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Biomedical subjects

M Friesen

Publications and source records attributed to M Friesen.

At least 37 records · Page 2Linked to original sources
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

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↗
PubMed1989

Formation of direct-acting genotoxic substances in nitrosated smoked fish and meat products: identification of simple phenolic precursors and phenyldiazonium ions as reactive products.

Epidemiological studies have associated the consumption of smoked fish and meat products with an increased risk of stomach cancer. Therefore, the reaction of such smoked foods with nitrite under acidic conditions was investigated and was shown to produce potent direct-acting genotoxic substances as detected by the SOS Chromotest. Similar genotoxic activity was observed in nitrosated samples of wood-smoke condensates. Simple phenolic compounds such as phenol, 3-methoxycatechol, catechol and vanillin were identified as the precursors of the genotoxic substances. These phenolic compounds also exhibited direct-acting genotoxicity after nitrosation. The major genotoxic substances formed after nitrosation of phenol were isolated and identified as 4- and 2-hydroxyphenyldiazonium ions. Nitrosation of various wood-smoke condensates was found to generate the same type of diazonium compounds, which in part account for the genotoxicity of nitrosated smoked foods.

Animals↗
PubMed1989

Identification in rats of N-nitrosonipecotic acid as a major urinary metabolite of the areca-nut alkaloid-derived nitrosamines, N-nitrosoguvacoline and N-nitrosoguvacine.

N-Nitrosamines derived from areca-nut alkaloids have been implicated in cancer of the oral cavity and esophagus caused by betel quid chewing in India and other Asian countries. A major urinary metabolite of N-nitrosoguvacoline and N-nitrosoguvacine, both present in saliva of betel quid chewers of ppb levels, was isolated from rat urine and identified as N-nitrosonipecotic acid by comparison with the authentic compound. When a dose of 50 or 500 micrograms/rat of either compound was administered orally to BDIV rats, 66-85% of the dose was excreted in the urine as N-nitrosonipecotic acid and 2-8% as N-nitrosoguvacine. These N-nitrosamino acids could be analysed in the urine of betel quid chewers as a marker of exposure to areca-nut specific nitrosamines.

Animals↗
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↗
PubMed1987

Formation of reactive oxygen species and of 8-hydroxydeoxyguanosine in DNA in vitro with betel quid ingredients.

The formation of reactive oxygen species (ROS) from betel quid ingredients, namely areca nut, catechu and tobacco, was studied using a chemiluminescence (CL) technique. Aqueous extracts of areca nut and catechu were capable of generating superoxide anion and hydrogen peroxide at pH greater than 9.5. The formation of O2 was enhanced by Fe2+, Fe3+ and Cu2+ but inhibited by Mn2+. Tobacco extract failed to generate ROS under similar conditions. Saliva was found to inhibit both O2 and H2O2 formation from betel quid ingredients. Upon incubation of DNA at alkaline pH with areca nut extract and Fe3+ or catechu, 8-hydroxydeoxyguanosine was formed as quantified by high performance liquid chromatography (HPLC)/electrochemical detection. The data suggest a possible role of reactive oxygen species in the etiology of oral cancer in betel quid chewers.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1987

Synthesis, structure-activity relationships and a reaction mechanism for mutagenic N-nitroso derivatives of glycosylamines and Amadori compounds--model substances for N-nitrosated early Maillard reaction products.

A series of nine glycosylamines and an Amadori compound were synthesized, together with their N-nitroso derivatives. Their structures were established by physico-chemical and spectroscopic data and elemental analyses. The N-nitroso compounds were further characterized by denitrosation with hydrogen bromide-acetic acid, followed by detection of the liberated NO by a chemiluminescence detector. N-Nitroso derivatives of N-p-nitrophenyl/p-methylphenyl/p-carboxyphenyl pentopyranosylamines, N-p-methylphenyl-1-deoxy-D-fructosylamine (the Amadori compound) and N-3-ethylindole-D-xylopyranosylamine were shown to be direct-acting mutagens in Salmonella typhimurium TA100. The activity of some of the compounds was similar to that of N-ethyl-N-nitrosourea. Their mutagenic activity was shown to depend on the structure of the amine and the sugar moieties and to require the presence of free hydroxyl groups in the sugar. The mutagenicity of N-nitrosoglycosylamines was attributed to their hydrolysis to arenediazonium cations. The formation of these compounds was detected by azo-coupling with N-ethyl-1-naphthylamine, using spectrophotometric and mass spectrometric analyses. These data implicate arene(alkyl)diazonium cations as the ultimate mutagens of N-nitrosoglycosylamines (and possibly of N-nitroso Amadori compounds), a little-explored class of N-nitroso compounds that may be formed in vivo.

Amino Sugars↗
PubMed1987

Substituted hydroxyphenanthrenes in opium pyrolysates implicated in oesophageal cancer in Iran: structures and in vitro metabolic activation of a novel class of mutagens.

Previous epidemiological and laboratory studies have indicated an association between the ingestion of opium pyrolysates, dietary deficiencies and the high incidence of oesophageal cancer in subjects in north-east Iran. Pyrolysates of opium, and particularly of morphine, a major opium alkaloid, were both shown to contain similar highly mutagenic substances that were also clastogenic in mammalian cells and which transformed hamster embryo cells in culture. We now report the isolation and characterization of nine of the most abundant mutagenic compounds present in morphine pyrolysates, using h.p.l.c, GC-MS and n.m.r. spectroscopy. The hitherto unknown compounds, all containing a hydroxyphenanthrene moiety, were identified as: I, 3-methyl-3H-naphth[1,2-e]indol-10-ol; II, 1,2-dihydro-3-methyl-3H-naphth[1,2-e]indol-10-ol; III, 1-methyl-1H-naphth[2,1-g]indol-10-ol; IV, 2-methylphenanthro[3,4-d]-[1,3]oxazol-10-ol; V, 6-methylaminophenanthren-3-ol; VI, 2-methyl-3H-phenanthro[3,4-d]imidazol-10-ol; VII, 1,2-dimethyl-1H-phenanthro[3,4-d]imidazol-10-ol; VIII, 2,5-dimethyl-3H-phenanthro[3,4-d]imidazol-10-ol; and IX, 2-ethyl-3H-phenanthro[3,4-d]imidazol-10-ol. Structures for the heterocyclic rings of compounds IV and VI to IX are tentative. Mutagenicity in Salmonella typhimurium TA98 in the presence of rat liver homogenates increased in the order listed and ranged over four orders of magnitude, IX being 1000 times more active than benzo[a]pyrene. Compounds I and VII were converted by rat liver 9000 g supernatant into phenols and dihydrodiols, implicating arene oxides as ultimate mutagens. The formation and reaction of these arene oxides was shown by trapping experiments in vitro with ethanethiol and subsequent characterization of the ethyl sulfide reaction products. The order of biological activity of compounds I-IX, dependent on the structure of the heterocyclic ring, suggests that carbocations, resonance-stabilized as quinone methides, are their ultimate reactive metabolites. Our results lend additional support to the role of opium pyrolysates as an etiological factor in oesophageal cancer in north-east Iran.

Biotransformation↗
PubMed1987

Synthesis, analysis and mutagenic activity of N-nitroso derivatives of glycosylamines and Amadori compounds: nitrosated model substances for the early Maillard reaction products.

A series of nine glycosylamines and an Amadori compound and their N-nitroso derivatives were synthesized. The structures were ascertained by spectroscopy and elemental analysis. The N-nitroso compounds were further characterized by denitrosation with hydrogen bromide-acetic acid, followed by detection of the liberated NO by a chemiluminescence detector. N-Nitroso derivatives of N-p-nitrophenyl/p-methylphenyl/p-carboxyphenyl pentosylamines, N-p-methylphenyl-1-deoxy-D-fructosylamine (Amadori compound) and N-3-ethylindole-D-xylosylamine were shown to be directly-acting mutagens in Salmonella typhimurium TA100. The activity of some of the compounds was similar to that of N-ethyl-N-nitrosourea. Their mutagenic activity was shown to be dependent on the structure of the amine and the sugar moieties and requires the presence of free hydroxyl groups in the sugar. The mutagenicity of N-nitrosoglycosylamines was attributed to their hydrolysis to arene diazonium cations. Their formation was detected via azo-coupling with N-ethyl-1-naphthylamine, using spectrophotometric and mass-spectrometric analyses. Our data implicate arene (alkyl) diazonium cations as the ultimate mutagens of N-nitrosoglycosylamines and N-nitroso Amadori compounds, a little explored class of N-nitroso compounds which may be formed in vivo.

Amino Sugars↗
PubMed1987

Possible underestimation of nitrosatable amine levels in artificial saliva extracts of children's rubber pacifiers and baby-bottle teats.

Children's pacifiers and baby-bottle nipples from various countries were analysed for their content of N-nitrosamines and nitrosatable amines. Using a method involving extraction with artificial saliva, several nitrosamines including N-nitrosodi-n-butylamine (NDBA), N-nitrosodiethylamine (NDEA), N-nitrosodimethylamine (NDMA) and N-nitrosomorpholine (NMOR) were detected in addition to the three nitrosatable amines dibutylamine (DBA), diethylamine (DEA) and dimethylamine (DMA). Upon nitrosation in artificial saliva, these amines produced not only the related N-nitrosamines but also relatively high levels of the corresponding nitramines--N-nitrodibutylamine (NTDBA), N-nitrodiethylamine (NTDEA) and N-nitrodimethylamine (NTDMA). Thus, both N-nitramines and N-nitrosamines should be measured after nitrosation; otherwise, the method probably underestimates the quantities of nitrosatable amines present in artificial saliva extracts. Whether N-nitramines, some of which have been shown to be both mutagenic and carcinogenic, are formed in the saliva of babies exposed to these products remains to be confirmed.

Cooking and Eating Utensils↗
PubMed1986

Identification, occurrence and mutagenicity in Salmonella typhimurium of two synthetic nitroarenes, musk ambrette and musk xylene, in Indian chewing tobacco and betel quid.

During N-nitrosamine analysis of extracts of betel quid with tobacco and of the saliva of chewers of betel quid with tobacco for N-nitrosamines using a Thermal Energy Analyzer, two unknown compounds were detected. They were identified as synthetic nitro musks, musk ambrette (5-tert-butyl-1,3-dinitro-4-methoxy-2-methylbenzene, CAS No. 83-66-9) and musk xylene, (1-tert-butyl-3,5-dimethyl-2,4,6-trinitrobenzene, CAS No. 81-15-2), by gas chromatography-mass spectrometry and Fourier transform nuclear magnetic resonance spectroscopy. These compounds were detected in several samples of betel quid with tobacco and in perfumed tobacco used for chewing in India in amounts ranging from 0.45-23.5 mg/g wet weight. Musk ambrette was found to be mutagenic in Salmonella typhimurium TA100 requiring metabolic activation by rat-liver postmitochondrial supernatant but musk xylene lacked mutagenicity.

Animals↗
PubMed1986

Reaction kinetics and cytosine adducts of chloroethylene oxide and chloroacetaldehyde: direct observation of intermediates by FTNMR and GC-MS.

As it is not yet known which are the important miscoding adducts formed in the reaction of the relatively unstable compound chloroethylene oxide (CEO) with double-stranded DNA, proton FTNMR and GC-mass spectroscopy were used to directly detect and characterize reaction intermediates. Reaction of CEO with cytidine gave the (hydrated) 2-oxoethyl derivative at the N-3 position prior to ring closure to 3,N4-ethenocytidine; 5-methylcytosine gave an analogous reaction. However, reactions of CEO or chloroacetaldehyde (CAA) with 3-methylcytidine - i.e., with the N-3 blocked as in double-stranded DNA (ds DNA) - were shown by GC-MS of the silylated products to give, at a much slower rate, a pattern of at least 17 adducts all of which contained chlorine. Based on MS fragmentation and considerations of positional, optical and cis/trans isomerism, the reaction products of the 3-methylcytosine moiety were assigned as cis/trans N4-(2-chlorovinyl)-3-methylcytosine which may have arisen from the corresponding N4-(1-hydroxy-2-chloroethyl) adduct. It is postulated that formation of these cytosine-N4 adducts would be more rapid in double-stranded DNA than in the model compound, and that the N4-(2-chlorovinyl) group may be a miscoding adduct. The kinetics for CEO rearrangement, hydrolysis and nucleophilic attack have been studied by proton FTNMR and lead to the hypothesis that concerted nucleophilic attack by cytosine-N4 and CEO rearrangement produce the N4 adducts.

5-Methylcytosine↗
PubMed1985

Identification and occurrence of two new N-nitrosamino acids in tobacco products: 3-(N-nitroso-N-methylamino)propionic acid and 4-(N-nitroso-N-methylamino)butyric acid.

Two new N-nitrosamino acids, 3-(N-nitroso-N-methylamino)propionic acid (CAS: 10478-42-9) and 4-(N-nitroso-N-methylamino)butyric acid (CAS: 61445-55-4) were isolated and identified for the first time in various types of tobacco, including snuff, chewing and pipe tobacco, cigars and cigarettes. Their levels ranged from 0.15 to 7.4 and 0 to 2.2 mg/kg of dry weight tobacco, respectively. For comparison, amounts of other N-nitrosamino acids like N-nitrosoproline (NPRO) and tobacco-specific-nitrosamines (TSNA) were determined in the same samples. The levels of N-nitrosamino acids were highly correlated with the levels of TSNA.

Chromatography, Gas↗
PubMed1985

Tobacco-specific and betel nut-specific N-nitroso compounds: occurrence in saliva and urine of betel quid chewers and formation in vitro by nitrosation of betel quid.

In order to evaluate exposure of betel quid chewers to N-nitroso compounds, saliva and urine samples were collected from chewers of betel quid with or without tobacco, from tobacco chewers, from cigarette smokers and from people with no such habit, and were analysed for the presence of N-nitrosamines by gas chromatography coupled with Thermal Energy Analyzer and alkaloids derived from betel nut and tobacco by capillary gas chromatography fitted with nitrogen-phosphorous selective detector. The levels of the betel nut-specific nitrosamines, N-nitrosoguvacoline and N-nitrososoguvacine (the latter being detected for the first time in saliva), ranged from 0 to 7.1 and 0 to 30.4 ng/ml, respectively. High levels of tobacco-specific nitrosamines were detected in the saliva of chewers of betel quid with tobacco and in that of chewers of tobacco, ranging from 1.6 to 59.7 (N'-nitrosonornicotine), 1.0 to 51.7 (N'-nitrosoanatabine) and 0 to 2.3 [4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone] ng/ml. Urinary concentrations of certain N-nitrosamino acids, including N-nitrosoproline, were determined as a possible index of exposure to nitroso compounds and their precursors in the study groups: no clear difference was observed. The betel nut-specific alkaloid, arecoline, was present at high levels in the saliva of betel quid chewers with or without tobacco. Nicotine and cotinine were also detected in saliva and urine of chewers of tobacco and of betel quid with tobacco. In order to assess whether N-nitroso compounds are formed in vivo in the oral cavity during chewing or in the stomach after swallowing the quids, the levels of N-nitroso compounds in betel quid extracts were determined before and after nitrosation at pH 7.4 and 2.1. The results indicate that N-nitroso compounds could easily be formed in vivo. The possible role of N-nitroso compounds in the causation of cancer of the upper alimentary tract in betel quid chewers is discussed.

Adult↗
PubMed1984

Occurrence in human urine of new sulphur-containing N-nitrosamino acids N-nitrosothiazolidine 4-carboxylic acid and its 2-methyl derivative, and their formation.

To quantitate endogenous nitrosation reactions in man, the quantity of N-nitrosoproline (NPRO) excreted in the urine after ingestion of proline and/or nitrate was estimated. When this monitoring method (NPRO test) was applied in clinical and field studies, several hitherto unidentified N-nitroso compounds were frequently detected. These were recently identified as sulphur-containing N-nitrosamino acids, N-nitrosothiazolidine 4-carboxylic acid (NTCA), and trans- and cis-isomers of N-nitroso-2-methylthiazolidine 4-carboxylic acid (NMTCA). NTCA and NMTCA were readily formed in vitro following nitrosation at acidic pH of the respective precursor, thiazolidine 4-carboxylic acid (TCA) or of 2-methylthiazolidine 4-carboxylic acid (MTCA). As the latter compounds can be formed by reaction of L-cysteine with formaldehyde or acetaldehyde, respectively, NTCA and NMTCA were also formed by reacting L-cysteine with the respective aldehyde and with nitrite at optimal pH (2.5 for NTCA and 4.5 for NMTCA). Up to 95% of NTCA and NMTCA given orally to fasted rats was recovered as such in urine and faeces within 2 days. Administration of TCA or MTCA, together with nitrite increased the urinary excretion of NTCA and NMTCA, as did co-administration of L-cysteine, nitrite, and the respective aldehyde. NTCA and NMTCA were also detected in the 24-h urine of human volunteers, and smokers tended to excrete higher levels than nonsmokers. Daily excretion levels varied, however, and a diet supplemented with ascorbic acid significantly decreased the total amount of nitrosamino acids. NTCA and NMTCA may occur in human urine as a result of (i) intake of preformed N-nitroso compounds; (ii) intake of thiazolidine 4-carboxylic acid or its 2-methyl derivative and subsequent nitrosation in vivo; (iii) endogenous two-step synthesis by the reaction of L-cysteine with the respective aldehyde and a nitrosating agent. Thus, measurement of NTCA and NMTCA together with NPRO in urine may provide an index for the exposure of human subjects to nitrosamines or their precursors, i.e., nitrosating agents, certain aldehydes, or aldehyde-generating compounds. Our data demonstrate unequivocally that N-nitroso compounds are formed in the human body, as suggested previously by Druckrey. Their relevance to human cancer at specific sites should now be investigated.

Administration, Oral↗
PubMed1984

Presence in human urine of new sulfur-containing N-nitrosamino acids: N-nitrosothiazolidine 4-carboxylic acid and N-nitroso 2-methylthiazolidine 4-carboxylic acid.

A new type of sulfur-containing N-nitrosamino acid, N-nitrosothiazolidine 4-carboxylic acid (NTCA) and N-nitroso 2-methylthiazolidine 4-carboxylic acid (NMTCA), was isolated and identified in the urine of human subjects. Identification was based on identical chromatographic and mass spectral data for the purified urine sample and the synthesized authentic compounds. The amounts of NTCA and NMTCA excreted in 24-h urines of 15 volunteers varied from 0.9 to 35.9 micrograms/day and from 0.4 to 19.8 micrograms/day, respectively. These amounts were 2.4 and 1.6 times greater than that of N-nitrosoproline (NPRO) detected in the same urine samples. Thiazolidine 4-carboxylic acid and its 2-methyl derivative were found to be nitrosated in vitro about 250-500 and 60-300 times more rapidly than proline, respectively. In addition, NTCA and NMTCA were also readily formed by reaction of a mixture of nitrite and L-cysteine, with formaldehyde and acetaldehyde, respectively. Although their origin in human urine is unknown, preliminary results in one human volunteer have shown that some of these compounds are formed endogenously. Thus, measurement of these new sulfur-containing N-nitrosamino acids in the urine may (i) provide another index for endogenous nitrosation reactions in the human body and (ii) allow monitoring of exposure of humans to precursors such as aldehydes and nitrate/nitrite.

Chemical Phenomena↗
PubMed1983

Presence in human urine of a new N-nitroso compound, N-nitrosothiazolidine 4-carboxylic acid.

Urine samples collected in several countries from human subjects showed the presence of a number of N-nitroso compounds not previously identified. By several separative procedures and by comparison with authentic material, the major unknown N-nitroso compound was shown to be N-nitrosothiazolidine 4-carboxylic acid (NTCA). Although its origin in human urine is unknown, thiazolidine 4-carboxylic acid, the easily nitrosatable amine precursor, can be formed by reaction of formaldehyde with cysteine in vivo and in vitro. Thus measuring NTCA excreted in the urine may allow monitoring exposure of human subjects to precursors like formaldehyde and NO-3/NO-2.

Chromatography, Gas↗