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Biomedical subjects

H Bartsch

Publications and source records attributed to H Bartsch.

At least 253 records · Page 14Linked to original sources
PubMed1990

Structural basis of the genotoxicity of nitrosatable phenols and derivatives present in smoked food products.

The CASE methodology for studying structure-activity relationships has been applied to investigating the basis of the genotoxicity of phenols and derivatives following exposure to nitrous acid. The structural features identified include availability of positions para or ortho to the hydroxyl groups, that one meta position must remain unoccupied and one ortho or para position must be unsubstituted as well. The analyses revealed that genotoxicity is dependent upon the ease of formation of the active phenyldiazonium intermediate and is influenced only secondarily by the nature of the genotoxicant or its ease of entry into the cell. With this data base, CASE predicts the genotoxicity, following nitrosation, of a number of agents, including serotonin, acetaminophen, and of some naturally-occurring pesticides present in edible plants.

Food Analysis↗
PubMed1990

Exposure of humans to endogenous N-nitroso compounds: implications in cancer etiology.

Two sensitive procedures to quantitate human exposure to endogenous N-nitroso compounds (NOC) and/or methylating agents have been developed. One, the NPRO test, is based on the excretion of N-nitrosoproline (NPRO) and other N-nitrosoamino acids in the urine, that 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, esophagus, 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. In experimental animals 3-methyladenine (3-MeAde) is excreted in urine following exposure to methylating NOC. Humans normally excrete 3-MeAde, the origin of which remains unknown. Recently developed analytical methodology permits large numbers of human urine samples to be analyzed and a wide variation is observed. Preliminary results suggest a weak correlation between basal NPRO excretion and background 3-MeAde excretion. Taken together, the results point to an etiological role of endogenously formed NOC in certain human cancers, and provide an interpretation of epidemiological findings that have shown protective effects of fruits and vegetables against several malignancies.

Adenine↗
PubMed1990

Nitrotyrosine as a new marker for endogenous nitrosation and nitration of proteins.

3-Nitrotyrosine (NTYR) in tissue or blood proteins was evaluated as a possible exposure marker for exogenous and endogenous nitrosating or nitrating agents. A sensitive and selective method for analysing NTYR by gas chromatography with a thermal energy analyser (GC-TEA) was developed. Using this method, a number of kinetic studies were carried out. It was found that free and protein-bound tyrosine residues easily react with nitrating/nitrosating agents to yield NTYR. NTYR formation in vivo showed a dose-dependent increase in NTYR in both plasma proteins and haemoglobin obtained from rats 24 hr after ip injection of various doses (0.5-2.5 mumol/rat) of tetranitromethane. Major urinary metabolites of NTYR, given orally to rats, were isolated and identified as 3-nitro-4-hydroxyphenylacetic acid (NHPA) and 3-nitro-4-hydroxyphenyllactic acid (NHPL). About 44% and 5% of the oral dose of NTYR (100 micrograms/rat) was excreted as NHPA and NHPL, respectively. Eleven 24-hr human urine samples were analysed for NHPA by GC-TEA after ethyl acetate extraction and HPLC purification: quantities ranging from 0 to 7.9 micrograms/24 hr, mean +/- SD 2.8 +/- 2.3 (n = 11) were detected (detection limit 0.2 micrograms/litre). NTYR in proteins or its metabolites in urine can be readily analysed by GC-TEA as a new/additional marker for endogenous nitrosation and nitration.

Animals↗
PubMed1990

The determination of urinary 3-methyladenine by immunoaffinity chromatography-monoclonal antibody-based ELISA: use in human biomonitoring studies.

A mouse monoclonal antibody (Mab) was prepared which showed high specificity for a potential marker of exposure to methylating carcinogens such as 3-methyladenine (3-MeAde). In a low-temperature (4 degrees C) ELISA a linear calibration curve was obtained between 3 and 50 fmol/well. In combination with an immunoaffinity (IA) column prepared from a 3-MeAde rabbit antiserum, the ELISA was used to determine 3-MeAde in urine. The IA-ELISA method was validated by comparison with results obtained by an IA-GC-MS method. The effect of consuming a low 3-MeAde diet on urinary 3-MeAde excretion was investigated in a human volunteer. Urine collected during a 'normal' diet exhibited the characteristic variation in 3-MeAde levels previously observed (9.5 micrograms/24 h, SD = 4.4, n = 5). In contrast, 3-MeAde excretion was markedly lower and less variable on days when the diet was closely controlled (0.63 microgram/24 h, SD = 0.08, n = 3). Dietary intake of 3-MeAde on the latter days was between 0.37 and 0.43 microgram/day, indicating that most, if not all, of the 3-MeAde seen in previous experiments was derived from the diet. The origin of dietary 3-MeAde is not known, but may be related to fumigant use. Dietary manipulation affords the possibility of carrying out model studies, in volunteers, on 3-MeAde intake and formation in vivo.

Adenine↗
PubMed1990

Effects of a high fat diet on liver DNA methylation in rats exposed to N-nitrosodimethylamine.

Previous experiments have shown that a high fat diet changes incidence and tumour sites by N-nitroso-dialkylamines. The purpose of this study was to examine the effect of high and low fat diet on DNA methylation 6 weeks after the end of a chronic N-nitrosodimethylamine (NDMA) exposure (total dose 150 mg/kg). The concentration of O6-methyldeoxyguanosine (O6-MedG) in liver DNA was measured by immunoassays. The level of O6-MedG persisted 6 weeks after the last dose of NDMA and was 6-fold higher (P less than 0.05) in animals on high fat as compared to low fat diet. In another experiment, in which rats on a low and high fat diet received a single NDMA dose (2 mg/kg), the time-dependent removal of O6-MedG from liver and the hepatic O6-methylguanine DNA-alkyltransferase activity was not modified by the type of diet. These results indicate that a high fat diet enhances DNA methylation in the liver, after chronic treatment by NDMA, and that this effect is likely to be responsible for an increased incidence of liver haemangiosarcomas.

Animals↗
PubMed1990

Effect of lime composition on the formation of reactive oxygen species from areca nut extract in vitro.

Lime, representative of that used by betel quid chewers, was collected in a region of Papua New Guinea where the incidence of oral cancer is high. The free calcium hydroxide content and pH of 25 lime samples were highly correlated with the generation of reactive oxygen species from areca nut extract in vitro, and DNA damage in vitro, measured as 8-hydroxy-2'-deoxyguanosine. Fe2+ and Mg2+ levels in the lime samples were too low to modify formation of reactive oxygen species, but hydrogen peroxide formation was almost entirely inhibited by addition of Mg2+ to the reaction mixture. These results suggest that the calcium hydroxide content of lime in the presence of areca nut is primarily responsible for the formation of reactive oxygen species which might cause oxidative damage in the DNA of buccal mucosa cells of betel quid chewers.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1990

A new sensitive fluorometric assay for the metabolism of (--)-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene by human hair follicles.

A new sensitive fluorometric assay was established to measure the stereospecific formation of benzo[alpha]pyrene tetrols formed after cytochrome P450-dependent metabolism of (--)-7,8-dihydroxy-7,8- dihydrobenzo[a]pyrene by human hair follicles. This simple assay requires three human hair follicles and a low (0.5-2.0 microM) substrate concentration and has a limit of detection of approximately 0.3 fmol of tetrols. Freshly isolated human hair follicles from 20 adult volunteers (10 non-smokers and 10 smokers) were assayed. While intersubject and seasonal variations were observed, the assay was found to be reproducible for a given subject. This rapid and non-invasive assay provides a new means for metabolic phenotyping of human subjects for their capacity to metabolize (--)-7,8-dihydroxy-7,8-dihydrobenzo[alpha]pyrene to its carcinogenic form (+)anti-benzo[a]pyrene diolepoxide.

Adult↗
PubMed1990

Nucleophilic selectivity of alkylating agents and their hypermutability in Drosophila as predictors of carcinogenic potency in rodents.

The nucleophilic selectivity (Swain-Scott s constant or initial 7-alkylguanine/O6-alkylguanine ratio in DNA) of 60 alkylating agents, mostly monofunctional or cross-linking was compared to their carcinogenic potency in rodents (median TD50 estimates) and to two genotoxicity indices in Drosophila: (i) hypermutability, measured by the increased frequency of induced sex-linked recessive lethal mutations (SLRL) in a strain defective in DNA excision repair (exr-), as compared to the wild-type (exr+); (ii) relative clastogenic efficiency, expressed by the ratio of chromosomal aberrations (ring-X loss) to SLRL determined in the exr+ strain. For a subset of direct-acting, monofunctional alkylating agents, nucleophilic selectivity and TD50 values or hypermutability indices were linearly correlated. In addition, the hypermutability indices in Drosophila by methylating or ethylating procarcinogens were similar to the corresponding values of their ultimate metabolites. In contrast, cross-linking agents, including antitumour drugs, did not show these positive correlations. The relative clastogenic efficiencies in Drosophila of 26 direct-acting, alkylating carcinogens increased with both their cross-linking activity and nucleophilic selectivity. By analyzing mutational spectra in Drosophila induced in the vermilion gene by four monofunctional alkylating agents with contrasting s values, critical DNA lesions, i.e. type of base pair substitution mutations, deletions, insertions, involved in genotoxicity were pinpointed. Thus, these multi-endpoint analyses should, as a new approach, assist in the quantitative risk evaluation of genotoxic agents.

Alkylating Agents↗
PubMed1990

32P-postlabelling analysis of DNA adducted with urinary mutagens from smokers of black tobacco.

In order to characterize the tobacco-derived mutagens excreted in the urine of tobacco smokers, 32P-postlabelling techniques were used to examine DNA adducts formed from these mutagens with calf thymus DNA in the presence of a metabolic activation system (rat liver S9, Aroclor 1254-induced, with or without acetyl coenzyme A). Using either nuclease P1 or butanol extraction procedures, four-six and three spots, respectively, were reproducibly found on the autoradiograms in the case of the urine extract from two smokers of black tobacco. Using the urinary extract from a non-smoker, only three faint spots were detected after nuclease P1 enrichment. DNA adducts produced in smokers' urine were then compared with those formed by four N-hydroxyarylamines, N-hydroxy-2-amino-3,8-dimethyl-3H-imidazo[4,5-f]quinoxaline, N-hydroxy-2-amino-3-methyl-imidazo[4,5-f]quinoxaline, N-hydroxy-2-naphthylamine and N-hydroxy-4-aminobiphenyl. Visual inspection revealed that none of the reference aromatic amines contributed to the adduct pattern produced by the urinary mutagen(s). However, primary aromatic amines are mainly implicated as urinary mutagens because: (i) they produce frameshift mutations in Salmonella typhimurium strains, (ii) they are easily extractable with blue cotton and (iii) their mutagenicity is abolished by a nitrite treatment procedure for deamination.

Animals↗
PubMed1990

Contribution of DNA methylation and benzylation to N-nitroso-N-benzyl-methylamine-induced mutagenesis in bacteria: effects of rat liver cytochrome P450 isozymes and glutathione transferases.

The mutagenicity of N-nitroso-N-benzyl-methylamine (NBzMA), N-benzyl-N-nitrosourea (BzNU) and N-methyl-N-nitrosourea (MNU) in Salmonella typhimurium strains was investigated. BzNU selectively mutated TA100 strain as compared to TA1535, whereas MNU showed an inverse strain response, an effect probably related to the fact that benzylation of DNA is a stronger inducer of SOS DNA repair than methylation, as indicated by the higher activity of BzNU in the SOS chromotest. Benzylation of bacterial DNA by NBzMA, as deduced from the differential strain responsiveness, contributed predominantly to its mutagenicity in the presence of liver preparation from untreated, Aroclor- or ethanol-treated rats. Since benzyl alcohol, a metabolite of NBzMA, was not mutagenic in S. typhimurium, it appears that benzyl carbonium cations responsible for the mutagenicity of NBzMA in TA100 are formed via cytochrome P450-mediated hydroxylation of the methyl group. Neither ferric-EDTA nor desferrioxamine altered the mutagenicity of NBzMA, suggesting that activation occurs mainly within the catalytic site of P450. Experiments with isozyme-specific monoclonal antibodies showed that P450IIE1 did not contribute to N-demethylation of NBzMA at either low or high substrate concentrations and that P450IA contributed only weakly. Debenzylation was catalysed predominantly by P450IA at high NBzMA concentration. Antibodies against rat liver P450IIB enhanced NBzMA mutagenicity in S. typhimurium TA1535 strain up to 17-fold at low substrate concentration, but were without effect at high concentration. In liquid incubation assays, a 100% GSH-dependent reduction of NBzMA mutagenicity was found with liver S9 from untreated Wistar rats. The reducing effect of GSH was less pronounced in the presence of liver S9 from BDVI or Fischer 344 rats.

Animals↗
PubMed1990

Tumor-inhibiting activity in the rat pineal gland displays a circannual rhythm.

The aim of this study was to investigate whether the tumor-inhibiting activity present in the rat pineal gland undergoes seasonal fluctuations as do other pineal substances. Crude ethanol extracts of rat pineal glands were tested for tumor-inhibiting activity in an in vitro microbioassay using human erythroleukemia cells which could not be inhibited by melatonin. Highest activity was detected in summer and least inhibition and even stimulation were observed in winter. There were no differences in activity between animals of different age, sex, or strain. Therefore, season seems to be the factor that exerts the most important influence on the content of tumor-inhibiting activity in the rat pineal gland. Correlation with seasonality in the occurrence of cancer is discussed.

Animals↗
PubMed1990

Effect of the mammary carcinogen 7,12-dimethylbenz[a]anthracene on pineal melatonin biosynthesis, secretion and peripheral metabolism.

The aim of this study was to establish whether the nocturnal peak concentrations of circulating melatonin are affected by a single dose of 7,12-dimethylbenz[a]anthracene (DMBA) in female Sprague-Dawley rats as used for mammary tumor induction. Prior to this, the circadian rhythms of melatonin (N-acetyl-5-methoxytryptamine) and 6-sulfatoxymelatonin, the main metabolic product of melatonin, were determined in female Sprague-Dawley rats. The cosinor analysis revealed significant circadian rhythms with very similar acrophases around 1.00 a.m. for both substances. To enable explanations for possible changes in plasma melatonin after DMBA treatment, the biosynthesis in the pineal and the major metabolic product in the liver, 6-sulfatoxymelatonin, were measured 2 and 7 days after DMBA. Plasma melatonin was depressed by 31-37% (p less than 0.05) 2 and 7 days after DMBA but the pineal melatonin content remained unchanged. 2 days after DMBA, pineal serotonin and N-acetylserotonin showed a transient elevation of 35% (p less than 0.025) and 25% (p less than 0.05), respectively. The plasma concentrations of 6-sulfatoxymelatonin were the same in DMBA- and vehicle-treated animals. An elevation of the 6-sulfatoxymelatonin/melatonin ratio indicated a relative increase in the metabolism of melatonin due to DMBA. The absence of an absolute increase in 6-sulfatoxymelatonin after DMBA could be caused by an additional shift within the spectrum of different metabolic products of melatonin due to the carcinogen. Possible mechanisms are discussed.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1990

[Mucin-like carcinoma-associated antigen: sensitivity and specificity in metastatic breast cancer].

The clinical usefulness of a tumor marker essentially depends on its sensitivity and specificity for a certain tumor. To prove, wheather the new tumor marker 'mucin-like carcinoma-associated antigen' could be used for the management of breast cancer patients, we determined its serum concentration in 50 healthy blood donors, 130 patients with various non-malignant diseases, 138 patients with different metastazised tumors and 137 breast cancer patients. 78 of the breast cancer patients had known metastases while 59 had no evidence of disease after initial surgical and adjuvant therapy. Only 2% of the blood donors and 3% of the patients with non-malignant diseases exceeded the cut-off level of 15 U/ml. In contrast to these findings, 28% of patients with various metastazised tumors and 77% of patients with metastazised breast cancer had serum levels above 15 U/ml. Breast cancer patients without evidence of disease had elevated marker values in only 3%. In breast cancer the serum levels of this antigen depends on the type of metastases. Maximal concentrations were found in mixed metastases while cutaneous or lymph-node metastases showed the lowest rate of positivity. Furthermore a good correlation of serial determined marker levels with the course of the disease was observed, so that we conclude, that mucin-like carcinoma-associated antigen can be used in follow-up of patients with metastazised breast cancer. Because of its high sensitivity and specificity it provides some advantage over other markers used in this disease.

Antigens, Neoplasm↗
PubMed1990

Pulmonary lipid peroxidation in cigarette smokers and lung cancer patients.

Lipid peroxidation (LPO) was studied in lung tissues of patients with lung cancer (LC, n = 37) or nonlung cancer (NLC, n = 13) and its relationships with the smoking habits and the degree of airway obstruction were investigated. Specimens of peripheral lung parenchyma, free of tumor tissue, were taken and the malondialdehyde (MDA) content was measured in the S-12 fractions. Airway obstruction was assessed by flow-volume curves, and data were expressed as percentage of the predicted values. Cigarettes smoked were expressed as pack-years. The patients with LC and NLC did not differ by MDA content, age, and number of pack-years. On the contrary, FEF75-85 and MEF75 were significantly lower in LC than in NLC patients (p less than 0.05). The MDA content was inversely correlated to number of days patients had refrained from smoking (r = -0.66, p less than 0.001). The MDA content was higher in recent smokers (ie, people smoking during the last 30 days before surgery) than in the other patients (0.136 +/- 0.007 vs 0.116 +/- 0.007 mumol/g of tissue, p less than 0.05) and, by considering only recent smokers, MDA content was higher in LC patients (0.144 +/- 0.008 mumol/g of tissue) than in NLC patients (0.113 +/- 0.014 mmol/g tissue, p = 0.059). When patients were divided into "high MDA" and "low MDA" groups, MEF75 was much lower in the high MDA group (35.1 +/- 3.4 percent) than in the low MDA group (55.1 +/- 8.1 percent) (p less than 0.01). These results suggest the following: (1) enhanced level of prooxidant state in the lungs is associated with recent cigarette smoking; (2) LC patients may be more prone than respective NLC patients to oxidative stress; (3) MDA level and degree of small airway obstruction were associated and differed between LC and NLC patients even though these groups did not differ in the percentage of recent smokers; and (4) a common free-radical mediated pathway may be active for both LC and small airway obstruction.

Glutathione↗
PubMed1990

Are mycotoxins risk factors for endemic nephropathy and associated urothelial cancers?

Evidence supporting a role of mycotoxin, in particular ochratoxin A (OA) and citrinin, in the etiology of Balkan endemic nephropathy (BEN) and associated urinary tract tumours (UTT) is reviewed. Both diseases occur in subjects born and/or living in certain rural areas where home-produced and home-stored stable foods were found to be more frequently contaminated by the OA and citrinin. OA levels in blood and urine from patients with BEN or UTT were higher than in controls. OA and possibly other mycotoxins cause endemic porcine nephropathy, a disease with morphology and clinical course similar to those of BEN. OA was carcinogenic in two rodent species with kidney as a major target organ. Animals and strains phenotype as fast metabolizers of debrisoquine were more susceptible to OA-induced carcinogenicity. Among BEN/UTT patients, a greater proportion of fast metabolizers was reported. Although no epidemiological proof of a direct causal role of mycotoxins in BEN/UTT etiology has been presented, the data accumulated so far indicate a need for prospective studies in which mycotoxins as well as other risk factors should be considered.

Animals↗
PubMed1990

Screening assays for carcinogenic agents and mixtures: an appraisal based on data in the IARC Monograph series.

To determine whether genotoxic and non-genotoxic carcinogens contribute similarly to the cancer burden in humans and which types of short-term test are more relevant for predicting human hazards, an analysis was performed on agents that were evaluated in IARC Monographs Supplements 6 and 7 for their carcinogenic effects in humans and animals and for 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 multi-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 in 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 or mutational damage, to identify genotoxic carcinogens or in 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.

Animals↗