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Biomedical subjects

B Spiegelhalder

Publications and source records attributed to B Spiegelhalder.

At least 37 records · Page 2Linked to original sources
PubMed1999

Strong nasal carcinogenicity and genotoxicity of 1-nitroso-4-methylpiperazine after low dose inhalation in rats.

Sprague-Dawley rats were exposed by inhalation to 1-nitroso-4-methylpiperazine (NMPz) vapor at 2.4 p.p.m. for 15 h/day for 74 days over a 7.5 month period. After a dose of 1.1 mg/day NMPz (total dose 340 mg/kg body wt) 10/10 animals developed tumors of the nasal cavity, mostly invasive muco-epidermoidal carcinomas; no such tumors were observed in sham-exposed controls. This high tumor yield was seen at an 80 times lower dose and a shorter latency period when compared with rat carcinogenicity studies reported earlier. The single cell microgel electrophoresis (Comet) assay was used to determine genotoxicity in target tissues. Short-term in vitro exposure of rat and human nasal epithelial tissues to NMPz caused genotoxic effects in cells of both species. Short-term in vivo exposure of rats to NMPz vapor for 1 h induced DNA damage in nasal epithelial cells. Our results revealed NMPz as a potent genotoxic nitrosamine in rat and human nasal cells, the carcinogenicity of inhaled NMPz vapor in rats being remarkably higher as compared with oral uptake.

Adenocarcinoma, Mucinous↗
PubMed1998

Caffeine-derived N-nitroso compounds. V. Carcinogenicity of mononitrosocaffeidine and dinitrosocaffeidine in bd-ix rats.

Mononitrosocaffeidine (MNC) and dinitrosocaffeidine (DNC) are new N-nitroso compounds obtained from in vitro nitrosation of caffeidine, a hydrolysis product of caffeine present in a typically made and widely consumed tea from Kashmir (India), a high incidence area of esophageal and stomach cancer. The chemical synthesis, in vitro metabolic studies and mutagenicity of the compounds has been previously reported. DNC, a nitrosamide is highly mutagenic both with and without metabolic activation whereas MNC, like several other aromatic asymmetric nitrosamines, does not exhibit genotoxic or mutagenic properties. We now report the results of the first carcinogenicity experiments on chronic oral administration of these compounds in BD-IX rats. The acute LD50 of MNC and DNC were about 1300 and 230 mg/kg b.w., respectively. Lung oedema and gastrointestinal haemorrhages were the first symptoms of intoxication observed after 2 days for both the compounds. All three dose groups of MNC treated rats showed localization of tumours in nasal cavity (93.9-100% of all malignant tumours). The tumours were histologically diagnosed as neuroepitheliomas of the olfactory epithelium (neuroblastoma of the bulbus olfactorii) and squamous cell carcinoma of the nasal cavity in the ratio of 3:1. No tumours of the nasal cavity were observed in the untreated controls. DNC, in contrast, induced squamous cell carcinoma of forestomach in 100% animals at low and high doses, of which nearly half the tumours metastasized predominantly into the peritoneum. No forestomach tumours were seen in the untreated controls. The data presented here clearly show the potential for induction of malignant tumours and distinct organ-specificity by MNC and DNC in rats, and support the postulate that a chronic exposure to these compounds may provide a carcinogenic risk for high incidence of gastrointestinal cancers in Kashmir.

Administration, Oral↗
PubMed1998

Phytate, reactive oxygen species and colorectal cancer.

Reproducible high-performance liquid chromatography methods have been developed and validated which allow an accurate quantification of phytic acid in faeces and food and reactive oxygen species in an in vitro model system and in faecal specimens. When applied to the evaluation of reactive oxygen species generation by faeces, this method has shown that 1:100 dilutions of matrix obtained from stool samples of adenoma patients are capable of generating significant quantities of reactive oxygen species as evinced by the production of diphenols from salicylic acid. Moreover, it has been shown that the major product of HO. attack on salicylic acid is 2,5-dihydroxy benzoic acid and not 2, 3-dihydroxy benzoic acid as previously reported. In the presence of the antioxidant ascorbic acid the inhibitory capacity of phytic acid on the generation of reactive oxygen species is completely subverted. Therefore, the kinetics of reactive oxygen species production by faeces is currently under further investigation by high-performance liquid chromatography and chemiluminescence in various patient groups and may give an insight into the role of reactive oxygen species in the aetiology of colorectal cancer.

Animals↗
PubMed1997

N-nitrosation of medicinal drugs catalysed by bacteria from human saliva and gastro-intestinal tract, including Helicobacter pylori.

Micro-organisms commonly present in human saliva and three DSM strains (Helicobacter pylori, Campylobacter jejuni and Neisseria cinerea), which can be isolated from the human gastro-intestinal tract, were assayed in vitro for their capacity to catalyse N-nitrosation of a series of medicinal drugs and other compounds. Following incubation at pH 7.2 in the presence of nitrate (or nitrite) for up to 24 (48) h, the yield of N-nitroso compounds (NOC) was quantified by HPLC equipped with a post-column derivatization device, allowing the sensitive detection of acid-labile and acid-stable NOC. Eleven out of the 23 test compounds underwent bacteria-catalysed nitrosation by salivary bacteria, the yield of the respective nitrosation products varying 800-fold. 4-(Methylamino)antipyrine exhibited the highest rate of nitrosation, followed by dichlofenac > metamizole > piperazine > five other drugs, whilst L-proline and L-thioproline had the lowest nitrosation rate. Ten drugs including aminophenazone, cimetidine and nicotine, did not inhibit bacterial growth, allowing transitory nitrite to be formed, but no N-nitroso derivatives were detected. Three drugs inhibited the proliferation of bacteria and neither nitrite nor any NOC were formed. Using metamizole as an easily nitrosatable precursor, two strains, Campylobacter jejuni and Helicobacter pylori, were shown to catalyse nitrosation in the presence of nitrite at pH 7.2. As compared to Neisseria cinerea used as a nitrosation-proficient control strain, H. pylori was 30-100 times less effective, whilst C. jejuni had intermediary activity. The results of our sensitive nitrosation assay further confirm that bacteria isolated from human sources, possessing nitrate reductase and/or nitrosating enzymes such as cytochrome cd1-nitrite reductase (Calmels et al., Carcinogenesis, 17, 533-536, 1996), can contribute to intragastric nitrosamine formation in the anacidic stomach when nitrosatable precursors from exogenous and endogenous sources are present.

Bacteria↗
PubMed1996

Detection of methylating activity due to nitrosamide in some nitrosated Nigerian foodstuffs.

Popular vegetables, condiments and some Nigerian staple foods were evaluated for their relative methylating potential due to nitrosamide formation following nitrosation under standardized conditions. Methylating activity of nitrosated foodstuffs, expressed as N-nitroso-N-methylurea equivalents, was determined by gas chromatography-thermal energy analysis. In positive samples (detection limit 10 microgram/kg) methylating activity detected was in the range of 50-1200 microgram/kg, the highest activity being found in Telfairia occidentalis (ugwu). This value constitutes the highest amount ever detected for a fresh vegetable. The data suggest that some commonly consumed local foodstuffs might contribute to overall human burden of environmental carcinogens in Nigeria.

Carcinogens↗
PubMed1996

A high performance liquid chromatography system for quantification of hydroxyl radical formation by determination of dihydroxy benzoic acids.

The hypoxanthine/xanthine oxidase enzyme system is known to produce the superoxide ion and hydrogen peroxide during the hydroxylation of hypoxanthine via xanthine to uric acid. When chelated iron is included in this system, superoxide reduces iron (III) to iron(II) and the iron(II)-chelate further reacts with hydrogen peroxide to form the highly reactive hydroxyl radical. Because of the limitations of colourimetric and spectrophotometric techniques by which, to date, the mechanisms of hydroxyl radical formation in the hypoxanthine/xanthine oxidase system have been monitored, a high performance liquid chromatography method utilizing the ion-pair reagent tetrabutylammonium hydroxide and salicylic acid as an aromatic probe for quantification of hydroxyl radical formation was set up. In the hypoxanthine/xanthine oxidase system the major products of hydroxyl radical attack on salicylic acid were 2,5-dihydroxy benzoic acid and 2,3-dihydroxy benzoic acid in the approximate ratio of 5:1. That the hydroxyl radical is involved in the hydroxylation of salicylic acid in this system was demonstrated by the potency especially of dimethyl sulphoxide, butanol and ethanol as scavengers. Phytic acid, which is considered to be an important protective dietary constituent against colorectal cancer, inhibited hydroxylation of salicylic acid at a concentration one order of magnitude lower than the classical scavengers, but was only effective in the absence of EDTA. The method has been applied to the study of free radical generation in faeces, and preliminary results indicate that the faecal flora are able to produce reactive oxygen species in abundance.

Chromatography, High Pressure Liquid↗
PubMed1996

Faecal phytic acid and its relation to other putative markers of risk for colorectal cancer.

AIMS: Phytic acid, a major constituent of cereals, pulses, and seeds has been advocated as an important antioxidant component of dietary fibre that affords possible protection against colorectal cancer. This is supported by experimental studies showing it has antineoplastic activity in animal models of both colon and breast cancer. To date the concentration of faecal phytic acid in human clinical groups has not been evaluated. Therefore the faecal phytic acid content of adenoma patients drawn from a placebo controlled calcium intervention trial was evaluated. METHODS: Phytic acid was measured in faecal extracts by an improved ion-pair high performance liquid chromatography method. RESULTS: Phytic acid was detected in the range 0.68-4.00 mumol/g wet faeces and 55-2038 mumol/day. Linear regression analyses showed no association between stool phytic acid and lipid content. Strong correlations were seen, however, between phytic acid and iron content, both on a concentration (r = 0.52; p = 0.00004) and daily excretion (r = 0.76; p = 5.5 x 10(-12) basis. Phytic acid was also strongly correlated with the daily excretion of calcium (r = 0.59; p = 1.36 x 10(-6) and magnesium (r = 0.42; p = 0.001). Cell proliferation in the sigmoid colon, an intermediate biomarker of colorectal cancer was not significantly associated with faecal phytic acid, minerals or lipid content in this compromised clinical group. CONCLUSIONS: This improved method, developed for the determination of phytic acid in faeces should allow further studies on the role of phytic acid in the aetiology of colorectal cancer to be conducted on a population or case control basis.

Adenoma↗
PubMed1996

Biological monitoring of workers exposed to N-nitrosodiethanolamine in the metal industry.

Biological monitoring of occupational hazards was performed in workers using cutting fluids containing N-nitrosodiethanolamine (NDELA). The study involved a group of 25 male subjects from some metal factories in central Italy who used cutting fluids with an NDELA content of > or = 5 mg/l (high-exposure group) and a group of 37 males exposed to cutting fluids with an NDELA content < 5 mg/l (low-exposure group). For comparison, we recruited a control group consisting of 37 subjects living in the same area. For all subjects, internal dose (urinary excretion of NDELA, mutagens, and thioethers), early biological effects (sister chromatid exchanges in blood peripheral lymphocytes), and urinary excretion of D-glucaric acid (DGA) as an endpoint product in the glucuronidation pathway were assessed. The results showed that only the workers using cutting fluids with NDELA concentrations of > or = 5 mg/l excreted trace amounts of NDELA in their urine. Urine excretion of mutagens was similar in the two exposure groups and in the controls. High-exposure subjects had a higher mean value of urinary thioethers than low-exposure and control subjects, but no differences were found in urinary DGA or lymphocyte sister chromatid exchange among the three groups. Smoking status increased the mean values of all the biomarkers, and coffee drinking was associated with urinary DGA excretion.

Adult↗
PubMed1995

Tobacco-specific nitrosamines in some Nigerian cigarettes.

Ten popular brands of cigarettes on the Nigerian market were analyzed for tobacco-specific nitrosamines (TSNA) in tobacco and in mainstream smoke, as well as nitrate in tobacco. TSNA was analyzed using a gas chromatography/thermal energy analyzer (GC-TEA), while nitrate was determined spectrophotometrically as nitrite following on-line reduction with copper, diozatization with sulfanilamide and coupling with N-(1-naphthyl) ethylene diamine to form an azo dye. In mainstream smoke, the concentration of NNN, NAB/NAT and NNK were respectively, between 8 and 90 ng, 10 and 65 ng, and between 15 and 72 ng/cigarette. Preformed NNN ranged between 64 and 565 ng/cigarette, while preformed NAB/NAT and NNK ranged respectively from 109 to 476 ng/cigarette, and from 55 to 317 ng/cigarette. Nitrate levels ranged between 1.5 and 6.1 mg/g tobacco. In general, the results indicate that the TSNA content of Nigerian cigarettes are within the range found for European and American cigarettes.

Nicotine↗
PubMed1995

Nitrosatable amines and nitrosamide formation in natural stimulants: Cola acuminata, C. nitida and Garcinia cola.

Three varieties of kola nut, Cola acuminata, C. nitida and Garcinia cola, of Nigerian origin, were analysed for their content of primary and secondary amines, and assessed for their relative methylating potential due to nitrosamide formation. Primary and secondary amines were determined as benzene sulfonamides by gas chromatography/thermal energy analysis (GC/TEA). Dimethylamine, methylamine, ethylamine and isopentylamine were detected in all kola nut varieties, while pyrrolidine, piperidine and isobutylamine were detected in one or more varieties. Estimated average total daily intake of aliphatic amines by a typical kola nut chewer varied from 260 to 1040 micrograms/day for secondary amines and from 2430 to 9710 micrograms/day for primary amines. Methylating activity of the nitrosated kola nuts, expressed as N-nitroso-N-methylurea equivalents, was also determined by GC/TEA. Methylating activity was significantly higher in kola nuts (170-490 micrograms/kg) than has ever been reported for a fresh plant product. These data suggest that the possible role of kola nut chewing in human cancer aetiology should be explored in countries where kola nuts are widely consumed as stimulants.

Amines↗
PubMed1995

Nitrosation of Nigerian medicinal plant preparations under 'chemical' and 'simulated' gastric conditions.

Preparations of some tropical plants of medicinal importance, collected from the savannah vegetational belt of Nigeria, were nitrosated and analysed for volatile N-nitrosamines formed under chemical and simulated gastric conditions. N-Nitrosamines were determined on a Thermal Energy Analyser following gas chromatographic separation. Mean concentrations of N-nitrosodimethylamine (NDMA) in the range of 7 to 58 ppb and N-nitrosodiethylamine (NDEA) in the range of 23 to 26 ppb were formed in 31 and 7%, respectively, of the preparations using artificial gastric juice (simulated gastric condition). Under chemically optimal conditions, relatively high levels of NDMA (72-2008 ppb), NDEA (23-1528 ppb) and N-nitrosopyrrolidine (20-405 ppb) were formed in 100, 75 and 32% of the preparations, respectively; N-nitrosomethylethylamine, N-nitrosodibutylamine and N-nitrosomorpholine were formed in fewer preparations. These findings suggest that the endogenous formation of N-nitroso compounds from precursors present in medicinal plants might be another source of human exposure to environmental carcinogens in Nigeria and other developing countries.

Chromatography, Gas↗
PubMed1994

Nitrate, nitrite and N-nitroso compounds.

A risk assessment has been made on nitrate, nitrite and N-nitroso compounds encountered in the human diet. Vegetables constitute a major source of nitrate providing over 85% of the average daily human dietary intake. Nitrite and N-nitroso compounds present in the diet contribute relatively small amounts to the body burden and the major source of these biologically reactive compounds is derived from the bacterial and mammalian metabolism of ingested nitrate. Additionally, endogenous synthesis provides an important source contributing to the body burden of nitrate. Data from animal toxicological studies, human effects and epidemiological surveys have been reviewed and evaluated. It is concluded that there is no firm scientific evidence at present to recommend drastic reductions beyond the average levels of nitrate encountered in vegetables grown in keeping with good agricultural practice. Recommendations have also been made for further animal and human studies to be carried out to elucidate the potential risks to man from ingested nitrate.

Animals↗
PubMed1994

Identification of nitrophenols as nitrosation products from capsaicin and red chillies.

The in vitro nitrosation of sun-dried red chillies (Capsicum annuum) and of its constituents capsaicin and dihydrocapsaicin was studied. The nitrophenols 4-nitroguaiacol, 4,6-dinitroguaiacol, nitrocapsaicin and nitrodihydrocapsaicin were detected as final products, whereas no formation of nitrosamides was observed though this is expected from the amide precursors capsaicin and dihydrocapsaicin. The nitrosation occurs readily with remarkable yields of nitrophenols even at physiological pH and at nitrite concentrations which are within the range of those found in the human stomach. Due to their toxicity, nitrophenols need to be included in total risk assessment through potential endogenous nitrosation of foodstuffs.

Capsaicin↗
PubMed1994

Precursors of N-nitroso compounds in some Nigerian medicinal plants.

Twenty-seven tropical plants of medicinal importance were analysed for primary and secondary amines by chemiluminescence detection on a Thermal Energy Analyzer (TEA) modified for use on 'nitrogen mode' following derivatization with benzene sulphonyl chloride (BSC) and gas chromatographic (GC) separation of their sulphonamides. Nitrite was determined by colorimetry at 540 nm after diazotization with sulphanilamide and coupling with N-(1-naphthyl)ethylenediamine to form an azo dye. Nitrate was determined as nitrite following on-line reduction by granulated cadmium. Dimethylamine in the range of 0.5 ppm to 18.2 ppm was detected in 96% of samples, while pyrrolidine ranged between 0.7 ppm and 12.78 ppm in 14 samples. Isobutylamine, methylamine and ethylamine were the most ubiquitous primary amines. Largest number of secondary amines (four) was found in Azadirachta indica (Neem) while largest number of primary amines (six) was detected in Azadirachta indica and Tamarindus indica (Tsamiya) which also contained the highest amount of total primary amines (148.8 ppm). Nitrate and nitrite were seldom found in plant extracts whose pH were generally below 7.0. These findings suggests that early exposures to precursors of N-nitroso compounds via medicinal plants might contribute to total risk posed by environmental carcinogens in Nigeria.

Amines↗
PubMed1994

Caffeine-derived N-nitroso compounds. IV: Kinetics of mononitrosocaffeidine demethylation by rat liver microsomes.

The study describes the kinetics of demethylation of mononitrosocaffeidine (MNC), a new asymmetric N-nitrosamine derived from caffeine. The demethylation of its precursor compound caffeidine was also studied. The results presented here suggest (a) that liver microsomes from fasted rats preferentially demethylate the N-methylnitrosamine group in MNC indicating the demethylation by cytochrome P450IIE1, (b) demethylation of MNC shows two apparent Km values, one of 117-166 microM responsible for the demethylation at the N-methylnitrosamino group of MNC, and the other Km of 1.84-2.26 mM for the remaining N-demethylations, (c) in contrast, caffeidine is a low affinity substrate for microsomal demethylation as indicated by a high Km of 14.3-16.3 mM, and (d) the demethylation at amino-N amino-N, and N-1 in both these compounds are mainly catalysed by P450 enzymes induced by Aroclor 1245 in rats.

Animals↗