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Biomedical subjects

H Bartsch

Publications and source records attributed to H Bartsch.

At least 163 records · Page 9Linked to original sources
PubMed1995

Metabolic polymorphism affecting DNA binding and excretion of carcinogens in humans.

A case-control study on lung cancer patients demonstrated the pronounced effect of tobacco smoke on pulmonary carcinogen metabolism and suggested the existence of a metabolic phenotype at higher risk for tobacco-associated lung cancer. Lung cancer patients who were recent smokers showed in their lungs (i) significantly induced CYP1A1-related enzyme activity vs smoking non-lung cancer patients; (ii) increased benzo(a)pyrene (BP) tetrol formation from BP 7,8-diol by lung microsomes; and (iii) high levels of cytochrome P4501a1 by immunohistochemical staining. Levels of bulky aromatic DNA adducts (by 32P-postlabelling) and of BP-diol-epoxide (BPDE) adducts (by HPC/fluorometry) were quantified in lung parenchyma. Aryl hydrocarbon hydroxylase activity and the level of BPDE-DNA adducts (r = 0.91; p < 0.001) and to a lesser degree bulky DNA adducts were correlated. Thus pulmonary CYP1A1 expression (inducibility) controls in part polycyclic aromatic hydrocarbon-DNA adduct formation in tobacco smokers and, therefore, appears to be associated with lung cancer risk. High risk subjects for lung cancer among smokers may be identifiable through genotyping for polymorphic drug metabolizing enzymes in combination with molecular dosimetry of carcinogen-DNA adducts and mutation analysis in target (surrogate) cells. Such studies in a Finnish cohort of lung cancer patients and controls are in progress. Interim results of the effect of metabolic polymorphism on the level of PAH-DNA adducts and on the excretion of mutagens in urine are summarized.

Biotransformation↗
PubMed1995

Cancer biomarkers in human atherosclerotic lesions: detection of DNA adducts.

Since somatic mutations are suspected to contribute to the pathogenesis not only of cancer but also of atherosclerotic plaques, we measured DNA adducts in the smooth muscle layer of atherosclerotic lesions in abdominal aorta specimens taken at surgery from seven patients. DNA adducts were evaluated in three laboratories by means of different molecular dosimetry methods, including: (a) HPLC/fluorescence, which specifically identifies the DNA adducts of the anti-benzo(a)pyrene (BPDE) isomer; (b) two- and three-dimensional synchronous fluorescence spectrophotometries, which detect DNA adducts of BPDE and other reactive metabolites of polycyclic aromatic hydrocarbons; and (c) 32P postlabeling, which reveals the presence of a variety of types of DNA adducts. The HPLC/fluorescence method provided for the first time evidence for the presence of BPDE-DNA specific adducts in three of six specimens tested. Synchronous fluorescence spectrophotometry displayed broad areas of fluorescence in all seven specimens, thereby suggesting the occurrence not only of BDPE-DNA but also of other DNA adducts with similar fluorescence characteristics. All specimens were also positive at 32P postlabeling, which revealed multiple spots detectable following enrichment either with nuclease P1 or butanol, indicative of the presence of different aromatic DNA adducts. Thus, the data obtained by applying typical cancer biomarkers provide further support to the hypothesis that there may be similarities between the carcinogenic and the atherogenic processes, and in particular that genetic alterations caused by DNA-binding agents in the artery wall may be detected in atherosclerotic lesions.

Aged↗
PubMed1995

The influence of lung injury due to mechanical ventilation on the initiation of ECMO.

Before the entry criteria for extracorporeal membrane oxygenation (ECMO) are met, newborns may require aggressive mechanical ventilation which may result in lung injury. The question arises whether the presence of a pneumothorax in these infants plays a role in the prognosis. Of the 21 newborns transferred to our hospital for ECMO, 8 were treated with ECMO. 9 of the 21 newborns developed a pneumothorax with conventional ventilation and 6 of these 9 newborns subsequently required ECMO. Infants who developed a pneumothorax but did not meet ECMO criteria and remained in the oxygenation index (OI) range between 25 and 40 for more than 2 days had a poorer prognosis. If adequate oxygenation cannot be attained with acceptable mechanical ventilation and a more aggressive ventilation results in a pneumothorax, ECMO should be considered even if the oxygenation index is below 40.

Blood Gas Analysis↗
PubMed1995

Metabolic activation and DNA adduct detection of PhIP in dogs, rats, and humans in relation to urinary bladder and colon carcinogenesis.

The metabolic activation of the heterocyclic amine carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), was examined in dogs and rats as models for urinary bladder and colon carcinogenesis, respectively. The results indicate that unconjugated N-OH-PhIP is not excreted in the urine after oral dosing with PhIP and that the two isomeric N-glucuronides of N-OH-PhIP, which are formed as major metabolites, are stable under acidic conditions. These data suggest that PhIP is unlikely to serve as a urinary bladder carcinogen in either species. Using metabolic inhibitors, bile duct ligation, and intravenous dosing studies, a new hypothesis for colorectal carcinogenesis is proposed involving N-oxidation of PhIP by hepatic cytochrome P-4501A2 (CYP1A2) and O-acetylation by the polymorphic acetyltransferase (NAT2). The resulting N-hydroxy and N-acetoxy metabolites both appear to be transported through the circulation to the colon mucosa, forming covalent DNA adducts. Glucuronidation and reaction with glutathione appear to serve as detoxification pathways. In humans, individuals who are phenotypically rapid metabolizers for both CYP1A2 and NAT2 are significantly higher (p = 0.0015) in colorectal cancer/poly cases vs. controls; and PhIP-DNA adducts can be detected in human colon samples. These studies provide strong evidence that PhIP and other heterocyclic amines play an important role in the etiology of human colorectal cancer.

Animals↗
PubMed1994

Genetically based N-acetyltransferase metabolic polymorphism and low-level environmental exposure to carcinogens.

The metabolic activation or inactivation of carcinogens varies considerably in human populations, and is partly genetically determined. Inter-individual variability in the susceptibility to carcinogens may be particularly important at low degrees of environmental exposure. Examples of probable human carcinogens that present widespread low-dose exposures are environmental tobacco smoke and diesel exhaust. We have determined levels of DNA adducts in bladder cells and of 4-aminobiphenyl-haemoglobin adducts in 97 volunteers, together with the N-acetylation non-inducible phenotype, the corresponding genotype, and the levels of nicotine-cotinine in the urine. We find that among the slow acetylators, 4-aminobiphenyl adducts were higher than in rapid acetylators at low or null nicotine-cotinine levels, whereas the difference between slow and rapid acetylators was less evident at increasing nicotine-cotinine levels. The N-acetyltransferase genotype is highly predictive of the acetylation phenotype. Our results indicate that the clearance of low-dose carcinogens is decreased in the genetically based slow-acetylator phenotype. Such genetic modulation of low-dose environmental risks is relevant to 'risk assessment' procedures.

Acetylation↗
PubMed1994

Structure-activity studies in E. coli strains on ochratoxin A (OTA) and its analogues implicate a genotoxic free radical and a cytotoxic thiol derivative as reactive metabolites.

Ochratoxin A (OTA), its major metabolite in rodents, ochratoxin alpha, and seven structurally related substances were assayed for SOS DNA repair inducing activity in Escherichia coli strain PQ37. At concentrations of 0.1-4 mM, OTA, chloroxine, 5-chloro-8-quinolinol, 4-chloro-meta-cresol and chloroxylenol induced 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 chlorine at C-5 appears to be one determinant of genotoxicity in these substances. Amino oxyacetic acid, an inhibitor of the cysteine conjugate beta-lyase, decreased the cytotoxicity of OTA but did not alter its genotoxic activity, suggesting the formation of a cytotoxic thiol-containing derivative. The mechanisms by which OTA 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 strain PQ37 was measured in the absence and presence of Trolox C, a water-soluble form of vitamin E. Trolox C completely quenched the genotoxicity of OTA, and the effect was similar in the mutant and wild-type strains. These results implicate an OTA-derived free radical rather than reduced oxygen species as genotoxic intermediate(s) in bacteria.

Escherichia coli↗
PubMed1994

Chronic infections and inflammatory processes as cancer risk factors: possible role of nitric oxide in carcinogenesis.

Infection by bacteria, parasites or viruses and tissue inflammation such as gastritis, hepatitis and colitis are recognized risk factors for human cancers at various sites. Nitric oxide (NO) and other oxygen radicals produced in infected and inflamed tissues could contribute to the process of carcinogenesis by different mechanisms, which are discussed on the basis of authors' studies on liver fluke infection and cholangiocarcinoma development. A similar mechanism could apply to other suspected and known cancer-causing agents including Helicobacter pylori infection (stomach cancer) or asbestos exposure (lung mesothelioma). Studies on the type of tissue and DNA damage produced by NO and by other reactive oxygen species are shedding new light on the molecular mechanisms by which chronic inflammatory processes may initiate or enhance carcinogenesis in humans.

Bacterial Infections↗
PubMed1994

Metabolism of nitrosamines and aflatoxin B1 by hamster liver CYP2A enzymes.

Using a specific antibody against mouse CYP2A5 and coumarin as inhibitors, and pretreatments known to affect the activities of CYP2A-related enzymes, we studied the contribution of hamster liver CYP2As in the dealkylation of N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA) and hydroxylation of aflatoxin B1 (AFB1). CYP2A5 antibody inhibited AFB1 and NDEA metabolism by 40-60% in untreated hamsters and after treatment with phenobarbital (PB) or 3-methylcholanthrene (MC). After pyrazole (PYR) treatment, there was no inhibition, although PYR increased the metabolism above the controls. NDMA metabolism was inhibited only weakly in all groups. This suggests that CYP2As may contribute significantly to NDEA and AFB1 metabolism and less to NDMA metabolism in untreated hamster liver and after MC or PB treatments, but that PYR treatment may change the expression pattern of CYPs so that the metabolism is mainly catalysed by CYPs not recognized by the antibody. Coumarin inhibited NDEA and NDMA metabolism in all groups of hamsters, including pyrazole-pretreated animals, suggesting that it interacts not only with CYP2As but also with other CYPs that are important in nitrosamine metabolism. On the other hand, coumarin inhibited AFB1 metabolism significantly only in control and PB-treated animals but not at all after PYR or MC treatment. This suggests that enzymes involved in AFB1 metabolism may be different depending on the pretreatment. It is concluded that CYP2As may contribute significantly to nitrosamine and aflatoxin metabolism in hamster liver. However, in view of previous results showing essential differences in their regulation between mouse and hamster, interspecies comparisons may be difficult.

Aflatoxin B1↗
PubMed1994

Increased nitrosamine and nitrate biosynthesis mediated by nitric oxide synthase induced in hamsters infected with liver fluke (Opisthorchis viverrini).

We previously reported that increased endogenous nitrosation in human subjects infected with the liver fluke Opisthorchis viverrini in north-east Thailand could be a risk factor for the development of cholangiocarcinoma. In the present study we examined our hypothesis that this increased endogenous nitrosation is mediated by nitric oxide (NO) synthase induced by O. viverrini infestation. Syrian golden hamsters experimentally infected with O. viverrini liver fluke excreted in the urine significantly greater amounts of nitrate, a stable oxidization product of NO, than untreated hamsters (3.64 +/- 0.86 versus 2.64 +/- 0.60 mumol/hamster/day, P < 0.001). When the rapidly nitrosatable thiazolidine 4-carboxylic acid was administered orally, the infected hamsters also excreted significantly elevated levels of N-nitrosothiazolidine 4-carboxylic acid than untreated hamsters (4.27 +/- 2.20 versus 2.33 +/- 1.13 nmol/hamster/day, P < 0.01), indicating that endogenous nitrosation is elevated in the animals with liver fluke. NO synthase activity measured in liver cytosol was about twice as high in the infected hamsters as in untreated animals. The enzyme, whose biochemical characteristics were similar to that induced in activated murine macrophages, was immunohistochemically localized in the cytoplasm of macrophages and eosinophils in the inflammation zone surrounding the parasite-containing bile ducts. These results support our hypothesis that, in fluke-infected subjects, NO synthase induction leads to excess production of NO and the observed elevated endogenous nitrosation. Since high concentrations of NO exert cytotoxic and mutagenic effects per se, excess NO produced in chronically infected/inflamed tissues may also play a role in initiation and subsequent modulation stages of cholangiocarcinoma development.

Amino Acid Oxidoreductases↗
PubMed1994

Validation of a new fluorometric assay for benzo[a]pyrene diolepoxide-DNA adducts in human white blood cells: comparisons with 32P-postlabeling and ELISA.

A new fluorometric assay was validated for quantification of benzo[a]pyrene diolepoxide (BPDE)-DNA adducts in white blood cells (WBC) from humans exposed to polycyclic aromatic hydrocarbons (PAH). This assay has a detection limit of 2 pg of r-7,c-10,t-8,t-9-tetrahydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene derived from acid hydrolysis of BPDE-DNA, and can measure 1 BPDE adduct per 10(8) unmodified nucleotides. The quantity of WBC DNA required depends on the modification level and varies between 5 and 500 micrograms. The assay was applied to seven WBC DNA samples from lung cancer patients, six of whom were heavy smokers, and to three WBC DNA samples from healthy subjects employed in an aluminum production plant. High levels of BPDE-DNA adducts, ranging from 62 to 533 adducts/10(8) nucleotides were found in six out of seven DNA samples from the lung cancer patients. In WBC DNA from healthy persons BPDE-DNA adducts were detected only in two non-smokers, but at a much lower level than in lung cancer patients (4-10 adducts/10(8) nucleotides). Using coded WBC DNA samples, BPDE-DNA adduct levels measured by fluorometry of the B[a]P-tetrols, were compared with the results obtained by 32P-postlabeling (nuclease P1 enrichment) and ELISA measurements. A good correlation and proportionality was found between the levels of BPDE-DNA adducts measured by fluorometry and 32P-postlabeling (r = 0.95, P < 0.001, n = 8). The correlation between fluorometry and ELISA was much lower and not significant (r = 0.61, P = 0.1, n = 6). Moreover, the ELISA grossly overestimated BPDE-DNA adduct levels measured by the other two methods. The results demonstrate that the highly sensitive and specific fluorometric assay is suitable for measuring BPDE-DNA adducts in WBC from humans exposed to benzo[a]pyrene.

Benzo(a)pyrene↗
PubMed1994

Analysis of 4-aminobiphenyl-DNA adducts in human urinary bladder and lung by alkaline hydrolysis and negative ion gas chromatography-mass spectrometry.

Analysis of carcinogen-DNA adducts has been regarded as a useful means of assessing human exposure to chemical carcinogens. We have established a method for quantitation of 4-aminobiphenyl (4-ABP)-DNA adducts by alkaline hydrolysis and gas chromatography with negative ion chemical ionization mass spectrometry (GC-NICI-MS). Aliquots of DNA (typically 100 micrograms/ml) were spiked with an internal standard, d9-4-ABP, and were hydrolyzed in 0.05 N NaOH at 130 degrees C overnight. The liberated 4-ABP was extracted with hexane and derivatized using pentafluoropropionic anhydride in trimethylamine for 30 min at room temperature prior to GC-NICI-MS. With in vitro [3H]N-hydroxy-4-ABP modified DNA standards, we observed 59 +/- 7% (n = 9) recovery of the 4-ABP and a linear correlation between hydrolyzed 4-ABP and the adduct levels ranging from about 1 in 10(8) to 1 in 10(4) nucleotides (r = 0.999, n = 9). The method was further validated by comparison of the results with that obtained by the 32P-postlabeling method. There was excellent agreement (r = 0.994, p < 0.001) between the two methods for quantitation of the adduct in eight samples of Salmonella typhimurium DNA treated with 4-ABP and rat liver S9, although the 32P-postlabeling method gave slightly higher values. The DNA adducts in 11 human lung and 8 urinary bladder mucosa specimens were then determined by our GC-NICI-MS method. The adduct levels were found to be < 0.32 to 49.5 adducts per 10(8) nucleotides in the lungs and < 0.32 to 3.94 adducts per 10(8) nucleotides in the bladder samples.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkalies↗
PubMed1994

Seasonality of pineal melatonin production in the rat: possible synchronization by the geomagnetic field.

Pineal melatonin production was estimated by means of urinary 6-sulfatoxymelatonin (aMT6s) determination in two groups of female rats for 1 year each. Seasonal changes of nocturnal aMT6s excretion were found with peak levels in summer despite constant photoperiods. We hypothesize that the horizontal component H of the geomagnetic field may act as a seasonal zeitgeber because H shows a similar seasonal rhythm, and changes in the direction and intensity of H can affect pineal activity. The observed seasonal changes of pineal melatonin production stress that despite constant environmental conditions, endocrine experiments require consideration of season, neglect of which may lead to contradictory results.

Animals↗
PubMed1994

Diet and oxidative stress in breast, colon and prostate cancer patients: a case-control study.

OBJECTIVE: To study the changes in pro-oxidant-antioxidant status in breast, colon and prostate cancer patients as compared to respective controls. DESIGN: Cross-sectional case-control study. The pro-oxidant status was measured by analysing alkanes (ethane and pentane) in exhaled air and lipid peroxidation (as malonaldehyde) in blood samples. The antioxidant capacity was measured by studying blood glutathione concentration, vitamin concentrations and serum antioxidant capacity in liposomes in vitro. SETTING: Aberdeen hospitals. SUBJECTS: Breast, prostate and colon cancer cases, and age- and sex-matched control patients (hospitalized for a benign disease). Breast cancer patients were females, prostate cancer patients were males and colon cancer patients were both males and females. Controls were age-matched to within 5 years, sex-matched and matched for smoking habits. RESULTS: The dietary study suggested a higher monoene and polyene fat intake in prostate cancer than in controls while in other cancer patients no significant differences were found. Breast and colon cancer patients tended to have lower vitamin intakes than controls. Pentane concentration in exhaled air increased in breast cancer patients as compared to respective controls. In serum total antioxidant capacity no significant differences were found. Both breast and colon cancer patients showed decreased C18:2 and C20:4 fatty acid concentrations in red blood cells while C22:6 concentration was elevated in breast cancer patients. CONCLUSIONS: Oxidative stress may be associated with malignant diseases, suggesting the importance of simultaneous analysis of pro- and antioxidation in the search of mechanistic parameters leading to the tumour formation.

Adult↗
PubMed1993

Comparison of hamster and mouse reveals interspecies differences in the regulation of hepatic CYP2A isozymes.

Three CYP2A-related activities [coumarin 7-hydroxylase (COH), testosterone 7 alpha- (test7 alpha) and 15 alpha-hydroxylases (test15 alpha)], identified in hamster liver and analysed by immunoinhibition, and western and northern blotting, were found to be similar to mouse and human CYP2As. In the microsomal fractions, anti-mouse CYP2A5 antibody recognised three bands of about 48, 49 and 52 kDa, suggesting the presence of at least three proteins immunologically similar to mouse CYP2A5. The 49 kDa band migrated close to mouse CYP2A5 and changes in its expression followed COH and test15 alpha activities. Test7 alpha activity did not associate with any of the individual bands detected on western blots despite its strong inhibition by the antibody. Despite the immunological and catalytic similarities between mouse and hamster CYP2A enzymes, their regulation is different. In mice, the enzyme activities are higher in females than males, are induced by pyrazole (PY) and phenobarbital (Pb), and are not affected by 3-methylcholanthrene (MC). In hamsters, activities are not higher in females, induced by MC and reduced by PY. MC and PY appear to regulate expression at the mRNA level, while Pb seems to act post-transcriptionally by increasing either the synthesis or the stability of the protein. Our data indicate that the modes of expression and regulation of CYP2A-related enzymes make the hamster different from mice and humans with respect to the mechanism of metabolism of certain drugs and carcinogens.

Animals↗