounds deviated from this proportionality. The quantitative relationship between carcinogenicity in rodents (TD50) and mutagenicity was examined, using 10 alkylating agents. Mutagenicity in S. typhimurium TA100 strain (plate and liquid assays) showed no correlation with carcinogenic potency. However, there was a positive relationship between TD50 values and the initial ratio of N-7-alkyl/O6-alkyl guanine formed (predicted) after reaction with double-stranded DNA in vitro.

Alkylating Agents↗
PubMed1983

Comparison between carcinogenicity and mutagenicity based on chemicals evaluated in the IARC monographs.

The qualitative relationship between carcinogenicity and mutagenicity (DNA-damaging activity), based on chemicals which are known to be or suspected of being carcinogenic to man and/or to experimental animals, is analyzed using 532 chemicals evaluated in Volumes 1-25 of the IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. About 40 compounds (industrial processes) were found to be either definitely or probably carcinogenic to man, and 130 chemicals have been adequately tested in rodents and most of them also in various short-term assays. For a comparison between the carcinogenicity of a chemical and its behavior in short-term tests, systems were selected that have a value for predicting carcinogenicity. These were divided into mutagenicity in (A) the S. typhimurium/microsome assay, (B) other submammalian systems and (C) cultured mammalian cells; (D) chromosomal abnormalities in mammalian cells; (E) DNA damage and repair; (F) cell transformation (or altered growth properties) in vitro. The following conclusions can be drawn. In the absence of studies in man, long-term animal tests are still today the only ones capable of providing evidence of the carcinogenic effect of a chemical. The development and application of an appropriate combination of short-term tests (despite current limitations) can significantly contribute to the prediction/confirmation of the carcinogenic effects of chemicals in animals/man. Confidence in positive tests results is increased when they are confirmed in multiple short-term tests using nonrepetitive end points and different activation systems. Assays to detect carcinogens which do not act via electrophiles (promoters) need to be developed. The results of a given short-term test should be interpreted in the context of other toxicological data. Increasing demand for quantitative carcinogenicity data requires further examination of whether or not there is a quantitative relationship between the potency of a carcinogen in experimental animals/man, and its genotoxic activity in short-term tests. At present, such a relationship is not sufficiently established for it to be used for the prediction of the carcinogenic potency of new compounds.

Animals↗
PubMed1983

Inhibitory effect of betel nut extracts on endogenous nitrosation in humans.

Extracts of betel nut (Areca catechu) were tested for their capacity to inhibit the endogenous formation of nitrosamines by measurement of the amount of urinary N-nitroso-L-proline (NPRO) following ingestion of sodium nitrate (300 mg) and L-proline (300 mg) by 2 volunteers. A water extract of the dried nuts, an ether extract containing mainly (+)-catechin and (-)-epicatechin, and a caffeine-precipitated n-butyl alcohol extract containing primarily proanthocyanidins (tannins) strongly reduced the endogenous formation of NPRO. An average of 14.7 and 10.9 micrograms NPRO (8 expts per individual) was excreted in the urine of the 2 volunteers over a 24-hour period following the intake of sodium nitrate and L-proline. The water extract and the proanthocyanidin (tannin)-containing extract, both of which contain the dose equivalent of one-quarter of a nut, reduced the excreted NPRO to background levels, which varied from 0.5 to 3.6 micrograms and from 0.6 to 2.1 micrograms (6 expts) in 24-hour urine samples from the 2 volunteers. These results may exemplify the way in which naturally occurring phenolics, which are ingested daily in relatively large quantities, could affect the endogenous formation of carcinogenic nitrosamines.

Anthocyanins↗