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Biomedical subjects

H Bartsch

Publications and source records attributed to H Bartsch.

At least 235 records · Page 13Linked to original sources
PubMed1991

Epstein-Barr virus activators, mutagens and volatile nitrosamines in preserved food samples from high-risk areas for nasopharyngeal carcinoma.

Representative samples of preserved foods collected from high-risk areas for nasopharyngeal carcinoma were assayed for capacity to induce Epstein-Barr virus (EBV) by measuring induction of the DR promoter gene or of genes for early antigens in Raji cells. The two assays gave concordant results, but the DR induction assay detected EBV-inducing substances at lower concentrations and more reproducibly. Three of 17 preserved food items were active in both assays; they were also weakly mutagenic in the SOS chromotest and contained low or moderate levels of volatile N-nitrosamines. After in-vitro nitrosation, the levels of mutagens and nitrosamines increased, whereas EBV-inducing activity was unchanged or decreased. Thus, EBV inducers appear to be a different class of substances from mutagens and volatile N-nitrosamines but could act with them in the etiology of nasopharyngeal carcinoma.

Food Analysis↗
PubMed1991

Endogenous nitrosamines and liver fluke as risk factors for cholangiocarcinoma in Thailand.

Cholangiocarcinoma (CCA) is one of the most prevalent cancers in north-east Thailand and has been associated with infestation by the liver fluke Opisthorchis viverrini (OV). Two samples of 12-h overnight urine (after dosing with 500 mg proline and 200 mg ascorbic acid or 500 mg proline alone) were collected from about 100 inhabitants in five contrasting incidence areas for CCA and hepatocellular carcinoma. The incidences of CCA and hepatocellular carcinoma were not correlated with either the amount of NPRO or other nitrosamino acids, endogenous nitrosation potential (difference in NPRO levels between proline dose and proline and ascorbic acid dose), or nitrate level. However, when urinary levels of nitrosamino acids were compared in subjects living in high-risk areas, subjects who were positive for OV antibody excreted significantly more (p less than 0.01) NPRO (12.3 +/- 18.7 micrograms/12 h) after proline ingestion than those who were negative 3.5 +/- 3.2 micrograms/12 h). After ingestion of ascorbic acid, the NPRO levels in the positive subjects were significantly reduced (p less than 0.01) to 2.4 +/- 2.0 micrograms/12 h, suggesting that endogenous nitrosation of proline was inhibited. Thus, endogenous nitrosation potential estimated from the difference of NPRO and sum of nitrosamino acids excreted in the two urine samples was significantly higher in subjects positive for the OV antibody. In addition, of the representative food samples and beverages consumed frequently in high-risk areas for CCA, fermented fish and pork contained N-nitrosodimethylamine (0-26 micrograms/kg), N-nitrosopyrrolidine (0-117 micrograms/kg) and N-nitrosopiperidine (0-23 micrograms/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

Adenoma, Bile Duct↗
PubMed1991

Human ochratoxicosis in France.

The prevalence of human ochratoxicosis in France is being determined using serum and plasma collected from apparently healthy people. The analytical method is based on the partition coefficient of ochratoxin A in aqueous and organic solvents, according to pH. High-performance liquid chromatography and spectrofluorimetry are used for detection and quantification (limit of detection, greater than 0.2 ng/ml). The presence of ochrotoxin A is confirmed by the action of carboxypeptidase to yield ochratoxin alpha or by derivatization of ochratoxin A with boron trifluoride. The significance of the interim values obtained and the number of positive samples is discussed. A comparison with the distribution of known values in Germany and Scandinavia could be helpful in risk assessment with a view to prevention.

Chromatography, High Pressure Liquid↗
PubMed1991

Concentrations of ochratoxin A in the urine of endemic nephropathy patients and controls in Bulgaria: lack of detection of 4-hydroxyochratoxin A.

Ochratoxin A has been detected more frequently and at higher levels as a contaminant in staple food consumed by subjects affected by Balkan endemic nephropathy or urinary tract tumours in the Vratza district (Bulgaria) than in samples from control populations in and outside the endemic area. Serum from patients with Balkan endemic nephropathy also contained ochratoxin A more frequently and at higher levels than serum from controls. Metabolic phenotyping of subjects in the Vratza district with debrisoquine revealed a preponderance of extensive metabolizers among subjects at high risk for Balkan endemic nephropathy. In rats, ochratoxin A is metabolized to 4-hydroxyochratoxin A, and rat strains shown to be poor or extensive metabolizers of debrisoquine were also poor or extensive metabolizers of ochratoxin A. In order to determine whether the metabolic phenotype for debrisoquine also parallels that of ochratoxin A in humans, a sensitive method was developed for quantifying ochratoxin A and its 4-hydroxy metabolite in human urine. This method was subsequently used to analyse urine from subjects who had previously been phenotyped for debrisoquine. Ochratoxin A was detected more frequently and at higher levels in urine from members of families affected by Balkan endemic nephropathy than in samples taken from subjects in control areas. No 4-hydroxyochratoxin A was found in any of these samples (detection limit, 15 ng/l urine). On the basis of results from human studies and animal models, the role of genetic polymorphism in drug oxidation and disease susceptibility is discussed briefly.

Animals↗
PubMed1991

Genotoxicity of ochratoxin A and structurally related compounds in Escherichia coli strains: studies on their mode of action.

Ochratoxin A, ochratoxin alpha (its major metabolite in rodents) and seven structurally related substances were assayed for SOS DNA repair inducing activity in Escherichia coli PQ37 strain. At a concentration range of 0.1-4 mM, ochratoxin A, chloroxine, 5-chloro-8-quinolinol, 4-chloro-meta-cresol and chloroxylenol were found to induce SOS-DNA repair in the absence of an exogenous metabolic activation system. Ochratoxin B, ochratoxin alpha, 5-chlorosalicylic acid and citrinin were inactive, but all except ochratoxin alpha were cytotoxic. Thus, the presence of a chlorine at C-5 in ochratoxin A and in other analogues appears to be one determinant of their genotoxicity. In order to ascertain whether this reactivity involves a bacterial glutathione conjugation reaction, we investigated the modifying effect on the genotoxicity of ochratoxin A of amino oxyacetic acid, an inhibitor of cysteine conjugate beta-lyase. Amino oxyacetic acid decreased the cytotoxicity of ochratoxin A but did not alter its genotoxic activity, suggesting the formation of a cytotoxic thiol-containing derivative. The way in which ochratoxin A and some of its active analogues induce SOS DNA repair activity was further investigated in E. coli PQ37 and in three derived strains (PQ300, OG100 and OG400, containing deletions within the oxy R regulon). The response in PQ37 strain was measured in the absence and presence of Trolox C, a hydrosoluble form of vitamin E. Trolox C completely quenched the genotoxicity of ochratoxin A, which was no greater in mutated than in wild type strains. These results implicate an ochratoxin A-derived free radical rather than reduced oxygen species as genotoxic intermediate(s) in bacteria.

Aminooxyacetic Acid↗
PubMed1991

Characterization of the cytochrome P450 isozyme that metabolizes ochratoxin A, using metabolic inducers, inhibitors and antibodies.

The phenotypic pattern of drug biotransformation is determined by both host and environmental factors. Debrisoquine is a good probe for phenotyping individuals, as its metabolism is not affected by age, gender, smoking habits or alcohol intake. People with Balkan endemic nephropathy or with urinary tract tumours in endemic areas are more frequently extensive metabolizers of debrisoquine than are healthy people. This finding has led to studies of the possible relationship between the metabolism of ochratoxin A and its toxicity and carcinogenicity on experimental models. Ochratoxin A is metabolized mainly in the liver into R- and S-isomers of 4- and 10-hydroxyochratoxin A, and the reaction is catalysed by cytochrome P450 haemoprotein. Animal species that are genetically different in their capacity to metabolize debrisoquine differ similarly in their capacity to metabolize ochratoxin A: female DA rats that are poor metabolizers of debrisoquine also poorly metabolize ochratoxin A, as assayed by urinary excretion of both the parent compound and of 4-hydroxyochratoxin A. Ochratoxin A hydroxylase activity is low in DA rat liver (and kidney) but is inducible by phenobarbital and 3-methylcholanthrene; debrisoquine hydroxylase is not known to be inducible by enzyme inducers. The reaction of ochratoxin A hydroxylase thus resembles those induced by 3-methyl-cholanthrene and catalysed by cytochrome P450IA. Ochratoxin A hydroxylase activity was further characterized in the livers of B6 and D2 mice that had been treated with typical enzyme inducers. Ochratoxin A hydroxylase was weakly inducible by phenobarbital, 3-methyl-cholanthrene and 2,4,7,8-tetrachlorodibenzodioxin.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

N-nitroso compounds and human cancer: where do we stand?

Humans are exposed not only to preformed N-nitroso compounds (NOC) but also to a wide range of nitrogen-containing compounds and nitrosating agents which can react in vivo to form NOC, a versatile class of carcinogens. Nitrosating agents and NOC can also be synthesized endogenously in reactions mediated by bacteria and activated macrophages. Thus, endogenous formation of NOC can occur at various sites in the body. A sensitive procedure (the N-nitrosoproline (NPRO) test) has been developed to estimate exposure of humans to exogenous and endogenous NOC. Results of studies in human subjects with this test led to the following conclusions: (1) The process of endogenous nitrosation in humans is influenced by many factors; therefore, determination only of nitrate and nitrite in body fluids is insufficient to assess the extent of nitrosation in man in vivo. (2) In clinical studies to examine the model of gastric carcinogenesis based on bacterial colonization and nitrosation in vivo, progress has been made in explaining some steps, but several controversies remain. Although bacterial strains possessing enzymes that catalyse N-nitrosamine formation at neutrality have been isolated from the gastric juice of achlorhydric subjects, their precise role in gastric carcinogenesis remains to be clarified. (3) Formation of endogenous NOC was assessed by the NPRO test in: (i) subjects living in high- and low-incidence areas for stomach cancer in northern Japan, Costa Rica and Poland; (ii) subjects with different habits of betel-quid chewing and tobacco use; (iii) patients with urinary bladder infections; and (iv) subjects infested with liver fluke in Thailand. In all instances, greater exposure to endogenous NOC was found in high-risk subjects, but individual exposure was greatly affected by dietary modifiers of disease state: ascorbic acid efficiently lowered the body burden of intragastrically formed NOC. (4) Increased nitrosation is also observed in tobacco smokers, adding to the body burden of ingested or inhaled tobacco-related carcinogens. These results, together with the knowledge that NOC produce tumours in 40 animal species, clearly underline the potential role of NOC (and other nitrite-reactive compounds) in human cancer etiology, particularly when exposure starts early in life and persists over a long period. The demonstrated efficacy of certain vitamins as nitrosation inhibitors also provides a plausible interpretation of epidemiological findings that have shown protective effects of fruits and vegetables (sources of vitamins and polyphenols) against various malignancies and particularly stomach cancer.(ABSTRACT TRUNCATED AT 400 WORDS)

Esophageal Neoplasms↗
PubMed1991

Bacterial formation of N-nitroso compounds in the rat stomach after omeprazole-induced achlorhydria.

N-Nitrosamine formation by bacteria in the achlorhydric stomach has been proposed as an important factor in the development of gastric cancer. Thus, the effect of the presence of bacteria in the stomach on endogenous nitrosation was investigated in rats given omeprazole (an inhibitor of gastric H+, K((+)-ATPase) which reduces gastric secretion sufficiently to allow survival of a bacterial suspension of Escherichia coli or Pseudomonas. When rats were given both thiazolidine 4-carboxylic acid and nitrate, greater endogenous nitrosamine formation was observed in rats receiving omeprazole and an E. coli suspension than in control or omeprazole-treated rats. A similar result was obtained when rats were given morpholine and nitrate. Since the endogenous formation of N-nitrosomorpholine (NMOR) can be evaluated more precisely from the levels of its urinary metabolites, N-nitrosohydroxyethylglycine (NHEG), the metabolism of NMOR was studied in omeprazole-treated rats. In this preliminary study, we showed that 60% of an oral dose of NMOR was excreted as NHEG, while in rats with a higher gastric pH 20% was excreted as NHEG. The amount of endogenously formed NMOR was increased in omeprazole-treated rats given morpholine and nitrite together with bacteria, and greater excretion of unchanged urinary NMOR was observed. Thus, as shown in this in-vivo model, bacteria efficiently reduce nitrate to nitrite and catalyse nitrosation, resulting in increased endogenous formation of N-nitroso compounds in the achlorhydric stomach.

Achlorhydria↗
PubMed1991

Areca-nut toxicity in cultured human buccal epithelial cells.

In cultured human buccal epithelial cells, at doses of 3-540 micrograms/ml, areca-nut extract significantly decreased viability, as determined by colony-forming efficiency, clonal growth rate, ability to take up neutral red and ability to exclude trypan blue, and also caused significant formation of DNA single-strand breaks and DNA protein cross-links. Comparisons of the areca nut-related compounds, 3-(N-nitrosomethylamino)propion-aldehyde (NMPA), 3-(N-nitrosomethylamino)propionitrile (NMPN), N-nitrosoguvacoline, N-nitrosoguvacine, arecoline, arecaidine, guvacoline and guvacine, in terms of the above endpoints, indicate that NMPA is ten times more cytopathic to buccal cells than the other agents on a molar basis. Because metabolism of NMPA can potentially yield several reactive breakdown products, including aldehydes, this study indicates that both the parent compound and its metabolites may contribute to the observed pathobiological effects. Taken together, the observed pathobiological effects of areca-nut extract and certain related compounds in cultured human buccal epithelial cells indicate that these agents may contribute to the oral carcinogenicity associated with chewing betel quid.

Areca↗
PubMed1991

Nitrotyrosine as a new marker for endogenous nitrosation and nitration.

A sensitive and selective method has been developed for analysing 3-nitrotyrosine (NTTYR), an exposure marker for exogenous and endogenous nitrosating or nitrating agents, in tissue and blood proteins by gas chromatography-thermal energy analysis. Using this method, a number of kinetic studies were carried out. Free and protein-bound tyrosine were reacted easily to yield NTTYR. The method was also applied to the study of NTTYR formation in vivo; a dose-dependent increase in NTTYR was seen in both plasma proteins and haemoglobin obtained from rats 24 h after intraperitoneal injection of various doses (0.5-2.5 mumol/rat) of tetranitromethane. Major urinary metabolites of NTTYR, given orally to rats, were isolated and identified as 3-nitro-4-hydroxyphenylacetic acid (NHPA) and 3-nitro-4-hydroxyphenyllactic acid. About 44% and 5% of the oral dose of NTTYR (100 micrograms/rat), respectively, was excreted as these metabolites. Some human urine samples were analysed for NHPA by gas chromatography-thermal energy analysis after ethyl acetate extraction and high-performance liquid chromatography purification; 2.8 +/- 2.3 (mean +/- SD; n = 11) micrograms/24 h, ranging from 0-7.9 micrograms/24 h, were detected (detection limit, 0.2 micrograms/l). In conclusion, NTTYR in proteins or its metabolites in urine could be readily analysed by gas chromatography-thermal energy analysis as a new, additional marker for endogenous nitrosation and nitration.

Animals↗
PubMed1990

Carcinogen hemoglobin adducts, urinary mutagenicity, and metabolic phenotype in active and passive cigarette smokers.

In 100 healthy volunteers, we have studied the relationship between the type (air- or flue-cured) and number of cigarettes smoked and different biomarkers relevant to the risk of bladder cancer, including the levels of 4-aminobiphenyl (ABP) hemoglobin adduct (a marker of internal dose), urinary mutagenicity in Salmonella typhimurium TA98, and the N-acetylation phenotype (a marker of susceptibility). ABP is a potent bladder carcinogen that is N-acetylated as an overall detoxification step. Levels of the ABP hemoglobin adduct were higher in smokers of black tobacco (air-cured) than in smokers of blond tobacco (flue-cured), confirming our earlier study. In addition, "slow" acetylators had higher levels of the ABP hemoglobin adduct for the same type and quantity of cigarettes smoked. Urinary mutagenicity was also associated with quantity of cigarettes but not with the acetylation phenotype. Convex dose-response relationships were found between the amount smoked and ABP hemoglobin adduct levels or urinary mutagenicity. In 15 nonsmokers who reported exposure to environmental tobacco smoke, ABP hemoglobin adduct levels, unlike urinary mutagenicity, were found to be an aspecific exposure indicator.

Acetylation↗
PubMed1990

Quantity and saturation degree of dietary fats as modulators of oxidative stress and chemically-induced liver tumours in rats.

Male rats were fed, from weaning onwards, either 2, 12.5 or 25% sunflower seed oil (polyunsaturated fatty acids, PSA) or lard (saturated fatty acids, SFA) and from the age of 15 weeks subgroups were given N-nitrosodimethylamine (NDMA) for 30 weeks. Blood levels of lipids were assayed and during the study exhaled ethane was measured as an index of in vivo lipid peroxidation (LPO). At the age of 50 weeks, rats were killed and livers were analysed for tumours. PSA diets decreased plasma cholesterol and triglyceride concentrations vs. respective SFA diet; NDMA administration did not affect plasma cholesterol but enhanced triglyceride concentration. NDMA markedly enhanced LPO. An increase in dietary fat content from 2 to 25% enhanced ethane exhalation, more in rats fed PSA than the SFA diet. In the 25% PSA group, indomethacin in the diet strongly inhibited LPO. Prevalence of liver haemangiosarcomas increased from 42% to 80% (p less than 0.05) in NDMA-treated animals when PSA increased from 2 to 25%; in the group having a 25% PSA diet containing indomethacin, the NDMA-induced tumour incidence was reduced to 64%. In NDMA-treated rats fed SFA diets the prevalence of haemangiosarcoma increased from 43% (2% fat) to 67% (25% fat). The data show that NDMA modifies plasma lipids and increases LPO. The quantity and saturation degree of fats altered the frequency of chemically-induced tumours and modified LPO. As an index of free radical reactions, LPO may have an important role in carcinogenesis. Dietary fat thus appears to promote carcinogenesis through mechanisms that involve LPO.

Animals↗
PubMed1990

Isolation of an enzyme catalysing nitrosamine formation in Pseudomonas aeruginosa and Neisseria mucosae.

An enzyme catalysing nitrosamine formation was isolated and purified from two denitrifying microorganisms, Pseudomonas aeruginosa and Neisseria mucosae. The soluble enzyme has a molecular weight of 66 as determined by gel filtration and SDS-polyacrylamide gel electrophoresis and a pH optimum for P. aeruginosa of 7.25. A number of microorganisms isolated from human infections have previously been found to possess nitrosating enzymes.

Chromatography, DEAE-Cellulose↗
PubMed1990

Possible prognostic value of pulmonary AH-locus-linked enzymes in patients with tobacco-related lung cancer.

As prognosis in breast cancer patients has been related to the AHH activity in their breast tissue, we have conducted a similar analysis on pulmonary drug metabolizing enzymes as prognostic markers for male lung cancer patients, primarily investigated for other reasons. A subset of 50 patients with lung cancer related to tobacco use, who had undergone thoracic surgery, was re-analyzed. The activity of parenchymal aryl hydrocarbon hydroxylase (AHH) and epoxide hydrolase (EH) that had been determined previously in homogenates of non-neoplastic surgical lung specimens, was used for comparisons of the patients' survival after surgery. When the crude mortality percentages at 1 and 2 years by AHH or EH activity, subdivided into quarters of the distribution, were calculated, a lower mortality was related to lower enzyme levels. Subjects in the 1st and 4th quarters of the distribution showed significant differences in their 1-year survival for AHH (p = 0.05) and EH (p less than 0.01) activities. This relationship could not be accounted for by age, cumulative lifetime smoking, recent or continuing smoking, stage or histological type of disease. Thus, the levels of pulmonary AHH and EH may have some prognostic significance in tobacco-related lung cancer.

Aryl Hydrocarbon Hydroxylases↗
PubMed1990

Acetylation phenotype, carcinogen-hemoglobin adducts, and cigarette smoking.

Levels of 4-aminobiphenyl-hemoglobin adducts in smokers of blonde (flue-cured) and black (air-cured) tobacco have been found to be proportional to bladder cancer risk. In addition, risk of bladder cancer due to exposure to occupational carcinogens is elevated in genetically determined slow acetylators. In this study of normal male volunteers, 4-aminobiphenyl-hemoglobin adducts were found to be related to both the quantity and the type of tobacco smoked, as well as to the acetylator phenotype (independently of smoking habits). The demonstration that both the genetically determined slow acetylator phenotype and tobacco smoking are independently associated with levels of the carcinogen 4-aminobiphenyl in adducted hemoglobin suggests a single mechanism to explain the contribution of genetic susceptibility and environmental exposure in bladder carcinogenesis.

Acetylation↗
PubMed1990

Investigations on the relationship between DNA ethenobase adduct levels in several organs of vinyl chloride-exposed rats and cancer susceptibility.

The levels of 1,N6-ethenodeoxyadenosine (epsilon dAdo) and 3,N4-ethenodeoxycytidine (epsilon dCyd) were measured in DNA of several target organs of vinyl chloride (VC)-exposed rats. Seven-day-old (group I) and 13-week-old (group II) BD VI rats were exposed during 2 weeks to 500 ppm VC in air (7 hr per day and 7 days per week). epsilon dAdo and epsilon dCyd were measured by a combination of prepurification of DNA hydrolysates by HPLC and competitive radioimmunoassay using specific murine monoclonal antibodies. Both ethenodeoxynucleosides were detected in liver, lungs and brain (levels ranging from 0.6 x 10(-7) to 1.3 x 10(-7) for epsilon dAdo/2'-deoxyadenosine and from 1.95 x 10(-7) to 4.92 x 10(-7) for epsilon dCyd/2'-deoxycytidine) but not in kidneys of group I rats. In group II rats, only liver DNA was analysed and the levels of each adduct were six times lower than in young (group II) rats. These findings are in good agreement with the organotropism and the age-related sensitivity of VC-induced carcinogenesis in rodents.

Aging↗
PubMed1990

Nucleophilic selectivity and reaction kinetics of chloroethylene oxide assessed by the 4-(p-nitrobenzyl)pyridine assay and proton nuclear magnetic resonance spectroscopy.

The nucleophilic selectivity (Swain-Scott's constant s) of chloroethylene oxide (CEO), an ultimate carcinogenic metabolite of vinyl chloride, was determined to be 0.71 using the 4-(p-nitrobenzyl)pyridine (NBP) assay (Spears method). The molar extinction coefficient of the adduct formed between NBP and CEO was measured; and the second-order rate constants for the reactions of CEO with NBP and with thiosulfate were estimated at three temperatures. The disappearance of CEO and the formation of chloroacetaldehyde (CAA) and glycolaldehyde (GCA) were followed in D2O or a mixture of D2O/hexadeuterated acetone (acetone-d6), using Fourier transform proton nuclear magnetic resonance spectroscopy (1H-FTNMR). Evidence was obtained that CEO reacts with chloride ions to yield CAA at a rate constant of about 17 M-1 h-1 in D2O/acetone-d6 (1 : 1, v/v) at 280 K. Under the same conditions, the first-order rate constant kr for the thermal rearrangement of CEO into CAA was estimated to be approximately 0.41 h-1. These data suggest that the isomerization of CEO may be a minor reaction in physiological saline. These chemical properties of CEO are discussed in relation to the mechanism of vinyl chloride-induced carcinogenesis.

Acetaldehyde↗