Biomedical subjects

H Bartsch

Publications and source records attributed to H Bartsch.

At least 289 records · Page 16Linked to original sources

PubMed1989

Carcinogen metabolism studies in human bronchial and lung parenchymal tissues.

The pulmonary metabolism of xenobiotics was investigated by measuring the glutathione content and the activity of the aryl hydrocarbon hydroxylase, epoxide hydrolase, glutathione S-transferase, and uridine 5' -diphosphoglucuronosyl transferase enzymes in S-12 fractions of bronchial tree and peripheral lung parenchyma obtained at surgery from 21 patients. In parallel, the same preparations were used to assess either the activation of promutagens, i.e., benzo(a)pyrene, 2-aminofluorene, cyclophosphamide, and a cigarette smoke condensate, to metabolites reverting his- Salmonella typhymurium strains, or the decrease of direct-acting mutagens, i.e., sodium dichromate, 4-nitroquinoline N-oxide, epichlorohydrin, and ICR 191. As compared to bronchus preparations, parenchymal preparations contained considerably higher concentrations of reduced glutathione, had a significantly higher epoxide hydrolase activity, and, as assessed by means of a quantitative index, were more efficient in activating 2-aminofluorene and in reducing the mutagenicity of dichromate and 4-nitroquinoline N-oxide. These data may suggest that parenchymal lung tissue is more capable than bronchial tissue to detoxify reactive intermediates of xenobiotics, possibly explaining the greater susceptibility of bronchi to cigarette smoke-induced cancers.

4-Nitroquinoline-1-oxide↗

PubMed1989

Polymorphic ochratoxin A hydroxylation in rat strains phenotyped as poor and extensive metabolizers of debrisoquine.

1. Dark agouti (DA) and Lewis rat strains, which show a genetic polymorphism for debrisoquine-4-hydroxylation, were treated either with a single dose of ochratoxin A (OA) or for 8 weeks with 5 doses per week. Levels of OA and its 4-hydroxy metabolite (4-hydroxy-OA) excreted in urine were determined. 2. At all doses, the metabolic ratio of OA:4-hydroxy-OA was two to five times greater in DA than in Lewis rats, as was the metabolic ratio of debrisoquine:4-hydroxy-debrisoquine. These results are consistent with our previous findings in vitro that hepatic and renal OA 4-hydroxylase activity is three to four times lower in DA than in Lewis rats. These data give further support to the possible co-segregation of genes regulating OA and debrisoquine 4-hydroxylation.

Administration, Oral↗

PubMed1989

[The relation between carcinogenesis and mutagenesis: a re-evaluation].

To determine whether genotoxic and non-genotoxic carcinogens contribute similarly to the cancer burden in humans and which types of short-term tests are more relevant for predicting human hazards, an analysis was performed on agents that were evaluated in Supplements 6 and 7 to the IARC Monographs for their carcinogenic effects in human and animals and for the activity in short-term genotoxicity tests. The prevalence of genotoxicity among four groups of agents, consisting of established human carcinogens (group 1, n = 30), probable human carcinogens (group 2A, n = 37), possible human carcinogens (group 2B, n = 113) and agents with limited evidence of carcinogenicity in animals (a subset of group 3, n = 66) was determined. Each of the groups 1, 2A and 2B contained a high proportion (80-90%) of genotoxic carcinogens, which were also multiple-species or multi-tissue carcinogens. The distribution of carcinogenic potency in rodents did not reveal any specific characteristic of the human carcinogens in group 1 that would differentiate them from agents in groups 2A, 2B and many group 3. Although limited by the data-base available through the Monographs Series, this analysis implies that genotoxic carcinogens add more to the human cancer burden than non-genotoxic carcinogens. Thus, the continued use of in vitro/in vivo short-term tests, involving as endpoints DNA chromosomal damage, to identify genotoxic carcinogens or the isolation of carcinogenic components in complex mixtures is fully justified. It is concluded that a) an agent or complex mixture with unknown carcinogenic potential showing sufficient evidence of activity in genotoxicity assays in vitro or in vivo is likely to represent a hazard to humans and b) an agent or complex mixture showing lack of activity in this spectrum of genotoxicity assays should undergo evaluation for carcinogenicity for rodent bioassay, in view of the present lack of validated short-term tests for non-genotoxic carcinogens. Overall one can deduce that identification and subsequent lowering of exposure to genotoxic agents/mixtures will remain one of the main goals for primary cancer prevention in man.

Animals↗

PubMed1989

[Genotoxicity of carcinogenic substances in humans and animals].

To determine whether genotoxic and non-genotoxic carcinogens contribute similarly to the cancer burden in humans, an analysis was performed on agents that were evaluated in Supplements 6 and 7 to the I.A.R.C. Monographs for their carcinogenic effects in human and animals and for the activity in short-term tests. The prevalence of genotoxic carcinogens on four groups of agents, consisting of established human carcinogens (group 1, n = 30), probable human carcinogens (group 2A, n = 37), possible human carcinogens (group 2B, n = 113) and of agents with limited evidence of carcinogenicity in animals (a subset of group 3, n = 149) was determined. A high prevalence in the order of 80 to 90% of genotoxic carcinogens was found in each of the groups 1, 2A and 2B, which were also shown to be multi-species/multi-tissues carcinogens. Neither the prevalence of genotoxic carcinogens nor the distribution of carcinogenic potency in rodents reveal any specific characteristics of the human carcinogens in group 1 that differentiates them from agents in groups 2A and 2B or from many in group 3. This suggests that substances in group 2A and 2B and possibly several in group 3, are carcinogenic to humans. These results indicate that (a) an agent with unknown carcinogenic potential showing sufficient evidence of activity in in vitro/in vivo genotoxicity assays (involving as endpoints DNA damage, chromosomal/mutational damage) may represent a hazard to humans; and (b) an agent showing lack of activity in this spectrum of genotoxicity assays should undergo evaluation for carcinogenicity by rodent bioassay, in view of the present lack of validated short-term tests for non-genotoxic carcinogens.

Animals↗

PubMed1989

Human exposure to endogenous N-nitroso compounds: quantitative estimates in subjects at high risk for cancer of the oral cavity, oesophagus, stomach and urinary bladder.

A sensitive procedure to quantitate human exposure to endogenous N-nitroso compounds (NOC) has been developed. It is based on the excretion of N-nitrosoproline (NPRO) and other N-nitrosamino acids in the urine, which are measured as an index of endogenous nitrosation, following ingestion of precursors. The NPRO test has been applied to human subjects in clinical and epidemiological studies, and the kinetics and dietary modifiers of endogenous nitrosation have been investigated. Results obtained after application of the NPRO test to subjects at high risk for cancers of the stomach, oesophagus, oral cavity and urinary bladder are summarized. In most instances, higher exposures to endogenous NOC were found in high-risk subjects, but individual exposure was greatly affected by dietary modifiers or disease state. Vitamin C efficiently lowered the body burden of intragastrically formed NOC. The results point to an aetiological role of NOC in these human cancers and provide an interpretation of epidemiological findings that have shown protective effects of fruits and vegetables against several malignancies.

China↗

PubMed1988

Lipid peroxidation as a possible cause of ochratoxin A toxicity.

Addition of the mycotoxin ochratoxin A (OA), a nephrotoxic carcinogen, to rat liver microsomes greatly enhanced the rate of NADPH or ascorbate-dependent lipid peroxidation as measured by malondialdehyde formation. NADPH-dependent lipid peroxidation in kidney microsomes was similarly enhanced by OA. The process required the presence of trace amounts of iron but cytochrome P-450 and free active oxygen species appeared not to be involved. The efficiency of several ochratoxins (ochratoxins A, B, C, alpha and O-methyl-ochratoxin C) to enhance lipid peroxidation was related to the presence and reactivity of the phenolic hydroxyl group. Furthermore, the ability of these ochratoxins to enhance lipid peroxidation in microsomes correlated precisely with their known toxicities in chicks. Administration of ochratoxin A to rats also resulted in enhanced lipid peroxidation in vivo as evidenced by a seven-fold increase in the rate of ethane exhalation. These results suggest that lipid peroxidation may play a role in the observed toxicity of ochratoxin A in animals; a mechanism is proposed. (Formula: see text). Ochratoxin A: X = Cl; R1 = R2 = R3 = R4 = H Ochratoxin B: X = H; R1 = R2 = R3 = R4 = H Ochratoxin C: X = Cl; R1 = R2 = R3 = H; = R4 = CH3 O-Methyl-ochratoxin C: X = Cl; R2 = R3 = H; R1 = R4 = CH3 (4R)-4-hydroxyochratoxin A: X = Cl; R1 = R3 = R4 = H; R2 = OH (4S)-4-hydroxyochratoxin A: X = Cl; R1 = R2 = R4 = H; R3 = OH Fig. 1. Chemical structures of the various ochratoxins.

Animals↗

PubMed1988

Evaluation of sister chromatid exchange as an indicator of sensitivity to N-ethyl-N-nitrosourea-induced carcinogenesis in rats.

Sister chromatid exchange (SCE) frequencies in peripheral lymphocytes are a frequently used endpoint to indicate exposures to genotoxins in groups of humans. The aim of this study was to ascertain, in an experimental design, whether or not SCE rates have any association with the risk of cancer at the individual level in rats exposed to a known carcinogen. Individual SCE rates were determined in three consecutive analyses in cultured blood lymphocytes of 50 adult male Wistar rats. Analyses were done before as well as 24 hr and 7 days after a single intraperitoneal administration of 0, 25, 50, or 75 mg/kg of N-ethyl-N-nitrosourea (ENU). The animals were followed until death; also, the relationship between SCEs and carcinogenic outcome, i.e., the presence or absence of tumors, and their latency period were examined. ENU significantly decreased the life expectancy of the rats. The tumor types most clearly associated with ENU treatment were various gliomas and thyroid-gland and testicular tumors. ENU induced a moderate (maximally 1.6-fold) increase in the mean frequency of SCEs/cell at both sampling times after treatment. The effect was somewhat more pronounced 1 day rather than 1 week after treatment. The mean SCE rates in rats with ENU-specific cancers or in animals with early or multiple tumors did not differ from those in animals that survived no less than 65 weeks or longer without developing tumors. In ENU-treated animals with tumors, no relationship was found between the mean SCE rate and survival time. It is concluded that in outbred Wistar rats the SCE response in cultured lymphocytes does not indicate individual susceptibility to the carcinogenic action of ENU. On a group basis, however, animals with high SCE rates were shown to have increased risk of cancer.

Animals↗

PubMed1988

Partial purification of (a) low molecular weight ovine pineal compound(s) with an inhibiting effect on the growth of human melanoma cells in vitro.

An in vitro human melanoma cell assay was used to work up the partial purification of (a) low molecular weight (MW) substance(s) from aqueous extracts of ovine pineal tissue shown to contain a growth-inhibiting activity. A combination of paper chromatography, ion-exchange and reverse-phase high performance liquid chromatography with post-column antitumor assay has been developed. This allows a specific identification of an ovine pineal factor (MW less than 500) which inhibits the growth of human melanoma cells in vitro. The substance was partially purified to about 1,000 times as compared to the IC100-value of the starting material (retentate 5). The growth inhibition of human melanoma cells in culture was complete at a dose of 0.1 microgram/ml of purified pineal factor(s). It was demonstrated that the activity of this pineal compound differs from some substances known to be present in the pineal, such as melatonin, serotonin, peridines and beta-carbolines. The activity was not destroyed by treatment with proteolytic enzymes.

Animals↗

PubMed1988

Inhibitors of endogenous nitrosation. Mechanisms and implications in human cancer prevention.

Although the proof that N-nitroso compounds (NOC), a versatile class of carcinogens in animals, are also carcinogenic in man is lacking, humans are exposed through ingestion or inhalation to preformed NOC in the environment and through the endogenous nitrosation of amino precursors in the body. Activated macrophages can synthesize nitrate, nitrite and nitrosating agents that can form NOC. A number of bacterial strains isolated from human infections can produce NOC enzymatically from precursors at neutral pH. As a consequence endogenous nitrosation may occur at various sites of the body such as the oral cavity, stomach, urinary bladder, lungs, and at other sites of infection or inflammation. Since the demonstration by Mirvish et al. (1972) showing that ascorbate can reduce tumor formation in animals following feeding of nitrite plus amine, numerous substances to which humans are exposed have been identified and shown to inhibit formation of NOC in vitro, in animal models and in humans. Such inhibitors of nitrosation include vitamins C and E, phenolic compounds, and complex mixtures such as fruit and vegetable juices or other plant extracts. Nitrosation inhibitors normally destroy the nitrosating agents and thus act as competitors for the amino compound that serves as substrate for the nitrosating species. Independently, epidemiological studies have already established that fresh fruits and vegetables that are sources of vitamin C, other vitamins and polyphenols have a protective effect against cancers at various sites and in particular gastric cancer. Although the evidence that endogenously formed NOC are involved in human cancers is far from conclusive, it is suggestive and justifies preventive measures for reducing exposure to NOC. This article briefly reviews (i) the chemistry of NOC formation and inhibition, (ii) the studies in experimental animals which showed that inhibition of endogenous NOC synthesis leads to a reduction of toxic, mutagenic and carcinogenic effects, (iii) recent studies in humans where the degree of inhibition of endogenous NOC synthesis was directly quantified and lastly (iv) the contribution of nitrosation inhibitors to human cancer prevention.

Animals↗

PubMed1988

Partial hepatectomy of rats ten weeks before carcinogen administration can enhance liver carcinogenesis: preliminary observations.

Partial hepatectomy (PH) is known to enhance liver carcinogenesis when it is performed several hours before or after administration of a hepatocarcinogen. This effect has been attributed to cell proliferation, which is induced by PH and is a necessary step for fixation of DNA damage leading to initiated cancer cells. We now report for the first time that PH can also increase the tumour incidence, and decrease the latency period, when it is performed 8-10 weeks before treating rats with the hepatocarcinogen N-nitrosodiethylamine. This animal model may offer a tool for investigating the underlying mechanism of the 'memory effect' and increased tumour susceptibility of liver cells after PH. Additionally, it could be explored as a more sensitive rodent bioassay for testing putative carcinogens.

Animals↗

PubMed1988

Epstein-Barr virus activation in Raji cells by extracts of preserved food from high risk areas for nasopharyngeal carcinoma.

Epstein-Barr virus (EBV) activation of latent infection and traditional life styles, especially food habits, have been strongly associated with an increased risk of nasopharyngeal carcinoma (NPC) in humans. On the basis of anthropological studies in Tunisia, southern China and Greenland, extracts of representative preserved food items consumed frequently by the high-risk populations for NPC were assayed for the presence of EBV activators in Raji cells. A strong EBV activation activity was observed in aqueous extracts of some Cantonese salted dried fish from China, harissa (a spice mixture) and to a lesser extent qaddid (dry mutton preserved in olive oil) from Tunisia. These new data may support epidemiological evidence for the importance of Cantonese salted and dried fish and other food items in the etiology of NPC.

China↗

PubMed1988

Nitrosamine formation by denitrifying and non-denitrifying bacteria: implication of nitrite reductase and nitrate reductase in nitrosation catalysis.

Biochemical, microbiological and genetic studies were done to characterize the mechanism of bacterial formation of N-nitrosomorpholine (NMOR) from morpholine and nitrite at neutral pH. In Escherichia coli and Proteus morganii, the nitrosating activity was markedly induced when bacteria were cultured under anaerobiosis in minimal medium containing nitrate, while in the presence of nitrite there was no induction. However, induction of the nitrosating activity in Pseudomonas aeruginosa occurred in anaerobic cultures in the presence of either nitrate or nitrite. The nitrosation capacity was also examined in various E. coli K12 mutants whose structural gene of either nitrate reductase or nitrite reductase was deleted. Nitrosation was not linked to the three (NADH-, formate- and glucose-dependent) nitrite reductases but was directly dependent on the presence of a nitrate reductase.

Escherichia coli↗

PubMed1988

Formation of reactive oxygen species and of 8-hydroxy-2'-deoxyguanosine in DNA in vitro with betel-quid ingredients.

Using a chemiluminescence technique, superoxide anion (O2-.) and H2O2 were shown to be formed in vitro, above pH 9.5, from betel-quid (BQ) ingredients, such as areca-nut extract and catechu. The formation of O2-. was enhanced by Fe2+, Fe3+ and Cu2+ and inhibited by Mn2+. Saliva was found to inhibit both O2-. and H2O2 formation from BQ ingredients. Upon incubation of DNA at alkaline pH with areca-nut extract or catechu, in the presence or absence of Fe3+, 8-hydroxy-2'-deoxyguanosine was formed, as quantified by high-performance liquid chromatography. The data suggest a possible role of reactive oxygen species (ROS) in the etiology of oral cancer in betel quid chewers.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed1988

Urinary N-nitrosamino acids as an index of exposure to N-nitroso compounds.

On the basis of results from animal experiments and studies in human subjects, the amount of nitrosoproline (NPRO) excreted in 24-hr urine following ingestion of precursors (proline, nitrate) has been measured as an index of endogenous nitrosation. Several protocols of the NPRO test have been applied to human subjects, in order to study the kinetics and dietary modifiers of endogenous nitrosation, and in clinical and epidemiological studies. These studies have demonstrated that endogenous nitrosation in humans is highly complex and is influenced by factors such as gastric pH and amounts of precursors, catalysts and inhibitors. Thus, individual monitoring for nitrosation potential, rather than analyses of precursors in saliva, urine and gastric juice, is necessary in order to establish a causal relationship between endogenous nitrosation and human cancer. Results obtained after application of the NPRO test to subjects at high risk for cancers of the stomach, oesophagus, oral cavity and urinary bladder are summarized.

Environmental Monitoring↗

PubMed1987

Monoclonal antibody characterization of hepatic and extrahepatic cytochrome P-450 activities in rats treated with phenobarbital or methylcholanthrene and fed various cholesterol diets.

Monoclonal antibodies (MAb) against 3-methylcholanthrene (MC)- and phenobarbital (PB)-inducible forms of cytochrome P-450 isozyme were used to characterize changes in aryl hydrocarbon hydroxylase (AHH) and ethoxycoumarin O-deethylase (ECDE) activities modulated by dietary cholesterol. Rats were induced by MC or PB, and immunochemical inhibition of AHH and ECDE activities was studied as an indication of changes in cytochrome P-450 isozyme patterns. Feeding of a cholesterol-free diet markedly decreased enzyme activities both in liver and in small intestinal mucosa, and the highest activities were observed after feeding rats a high (2%)-cholesterol diet for one month. As a control, a normal pelleted diet (0.1% cholesterol) was used; in rats fed this diet, intermediate levels of monooxygenase activities were present. Although no diet-dependent change in total AHH and ECDE activities was observed in kidneys and lungs, diet apparently modulated isozyme composition in the lungs, as indicated by a change in the immunochemical inhibition pattern with MAb; no such shift was observed in the kidneys. In liver and intestine, in addition to changes in total activity, isozyme composition was also altered, as indicated by inhibition of the catalytic activities of cytochrome P-450 by MAb. Our data infer that dietary cholesterol can: (i) modulate total monooxygenase activities, especially in the intestine; (ii) change the cytochrome P-450 isozyme composition in liver and intestine; (iii) change isozyme composition without changing overall enzyme activity, e.g. in lungs; and (iv) have no effect in a tissue (e.g. kidney) that lacks constitutionally the P-450 isozyme responsive to cholesterol.

7-Alkoxycoumarin O-Dealkylase↗

PubMed1987

Rapid oxidative stress induced by N-nitrosamines.

We have investigated the generation of prooxidant state shortly after administration of N-nitrosamines (NA) to rats. N-Nitrosodimethylamine (NDMA) was found to increase ethane exhalation (EE) rapidly in a dose-related manner. EE remained elevated for several days after single doses of NDMA. Similarly, lipid peroxidation (LP) in the liver (measured by four methods) increased rapidly showing a peak 20 min after NDMA dose. The increase of LP was preceded by a decrease in retinol concentration in the liver. N-Nitrosodiethanolamine, too, increased EE and LP in the liver, whereas N-nitrosomethylbenzylamine had no effect. Thus, hepatocarcinogenic NA induced LP in their target tissue, and the LP enhancing effects of NA were not related to their acute toxic effects.

Animals↗

PubMed1987

Volatile nitrosamine levels in common foods from Tunisia, south China and Greenland, high-risk areas for nasopharyngeal carcinoma (NPC).

On the basis of anthropological pilot studies on diet in Tunisia, south China and Greenland, food items consumed frequently by these populations at high risk for NPC were analysed for volatile nitrosamines using gas chromatography combined with a thermal energy analyzer. Relatively high levels of N-nitrosodimethylamine (NDMA), N-nitrosopyrrolidine (NPYR) and N-nitrosopiperidine (NPIP) were detected in Tunisian stewing base ("Touklia") and dried mutton preserved in olive oil ("Qaddid"). NDMA was also detected at levels ranging from trace amounts to 133 micrograms/kg in several Chinese salted and dried marine fish and in Greenland dried, unsalted fish preparations. NPYR and NPIP were also occasionally detected in several vegetables fermented in brine collected in Tunisia and China. The possible role of nitrosamines in the etiology of NPC is discussed.

China↗

PubMed1987

Growth-inhibiting effect of crude pineal extracts on human melanoma cells in vitro is different from that of known synthetic pineal substances.

The effect was studied of a number of synthetic indoleamines, pteridines, beta-carbolines, of AVT and of crude extracts from rat and ovine pineal glands on human melanoma cells in vitro. The identified pineal substances as well as some of their analogues showed an inhibitory effect only at non-physiologically high concentrations. However, crude pineal extracts were more active than the synthetic pineal substances tested. They contain a compound which may have a tumor-inhibiting potency comparable to that of methotrexate but a different mechanism of action.

Animals↗