[Reactions of aromatic epoxides with sodium diethyldithiocarbamate].
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Carcinogens↗
Biomedical subjects
M Wiessler
Publications and source records attributed to M Wiessler.
Effects of disulfiram on the metabolism of nitrosodiethylamine during liver carcinogenesis.
We have studied the effects of disulfiram (DSF) administration on the metabolism of nitrosodiethylamine (NDEA) in rats during acute and chronic administration. DSF was found to have the following effects during the course of carcinogenesis: (a) marked decrease in the exhalation of 14CO2 derived from 14C-NDEA; (b) reduction of the total levels of DNA and RNA ethylation in the liver. In acute experiments DSF caused an increase in the amount of NDEA in organs and in the urine. We suggest that inhibition of NDEA biotransformation and the subsequent decrease in the total level of DNA ethylation may prevent specific chemical interactions relevant to carcinogenesis.
Alkylation↗
Metabolism of, and DNA methylation by, N-nitrosomethylbenzylamine in chicken.
The metabolism of 14C-nitrosomethylbenzylamine (NMBA) was studied in chicken. Following a single IV dose of 2 mg/kg, 14C-NMBA was cleared from the blood with a half-life of 3.8 min. At 10 min after administration 14C-NMBA was totally metabolized in the liver, whereas in the esophagus no measurable metabolic degradation had taken place. Maximum exhalation of radioactive CO2 occurred 1 h after IV administration of NMBA, and 11% of the total radioactivity had been exhaled as CO2 by 8 h. These results are compared with data on the metabolism of NMBA in the rat. The analysis of methylated bases in the DNA of different organs of chicken revealed that 7-me guanine was formed in all organs. The highest amount of 0(6)-me guanine was found in liver DNA, followed by kidney DNA. O6-me guanine was not detectable in any other organ. The O6-/7-me guanine ratio in DNA was calculated to be 0.05 and 0.02 for liver and 0.01 for kidneys.
Animals↗
Mutagenicity of the two main components of commercially available carcinogenic aristolochic acid in Salmonella typhimurium.
One of the 2 main components of the commercially available carcinogenic aristolochic acid (AA) was isolated, the other was enriched. Three different aristolochic acid samples (AAI 99% pure; AAI 65% + AAII 35%; AAI 32% + AAII 68%) were assayed for mutagenic activity in Salmonella typhimurium TA1537, TA100 and TA100 NR with and without the addition of a metabolizing mixture. The two main components (AAI and AAII) were direct mutagens in Salmonella strains TA1537 and TA100 with almost equal mutagenic potency. In TA100 NR the aristolochic acid samples showed no or only a very low level of biological activity, indicating the necessity of nitroreduction for the bioactivation of the samples. These findings suggest that both AAI as well as AAII can be used in further studies to elucidate the metabolism of aristolochic acid.
Aristolochic Acids↗
Stability of various alpha-esters of 1-(N-methyl-N-nitrosamino)-methanol in vitro and in vivo.
The hydrolytic activities of various rat tissue homogenates on the substrates 1-(N-methyl-N-nitrosamino)-methylacetate (NNMA), 1-(N-methyl-N-nitrosamino)-methylbutyrate (NNMB), 1-(N-methyl-N-nitrosamino)-methylbenzoate and 1-(N-methyl-N-nitrosamino)-methylpivaloate (NNMP) were investigated+. The hydrolytic enzymes of liver and serum showed similar activities toward all investigated compounds, while those of kidney, lung, heart, stomach and forestomach hydrolyzed the various esters differently. Differences in the in vivo elimination of NNMA, NNMB and NNMP from blood could not be found. After 20 s only 10% of the initial concentrations still occurred in blood after i.v. application.
Animals↗
Chemical interaction of disulfiram with nitrosodimethylamine after in vitro enzymatic activation.
The in vitro reaction between disulfiram (DSF) and N-nitroso[14C]dimethylamine [( 14C]NDMA) was studied. Incubations of DSF with [14C]NDMA were carried out in the presence of rat liver microsomes, control 9000 g (S9) supernatant fraction and phenobarbital-induced S9 fraction. H.p.l.c. analysis and liquid scintillation measurement provided evidence for the formation of methyldiethyldithiocarbamate (MeDDTC) as a product of the reaction between diethyldithiocarbamate (DDTC), the main active metabolite of DSF and the 'methyl-cation' released by NDMA after enzymatic activation. The amount of MeDDTC found here was consistent with the rate of oxidation of NDMA to formaldehyde. Scintillation counting confirmed that other radioactive peaks, not due to MeDDTC, were unrelated to the methylation of L-cysteine by [14C]NDMA.
Animals↗
Mutagenic properties of N-cyclopropyl and N-allyl-N-nitroso compounds. Studies on the nature of alkylating species.
A series of directly acting N-nitroso compounds, N-nitroso-N-allyl urea 6, N-nitroso-N-cyclopropyl urea 7, N-nitroso-acetoxymethyl-allylamine 8, N-nitroso-acetoxymethyl- cyclopropylamine 9, N-nitroso(1- acetoxyethyl )allylamine 10 and N-nitroso(1- acetoxyethyl ) cyclopropylamine 11, which may hydrolize to liberate either cyclopropylating or allylating electrophiles, were synthesized and comparatively investigated for mutagenicity in Salmonella typhimurium TA 1535. Hydrolysis rates in aqueous buffered solution do not differ significantly in the allyl- and cyclopropyl series. Analysis of the hydrolysate of all compounds revealed only the presence of allylalcohol and not cyclopropanol . In contrast to the expected equal potencies, due to chemical rearrangement of the alkylating species from cyclopropylcation to allylcation , the results showed that the cyclopropylating analogs were much more effective mutagens than were the allylating compounds. We conclude that for the cyclopropylating compounds the diazonium ion intermediate - and not the free cation - is the alkylating species, during mutagenesis.
Alkylation↗
Formaldehyde as a possible mutagenic metabolite of N-nitrodimethylamine and of other agents which are suggested to yield non-alkylating species in vitro.
N-Nitramines are biologically active compounds of environmental significance. In this study the suggested bioactivation of N- nitrodimethylamine via oxidation at the methyl-group was confirmed, as was indicated by formaldehyde liberation. N- Nitrodimethylamine and formaldehyde as well as the suggested metabolites, N- nitrohydroxymethylmethylamine and N- nitromethylamine were tested for mutagenicity in histidine auxotrophic Salmonella typhimurium strains in a variety of conditions. N- Nitrodimethylamine was mutagenic only in S. typhimurium TA 100 after pre-incubation with bacteria and a complete metabolizing mixture containing 9000 g liver supernatant and NADPH-regenerating cofactors. N- Nitrohydroxymethylmethylamine and formaldehyde were approximately equally mutagenic without the metabolizing mixture in TA 100 and TA 98, but not in TA 1535. The addition of the 9000 g supernatant of homogenized liver increased the yield of his+ revertants induced by the two compounds. N- Nitromethylamine was not mutagenic with or without the metabolic activation system. The results suggest that formaldehyde is possibly the mutagenically active intermediate formed during in vitro metabolism of N- nitrodimethylamine . Furthermore the participation of formaldehyde as the mutagenic intermediate of other non-alkylating N-nitro and N-nitroso compounds is demonstrated.
Animals↗
Biochemical and biological properties of prospective N-nitrodialkylamine metabolites and their derivatives.
The metabolic conversion of N-nitrodimethylamine and of N-nitrosodimethylamine was compared in vitro. The biochemical properties of the two compounds were nearly identical; however, the biological activities (carcinogenicity, mutagenicity and toxicity) of the nitramine are many times less potent. N-Nitrodimethylamine was found to be mutagenic to Salmonella typhimurium TA100 when applied at above 200 mumol/plate with metabolic activation. Its suggested metabolite, N-nitromethylamine, was not mutagenic, N-Nitromethylhydroxymethylamine, N-nitromethylacetoxymethylamine and formaldehyde were mutagenic only to S. typhimurium TA100 at low concentrations and toxic above 2 mumol/ plate. The evidence suggests that formaldehyde is the intermediate responsible for the mutagenicity of the nitramine derivatives and of the parent compound, N-nitrodimethylamine.
Animals↗
Conjugates of N-nitroso-tert-butylmethylamine in urine.
The glucuronide (alpha-anomer) and the mercapturic acid of N-nitroso-tert-butylhydroxymethylamine were synthesized. An analytical procedure was developed using high-performance liquid chromatography, which allowed the detection of both conjugates in a single run. A new and efficient synthesis of N-nitroso-tert-butyl-14C-methylamine was developed, based on 14C-formaldehyde. After subcutaneous administration of 23 mg/kg to a rat, the nitrosamine was metabolized to a high degree, and two conjugates were excreted in the urine.
Animals↗
Influence of disulfiram on the metabolism of N-nitrosodiethylamine.
The effect of disulfiram (DSF) on the biological activity of N-nitrosodiethylamine (NDEA) was studied in vivo. We determined its influence on NDEA level, on NDEA-induced DNA damage and on DNA alkylation in the liver and oesophagus. It was found that 500 mg/kg DSF given 2 h before a single dose of 28 mg/kg NDEA inhibited the metabolism and increased the concentrations of NDEA in the organs, especially in the oesophagus. Consequently, DNA damage and the alkylation of DNA are inhibited in both the liver and the oesophagus.
Alkylation↗
Induction of oral mucosal tumors in hamsters and rats treated with methyl(acetoxymethyl)nitrosamine.
An oral tumor model has been developed in inbred Syrian golden hamsters by continuous applications every 2 weeks of methyl(acetoxymethyl)nitrosamine [(DMN-OAC) CAS: 56856-83-8; methylnitrosaminomethyl ester acetic acid] at 2 mg/kg body weight alone or by a single application of DMN-OAC followed by continuous twice weekly applications of 12-O-tetradecanoylphorbol 13-acetate (TPA) (1 microgram/animal). Similar studies were done in the W rat buccal mucosa. In the hamsters treated continuously with DMN-OAC, 100% of the tumors were observed in the cheek pouch; none were observed at other sites. In contrast, in the rats treated similarly, only a 67% tumor incidence was observed, of which only 42% were oral tumors. A promoter effect of TPA was observed in hamster cheek pouch tumors induced by DMN-OAC, whereas rat oral mucosa did not respond to TPA treatment.
Animals↗
DNA modification and repair in vivo: towards a biochemical basis of organ-specific carcinogenesis by methylating agents.
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Alkylating Agents↗
Glutathione inhibits the alkylation of liver dna by n-nitrosodimethylamine.
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Alkylation↗
Interference of acetoxyalkyl-nitrosamines with limb bud differentiation in organ culture.
alpha-acetoxynitrosamines have been used as model compounds to study biological activity of N-nitrosamines. After hydrolytic cleavage they yield an "active intermediate" (the hydroxynitrosamine) which presumably also arises as metabolite of N-nitrosamines. We tested eight N-nitrosamines mono-substituted at the alpha-carbon with an acetoxy group for their teratogenic potential in a mouse limb bud culture system. The following results were obtained: 1. The methyl compound (MOAc-MNA) - a derivative of dimethynitrosamine - proved to be the strongest teratogen in this group of chemicals. 2. The tertiary-butyl derivative - releasing a carbonium ion of low chemical reactivity - possessed the lowest activity in our test system. 3. The primary alpha-acetates with unbranched side chains (POAc-MNA or BOAc-MNA) were more active than the corresponding derivatives with branched side chains. 4. The secondary alpha-acetate (EOAc-ENA) was clearly less active than the primary alpha-acetate (EOAc-MNA). 5. A teratogenic potential could also be demonstrated in the organ culture system with the cyclic derivative: N-nitroso-alpha-acetoxy-pyrrolidine (NAPYR). 6. With the use of limb buds from 12-day-old mouse embryos the explants showed the highest susceptibility to the teratogens on the first day of culture. No effect could be produced if the substances were added to the culture medium at the third day of culture or later. 7. When initiating the culture with limb buds from 11-day-old mouse embryos the concentrations needed to induce typical effects were lower than those tested with 12-day-old explants. 8. Typical and pronounced impairment with morphogenetic differentiation could be induced by MOAc-MNA if the substance was present in the medium for less than 60 min - the shortest period tested was 15 min. 9. A different abnormality pattern could be induced with the various substances tested. This may partly be explained by a quite different stability of the compounds in the test system. 10. N-Nitrosamines must be expected to be highly teratogenic if they can be "activated" in embryonic tissues. Such an activation into potent electrophilic agents does not occur in rodents under normal conditions. It will be interesting to study if such activity can be "induced" in embryonic tissues of rodents or if it is already present in embryonic tissues of primates.
Animals↗
Alkyldiazohydroxides are stable intermediates in the degradation of n-nitroso-(acetoxyalkyl)-alkylamines in rat serum.
The decomposition in rat serum of N-nitroso-(acetoxyalkyl)-alkylamines 14C-labelled in different positions, was monitored. The determination of radioactivity of individual fractions permitted the determination of the rate-limiting step in their degradation scheme. From the primary nitroso-acetoxy-compounds the alkyldiazohydroxide shows the highest stability. Furthermore, it was shown that the alpha-hydroxy compounds of the secondary nitrosamines seem to be more stable than the hydroxylated primary ones.
Animals↗
Biological activity of benzylating N-nitroso compounds. Models of activated N-nitrosomethylbenzylamine.
Unsymmetrically substituted N-nitrosomethylbenzylamine is an oesophageal carcinogen with potential methylating and benzylating properties. Whereas the methylating activity of the compound has been investigated, little is known of its potential benzylating properties. In order to elucidate the biological consequences of benzylation, related model compounds which are presumed benzylating agents were synthesized and tested for mutagenicity. N-nitrosobenzylurea and its structural analogue N-nitroso-p-methylbenzylurea were direct acting mutagens in Salmonella typhimurium TA 98. Activity was also present in TA 1535, but it was less pronounced. N-nitroso-alpha-acetoxybenzyl-benzylamine was equally mutagenic in S. typhimurium TA and TA 1535. N-nitroso-acetoxymethyl-benzylamine and N-nitrosoacetoxy-methyl-p-methylbenzylamine are two model compounds which may decompose by hydrolysis or through esterases to yield intermediates also though to arise after alpha-C hydroxylation of the methyl group of the parent nitrosamines. These compounds needed additional activation by enzymes present in the post-mitochondrial supernatant of rat liver. They were distinctly mutagenic in TA 98. Furthermore, all compounds also caused the induction of phage lambda in a qualitative assay with Escherichia coli Br 513. Thus, benzylation of DNA clearly results in a biological consequence. These findings are supportive of the theory that if enzymic attack occurs on the methyl group of N-nitrosomethylbenzylamine, benzylation may also contribute to the overall biological activity of the compound.
Animals↗
Effects of disulfiram on mixed function oxidase system and trace element concentration in the liver of rats.
Disulfiram (DSF), an inhibitor of chemically induced carcinogenesis, and its metabolite diethyldithiocarbamate (DDTC) have been investigated for their influence on trace element distribution and on certain enzymes of the drug metabolizing system in the livers of phenobarbital (PB) treated rats. Both substances diminished the PB induced enzyme response in liver microsomes, DDTC being more effective (-85%) than DSF (-60%). The copper, cobalt and zinc content of the livers of DSF treated animals were increased by factors of 6, 3 and 1.5 respectively as compared to controls, while DDTC treatment had no influence on liver trace element content. A correlation between enzyme inhibition and enhanced trace element uptake of the liver after DSF administration could not be observed. The change of trace element transport into the liver during DSF treatment is discussed.
Animals↗