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PubMed1988

Alkylating activity in food products--especially sauerkraut and sour fermented dairy products--after incubation with nitrite under quasi-gastric conditions.

N-Nitroso compounds may well rank high among the genotoxic carcinogens present in our environment. Small amounts of such compounds may be formed in the human stomach after consumption of high-nitrate vegetables. Volatile nitrosamines can be conveniently determined but reliable methods of analysis for non-volatile N-nitroso compounds are still lacking. In this study we have used the 4-(4-nitrobenzyl)pyridine test to look for the formation of alkylating compounds such as N-nitroso-N-methylurea in a wide range of food products after incubation with nitrite under simulated gastric conditions. Our results indicate that many food products do not form alkylating compounds in appreciable amounts, even though the nitrite concentration used was five to ten times that found in saliva after a high-nitrate meal. Comparatively strong alkylating activity, however, was detected after incubation of samples of sauerkraut, certain dairy products (yoghurt, biogarde, quark, buttermilk and milk), wine and smoked mackerel. Samples of sauerkraut incubated with simulated gastric fluid, but without (added) nitrite, also displayed appreciable alkylating activity. The formation of alkylating substances in non-fat yoghurt was markedly inhibited by addition of ascorbic acid. The identity of the alkylating agents remains unknown. The isolation procedure was optimized for N-nitroso-N-methylurea, but will certainly result in the isolation of other compounds, such as C-nitroso-, C-nitro- or perhaps even C-nitroso-C'-nitro-compounds as well. Biogenic amines, glucosinolates, indole derivatives or other compounds may be involved as precursors. If alkylating agents are formed in vivo after ingestion of high-nitrate vegetables or drinking water, this is likely to occur only when the food products mentioned above are ingested simultaneously with or shortly after the nitrate load and not appreciably (except perhaps in the case of sauerkraut) when they are ingested alone, without a nitrate source. The health implications of these findings cannot yet be established. Many alkylating agents, however, have strong carcinogenic properties and continued investigation of food products (and their interaction products with nitrite) is indicated.

Alkylating Agents↗
PubMed1986

Superoxide generation by 1-nitropyrene in rat lung microsomes.

1-Nitropyrene (1-NP) is a potent mutagen which has been found in diesel exhaust particulates and photocopy toners. 1-NP is known to undergo reduction and oxidation by mammalian enzymes. Research into the biological activity of 1-NP has concentrated on its possible mutagenic and carcinogenic properties. Because other nitro compounds, such as nitrofurantion, are reduced to a nitro anion radical which can react with molecular oxygen to produce superoxide, it was of interest to determine if 1-NP produced superoxide. This study used acetylated cytochrome c/superoxide dismutase as a detection system in a lung microsomal system. Results show that 1-NP catalyzes the formation of superoxide, that the reaction obeys Michaelis-Menten kinetics and that this reaction is saturable. The significance of this study is that 1-NP may have toxic effects which are related to oxidant stress.

Animals↗
PubMed2004

Benzoyl ring halogenated classical 2-amino-6-methyl-3,4-dihydro-4-oxo-5-substituted thiobenzoyl-7H-pyrrolo[2,3-d]pyrimidine antifolates as inhibitors of thymidylate synthase and as antitumor agents.

In an attempt to circumvent resistance to and toxicity of clinically used folate-based thymidylate synthase (TS) inhibitors that require folylpoly-gamma-glutamate synthetase (FPGS) for their antitumor activity, we designed and synthesized two classical 6-5 ring-fused analogues, N-[4-[(2-amino-6-methyl-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl)thio]-2'-fluorobenzoyl]-l-glutamic acid (4) and N-[4-[(2-amino-6-methyl-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl)thio]-2'-chlorobenzoyl]-l-glutamic acid (5), as TS inhibitors and antitumor agents. The key intermediates in the synthesis of these classical analogues were the mercaptans 10 and 11, which were obtained from the corresponding nitro compounds 6 and 7 respectively, by reduction of the nitro groups followed by diazotization of the amines. The syntheses of analogues 4 and 5 were achieved via the oxidative addition of the sodium salt of ethyl 2-halo-substituted-4-mercaptobenzoate (16 or 17) to 2-amino-6-methyl-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidine (18) in the presence of iodine. The esters obtained from the reaction were deprotected and coupled with diethyl-l-glutamate followed by saponification. Compounds 4 and 5 were both more potent inhibitors of human TS (IC(50) values of 54 and 51 nM, respectively) than were PDDF and the clinically used ZD1694 and LY231514. Compounds 4 and 5 were not substrates for human FPGS up to 250 muM. In addition, 4 and 5 were growth inhibitory against CCRF-CEM cells as well as a number of other tumor cell lines in culture, and protection studies established TS as the principal target of these analogues.

Antineoplastic Agents↗
PubMed2000

Structure-activity relationships of polycyclic aromatic amines with calcium channel blocking activity.

8-Benzylamino-8, 11-oxapentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecane (1) inhibits the calcium current in L-type calcium channels. A series of nitrobenzylamines (2, 3, 4), methoxybenzylamines (5, 6, 7), methylpyridines (8, 9, 10), and a phenylhydrazine derivative (11) of 8,11-oxapentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecane was synthesized. By substituting the 8,11-oxapentacyclo-[5.4.0.0(2,6).0(3,10).0(5,9)]undecane skeleton with 3-hydroxyhexacyclo-[6.5.0.0(3,7).0(4,12).0(5,10).0(9,13)]tridec ane (12), 8,13-dioxapentacyclo[6.5.0.0(2,6).0(5,10).0(3,11)]tridecane- 9-one (13), and pentacyclo-[5.4.0.0(2,6).0(3,10).0(5,9)]undecane (14), the effect of the polycyclic skeleton could also be investigated. Increased inhibition of calcium current was observed with aromatic substitution (especially ortho and meta substitution) in the pentacycloundecane series. The calcium channel activities of the methoxy compounds were slightly higher than those of the corresponding nitro compounds while a definite decrease in activity was observed for the phenylhydrazine and aminomethylpyridine derivatives. Increased inhibition of the calcium current was also observed for structures in which the polycyclic 'cages' were enlarged. Structure-activity relationships in this series of compounds therefore appear to be dominated by geometric or steric constraints.

Animals↗
PubMed1985

The metabolism of xenobiotic compounds by Hymenolepis diminuta (Cestoda: Cyclophyllidea).

The hydrolytic, reductive and oxidative enzyme systems involved in the phase I biotransformation of xenobiotic compounds have been investigated in Hymenolepis diminuta. Adult H. diminuta are able to carry out a range of hydrolytic and reductive reactions, but in common with other helminths oxidative detoxification reactions were absent (oxidative demethylation, aniline hydroxylation, nitrobenzene hydroxylation, biphenyl hydroxylation). These oxidative reactions were readily demonstrated in rat liver. Extracts of H. diminuta hydrolysed nitrophenylphosphates and inorganic pyrophosphate, but not arylsulphates, nor could epoxide hydratase activity be detected. N-Deacetylase activity was present. However, O-deacetylase activity could not be demonstrated, although butyrate and palmitate, but not benzoate, esters were hydrolysed. H. diminuta was capable of hydrolysing a range of alpha-and beta-glycosides, but not beta-glucuronides. Extracts of H. diminuta reduced azo-compounds, aldehydes and disulphides, but ketones and aromatic nitro-compounds were not reduced. The phase I detoxification systems of H. diminuta differ considerably from those of its rat host; the results also suggest that, within the cestodes, there may be considerable species variation in detoxification reactions.

Aniline Compounds↗
PubMed1986

Notifications of industrial chemical cyanosis poisoning in the United Kingdom 1961-80.

In 325 cases of industrial chemical cyanosis notified to Her Majesty's Factory Inspectorate for 1961-80 the incidence of poisonings showed considerable seasonal variation with substantially greater numbers occurring in the summer months. A correlation between the number of poisonings in any one year and the hotness of that summer was also shown. The vast majority of incidents occurred during the manufacture of chemicals or dyestuffs, and two particular workplaces were responsible for 70% of the cases. Poisoning by amino compounds appear to produce early cyanosis whereas poisoning by nitro compounds tended to produce delayed cyanosis. These latter compounds were also more likely to produce anaemia. Methaemoglobin was determined in 45% of cases with results ranging from less than a few per cent to over 50%. Despite concentrations of MetHb over 50%, several workers complained only of headache and their blue appearance.

Adolescent↗
PubMedDate not supplied

5-(4'-Substituted-2'-nitroanilino)-1,2,3-triazoles as new potential potassium channel activators. I.

By the hypothesised correlation with the large conductance Ca(++)-activated potassium channel (BK(Ca)) openers NS 004 and NS 1619, bearing a benzimidazolone ring, a series of new 5-(4'-substituted-2'-nitroanilino)-1,2,3-triazoles were synthesised and tested on in vitro isolated vascular preparation. The compounds were prepared starting from the appropriately substituted 2-nitro-phenylazides by 1,3-dipolar cycloaddition reaction to cyanoacetamide and following Dimroth isomerisation of the corresponding 1-arylsubstituted-5-amino-1,2,3-triazoles. The analogous 5-(4'-substituted-2'-amino-anilino)-1,2,3-triazoles were also prepared to assess the role of the nitro group in the pharmacophoric model. Almost all the nitro compounds showed a vasorelaxant activity on endothelium-denuded rat aortic rings with a potency comparable to that recorded for the reference compound NS 1619. Such a vasorelaxing activity was significantly reduced by the increase of the level of membrane depolarisation and by the potassium channel blocker 4-aminopyridine with a pharmacodynamic behaviour consistent with a potassium channel activation.

Animals↗
PubMedDate not supplied

Effect of nitro-substitution of environmental polycyclic aromatic hydrocarbons on activities of hepatic phase II enzymes in rats.

A series of environmentally occurring nitro-polycyclic aromatic hydrocarbons (nitro-PAHs) including those containing nitro-groups oriented coplanarly to the aromatic rings, such as 1- and 3-nitrobenzo[a]pyrene (1- and 3-NBAP), 6-nitrochrysene, and 1- and 4-nitropyrene, and those with a molecular orientation of the nitro-groups perpendicular to the aromatic moieties, such as 7-nitrobenz[a]anthracene and 6-nitrobenzo[a]pyrene (6-NBAP), were used to study the induction of certain rat hepatic phase II conjugating enzymes. Effects of these two different classes of nitro-PAHs on microsomal UDP-glucuronyltransferase (UDPGT), cytosolic glutathione S-transferases (GSTs) and sulfotransferases (STs) were investigated. After three consecutive daily i.p. injections, 1- and 3-NBAP and 6-nitrochrysene significantly increased the activities of UDPGT and GST, whereas their parent PAHs did not induce UDPGT (and GST activity was also unaltered by benzo[a]pyrene). UDPGT and GST activities were also significantly increased by 1-nitropyrene. In contrast, the sulfotransferases directed to 2-naphthol were not significantly induced by any PAH or nitro-PAH when assayed at either pH 5.5 or 7.5; however, the activities of aryl STs III and IV (pH 5.5) were significantly decreased following treatment with pyrene and two nitro-compounds, 6-NBAP and 7-nitrobenz[a]anthracene, in which the nitro-group is oriented perpendicular to the aromatic moiety. These results indicate that a coplanar orientation of the nitro-group of certain nitrated PAHs facilitates the induction of hepatic phase II enzymes by these compounds in rats, and the comparable induction patterns for P450IA1, UDPGT, and GST provide further evidence supporting the coordinate regulation (through the Ah receptor) of these phase I and phase II activities.

Animals↗
PubMed1996

Electron transfer reactions in RB90745, a bioreductive drug having both aromatic N-oxide and nitroarene moieties.

The bifunctional hypoxia-specific cytotoxin RB90745, has a nitroimidazole moiety attached to an imidazol[1,2-a]quinoxaline mono-N-oxide with a spacer/linking group. The reduction chemistry of the drug was studied by pulse radiolysis using the one electron reductant CO2.-. As N-oxides and nitro compounds react with CO2.- at diffusion controlled rates, initial reaction produced a mixture of the nitro radical (lambda max 410 nm) and the N-oxide radical (lambda max 550 nm) in a few microseconds. Subsequently an intramolecular electron transfer (IET) was observed (k = 1.0 +/- 0.25 x 10(3) s-1 at pH 5-9), from the N-oxide to the more electron-affinic nitro group. This was confirmed by the first order decay rate of the radical at 550 nm and formation at 410 nm, which was independent of both the concentration of the parent compound and the radicals. The rates of electron transfer and the decay kinetics of the nitro anion radicals were pH dependent and three different pKas could be estimated for the one electron reduced species: 5.6 (nitroimidazole group) and 4.3, and 7.6 (N-oxide function). The radicals react with oxygen with rate constants of 3.1 x 10(7) and 2.8 x 10(6) dm3 mol-1 s-1 observed at 575 nm and 410 nm respectively. Steady state radiolysis studies indicated four electron stoichiometry for the reduction of the compound.

Carbon Dioxide↗
PubMed1994

Inhibitory activity of chlorophyllin on the genotoxicity of carcinogens in Drosophila.

Antimutagenic activity of copper chlorophyllin against various carcinogenic mutagens was assayed with Drosophila genotoxicity tests, i.e., the wing spot test for detecting somatic cell mutations and the DNA repair test for detecting DNA damage. In these tests, Drosophila larvae were fed carcinogens together with chlorophyllin. Polycyclic aromatic compounds, including heterocyclic amines, polycyclic aromatic hydrocarbons, aromatic amines and aromatic nitro compounds, were subject to inhibition, with a few exceptions. The results support the view that chlorophyllin traps carcinogens by forming complexes, thereby inhibiting the absorption of these compounds from the digestive tract. Consistent with this mechanism, Sepharose-supported chlorophyllin in the feed inhibited the Trp-P-2-induced wing spot formation, while Sepharose itself was ineffective.

Animals↗
PubMed1992

Inhibitors of protein kinase C. 1. 2,3-Bisarylmaleimides.

The design and synthesis of a series of novel inhibitors of protein kinase C (PKC) is described. These 2,3-bisarylmaleimides were derived from the structural lead provided by the indolocarbazoles, staurosporine and K252a. Optimum activity required the imide NH, both carbonyl groups, and the olefinic bond of the maleimide ring. 2,3-Bisindolylmaleimides were the most active, and the potency of these was improved by a chloro substituent at the 5-position of one indole ring (compound 28, IC50 0.11 microM). In a series of (phenylindolyl)maleimides, nitro compound 74 was most active (IC50 0.67 microM). Naphthalene 19 and benzothiophene 21 showed greater than 100-fold selectivity for inhibition of PKC over the closely related cAMP-dependent protein kinase (PKA).

Animals↗
PubMed1982

Studies on the induction of sex-linked recessive lethal mutations in Drosophila melanogaster by nitroheterocyclic compounds.

24 nitroheterocyclic compounds were investigated for their capacity to induce sex-linked recessive lethals in Drosophila, by the adult feeding technique, and in some cases injection or larval-feeding methods. Out of 9 5-nitroimidazoles, ZK 26.173 and ZK 25.095 (moxnidazole) were clearly active whereas nimorazole and ronidazole were marginally mutagenic. Out of 10 5-nitrofurans, nitrovin, furazolidone and furaltadone were unambiguously mutagenic, whereas nitrofurantoin was a borderline case. Nitrofurans were active at lower molar concentrations than nitroimidazoles. Out of a group of 5 related nitro compounds (2 nitrothiophenes, picrolonic acid, niridazole and 4-NQO), only 4-NQO was clearly mutagenic, when fed to larvae. Experiments with germ-free flies showed that, for ZK 26.173 and furazolidone, the gut flora of Drosophila do not play a role in the activation of the compounds to mutagenic metabolites. Furazolidone, 4-NAO, ZK 26.173, ZK 25.095 and furaltadone were tested in mal and cin strains, both of which lack xanthine dehydrogenase and aldehyde oxidase. The latter enzyme and xanthine oxidase are known to carry out nitro reduction in mammalian tissues. For ZK 26.173, the mutation frequencies were drastically reduced in the enzyme-deficient strains, indicating the involvement of one of these enzymes in the activation of this substance.

Animals↗
PubMed2006

Development of hypoxia selective cytotoxins for cancer treatment: an update.

Increased attention has centered on exploiting hypoxia in tumors for targeting the design of selective antitumor agents. This review presents an update of the principal families of compounds under study and in clinical trials, such as N-oxide derivatives, nitro compounds and quinone derivatives. Especially promising for bioreductive activation is the reduction of some moieties able to trigger a mechanism that releases cytotoxic antitumor drugs. The most remarkable redox-activated triggers are presented, N-oxide, nitro, azido, quinone, metal ions, 1,2-benzisoxazolyl and sulfoxide moieties.

Animals↗
PubMed1995

Evaluation studies on the in vitro rat hepatocyte micronucleus assay.

Based on a previous study with 8 chemicals (Müller et al., 1993) the applicability of the in vitro rat hepatocyte micronucleus assay was evaluated by testing a further 21 compounds of different chemical classes. The obtained results are in good agreement with the known genotoxic profiles of about 90% of the in total tested compounds. Several known mutagens and carcinogens, i.e., alkylating agents, aromatic amines, nitrosamines, nitro compounds, cross-linking agents, and pyrrolizidine alkaloids gave clear positive results in this assay, whereas all of the tested non-carcinogens were negative. The hepatocyte micronucleus assay was shown to distinguish between carcinogenic/non-carcinogenic isomers, such as 2- and 4-acetylaminofluorene (AAF) and 2- and 1-nitropropane (NP). Furthermore, the non-genotoxic nature of several hepatocarcinogens, i.e., the peroxisome proliferating agents fenofibrate, nafenopin, Wy-14,643, diethyl(hexyl)phthalate (DEHP), and the sedative phenobarbital, could be confirmed in this assay. The hepatocarcinogen coumarin exerted mitogenic but no mutagenic properties in the rat hepatocyte micronucleus assay. This compound may act as a liver tumor promoter. Benzo[a]pyrene (B[a]P) and 7,12-dimethylbenzanthacene (DMBA), both belonging to the group of known carcinogenic and mutagenic polycyclic aromatic hydrocarbons, failed to induce micronucleus formation in rat hepatocytes. The high susceptibility of in vitro proliferating hepatocytes to mitotic inhibition, exerted by the strong cytotoxic actions of these compounds, seems to be responsible for these negative results. A strongly reduced mitotic activity can prevent the formation of micronuclei, even when clastogenic effects may have occurred. In the present stage, the in vitro rat hepatocyte micronucleus assay cannot be recommended for screening genotoxicity testing. It should rather be used for special purposes, e.g., when liver-specific mutagenic effects are expected.

Animals↗
PubMed1990

Effect of lindane on nitroreductase and dechlorinase enzyme activity in the gastrointestinal tract.

A previously reported acceleration of parathion metabolism in the gastrointestinal (GI) tract of lindane-pretreated rats could have been due to either a prolonged residence time of parathion or increased GI nitroreductase activity or both. Thus to determine the effect on GI nitroreductase and dechlorinase activity, 20 mg/kg lindane or 535 mg/kg neomycin were administered daily, by gavage, to weanling F-344 rats. Enzyme activity in the small intestine and cecum were assayed after 2 weeks and 5 weeks of treatment. Neomycin treatment inhibited the activity of both enzymes in the cecum but had no significant effect on enzyme activity in the small intestine, suggesting the presence of mucosal nitroreductase and dechlorinase in the small intestine. In contrast, lindane, which had no effect on enzyme activity in the cecum, significantly increased nitroreductase activity in the small intestine after treatment for 5 weeks. This increased nitroreductase may account for the previously reported lindane-parathion interaction and could influence the metabolism, toxicity, and risk assessment of many other environmental nitro-compounds that become toxic, mutagenic or carcinogenic upon reduction of their nitro-groups.

Animals↗
PubMed1987

Evaluation of various types of new hypoxic cell sensitizers using the EMT6 single cell-spheroid-solid tumour system.

Eleven new hypoxic cell sensitizers representative of those developed in Japan between 1980 and 1985 were evaluated in vitro and in vivo in comparison with misonidazole (MISO), SR-2508, Ro 03-8799, and ANT (2-amino-5-nitrothiazole). The new compounds included 2-nitroimidazole nucleoside analogues, nitrotriazoles and other nitroaromatics, non-nitro compounds, and electron-affinic compounds that readily intercalate DNA. The sensitizing activity in the EMT6 single cells correlated not only with the reduction potential but, for some compounds, also with the reactivity with non-protein sulphydryls. The sensitizers were also tested using the EMT6 spheroids and solid tumours. The patterns of changes in sensitizer enhancement ratios (SERs) for single cells, spheroids, and solid tumours were classified into two types: (1) SERs for the three testing systems were similar; and (2) SERs decreased in the order of: single cells, spheroids, and solid tumours. Only nitroimidazole and nitrotriazole derivatives belonged to the former type. RK-28 and RK-29, 2-nitroimidazoles with sugar analogue components, had in vivo effects almost equal to those of MISO. Also 3- and 4-nitrotriazole derivatives had definite in vivo effects.

Animals↗