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Biomedical subjects

M Wiessler

Publications and source records attributed to M Wiessler.

At least 127 records · Page 7Linked to original sources
PubMed1982

In vitro formation of methyldiethyldithiocarbamate after the reaction of nitrosoacetoxymethylmethylamine or methylnitrosourea with disulfiram.

Analysis by scintillation measurement, mass spectrometry and h.p.l.c. showed that diethyldithiocarbamic acid (DDTC), the main metabolite of disulfiram (DSF), forms methyldithiocarbamate (MeDDTC) when incubated with [14C]nitrosoacetoxymethylmethylamine ([14C]NAMM) or [14C]methylnitrosourea ([14C]MNU) in different media (bacteria, esterases, rat liver 9000 x g supernatant fraction and microsomes). When DSF instead of DDTC was used, MeDDTC was formed only when soluble enzymes were present which are required to split DSF into two DDTC moieties. No physiological methylation of DDTC takes place as was shown by experiments with [3H]MNU. [14C]Methanol, formed by the decay of [14C]NAMM and [14C]MNU was shown to have no alkylating properties.

Animals↗
PubMed1982

Mutagenicity and synthesis of alpha-substituted N-nitrosamines: derivatives with dithiocarbamic acid.

Disulfiram (DSF) can considerably alter the organotropy of chemical carcinogens. For N-nitrosodimethylamine and for N-nitrosodiethylamine the organotropy is shifted from the liver to the nasal cavity or the oesophagus, respectively. Whereas the influence of DSF or its metabolites on enzyme systems has been studied, little is known about its interaction with the carcinogens at a molecular level. Therefore, postulated reaction products of a series of alpha-hydroxylated N-nitroso-dialkylamines and dithiocarbamate were synthesized and tested for mutagenicity in Salmonella typhimurium TA 1535. The results show that the compounds conjugated at a primary alpha-C-atom are not mutagenic, whereas those conjugated at a secondary alpha-C-atom are active. The primary N-nitroso-dithiocarbamates represent unique examples of inactivated dialkyl-nitrosamine derivatives. In addition, their formation in vitro was indirectly demonstrated. The possible role these inactivated compounds may play during the DSF-modulation of carcinogenesis will be discussed.

Chemical Phenomena↗
PubMed1982

Mechanism of esophageal tumor induction in rats by N-nitrosomethylbenzylamine and its ring-methylated analog N-nitrosomethyl(4-methylbenzyl)amine.

The metabolism of the esophageal carcinogen N-nitrosomethylbenzylamine (MBN) and its ring-methylated analog N-nitrosomethyl(4-methylbenzyl)amine (4-MeMBN) was investigated in male Wistar rats. When given in the drinking water, both compounds have been shown to induce a high incidence of esophageal carcinomas but, after systemic administration of equimolar doses, 4-MeMBN is considerably less toxic and carcinogenic than is MBN. Following a single i.v. injection, 4-MeMBN disappeared from serum faster than did MBN. After 5 hr, neither compound was detectable in serum. Within 12 hr after a single i.v. injection (0.017 mmol/kg) of [methyl-14C]-MBN, 49% of the radioactivity was exhaled as 14CO2, and less than 5% was in the urine, compared with only 13% as 14CO2 and 65% in the urine after an equimolar dose of 4-Me[methyl-14C]MBN. The urinary metabolite of 4-MeMBN was identified as its benzoic acid derivative. Methylation of DNA purines 4 hr after a single i.v. injection (0.017 mmol/kg) of [methyl-14C]MBN was highest in the esophagus (344 mumol 7-methylguanine per mol guanine), followed by liver, lung, and forestomach. Considerably less DNA methylation was produced by an equimolar dose of 4-MeMBN, with highest values in liver, followed by esophagus (22 mumol 7-methylguanine per mol guanine) and lung. However, s.c. injections of equitoxic doses of MBN (18 mg/kg) and 4-MeMBN (394 mg/kg) produced similar amounts of 7-methylguanine in esophageal nucleic acids. These data indicate that the lower toxicity and carcinogenicity of 4-MeMBN after systemic administration are due to the rapid formation (mainly in the liver) and excretion via the urine of its benzoic acid derivative. The strong carcinogenic effect of orally administered 4-MeMBN can be explained by direct uptake from the drinking water into the esophageal mucosa. Following a single i.v. injection (0.017 mmol/kg) of [methylene-14C]MBN and 4-Me[methylene-14C]MBN, no benzylated bases were detectable in rat tissues. This indicates that the bioactivation of these compounds is initiated predominantly by hydroxylation at the methylene bridge leading to a methylating rather than a benzylating intermediate as the ultimate carcinogen.

Animals↗
PubMed1982

[Enhancement of the toxic effect of endoxan after pretreatment with brain homogenates in rats].

Following monotherapy with cyclophosphamide rat leukemia cells (L 5222) survive only in the CNS, as has been described previously. Here we report on investigations performed to elucidate the influence of rat brain tissue on cyclophosphamide activity. It was found that the toxicity of cyclophosphamide is enhanced 5 fold after incubation with freshly prepared brain homogenate. In parallel experiments it was also found that cyclophosphamide preincubated with brain homogenates is therapeutically less effective toward L 5222 cells than cyclophosphamide alone. The incubation of cyclophosphamide with liver homogenate did not result in the same enhancement of cyclophosphamide toxicity nor in the decrease of therapeutic effects. The different influence of the two tissues on cyclophosphamide suggests two different metabolic mechanisms.

Animals↗
PubMed1981

[Selective induction of tumors in Wistar rats with loop colostomy after administration of methyl-(acetoxymethyl)-nitrosamine (MAOMN) (author's transl)].

A single dose of 7 mg/kg methyl-(acetoxymethyl)-nitrosamine in Wistar rats with double loop colostomy induced adenomas, papillomas, and adenocarcinomas at the site of colostomy in 83% of the treated animals. The mean induction time was 320 days. The pronounced local effect as well as the high tumor yield are discussed in regard to the evident high epithelial sensitivity at the colostomy site.

Adenocarcinoma↗
PubMed1981

N-Nitroso-N-methylurea elicits mammary cancer in resistant and sensitive rat strains.

A single intravenous (i.v.) injection of the water-soluble mammary carcinogen N-nitroso-N-methylurea (NMU; 35 mg/kg of body weight) elicited cancer of the breast in young female rats of two strains in the following incidence: Long-Evans strain, 4%; Sprague-Dawley strain, 70%. In sisters of these rats, a set of 5 i.v. injections of NMU (35 mg/kg at biweekly intervals) evoked mammary carcinoma as follows: Long-Evans strain, 76%; Sprague-Dawley strain, 100%. In its effectiveness in evoking mammary cancer in Sprague-Dawley rats, the lipid-soluble mammary carcinogen 7,8,12-trimethylbenz[a]anthracene exceeded NMU in rapidity of development of cancer and in tumor yield.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1981

Investigations on the mutagenicity of primary and secondary alpha-acetoxynitrosamines with Salmonella typhimurium: activation and deactivation of structurally related compounds by S-9.

alpha-Acetoxynitrosamines may serve as model compounds to study mechanisms of action of N-nitrosamines. They are readily cleaved through hydrolysis, or by esterases, to yield the same ultimate, reactive species presumably also arising after metabolic activation of N-nitrosamines, Structure-activity investigations on alpha-acetoxynitrosamines promise to aid in elucidating mechanisms involved during the activation of N-nitrosamines. A series of alpha-acetoxyalkynitrosamines was therefore tested for mutagenicity with Salmonella typhimurium TA 1535. The compounds were readily cleaved, by hydrolysis, to mutagenic intermediates. When comparing compounds according to their proposed alkylating properties, unstable secondary alpha-acetates were considerably more mutagenic than the corresponding relatively stable primary alpha-acetates. Addition of S-9 mix caused both activation as well as deactivation in an unexpected structure-related pattern. This was so because an exactly opposite influence of S-9 components on the mutagenicity was observed for each pair of primary and secondary compounds containing the same alkylating spices. Furthermore, pairs of compounds with both methylating and ethylating properties were differently influenced by S-9 addition than those with propylating or butylating effects. This clearly demonstrates how different chemical properties of intermediate forms may strongly influence the biological activity of otherwise quite similar compounds.

Aldehydes↗
PubMed1981

DNA methylation by N-nitrosomethylbenzylamine in target and non-target tissues of NMRI mice.

Adult female NMRI mice received a single i.p injection of N-nitroso(methyl-14C)methylbenzylamine (2.5 mg/kg body weight). Multiple weekly applications of such a dose, by this route, have previously been shown to induce lung adenomas and forestomach carcinomas in all experimental animals. After a survival time of 6 h, DNA was isolated from various tissues and analysed for methylated purines by separation of the acid hydrolysate on Sephasorb columns. Highest concentrations of 7-methylguanine and 06-methylguanine were present in hepatic DNA, followed by lung and forestomach. DNA methylation in the oesophagus was only 21% less than in forestomach. Since both tissues develop a high tumour incidence after oral administration of N-nitrosomethylbenzylamine (MBN), this observation suggests that despite their anatomical similarities the level of DNA modification required for malignant transformation differs considerably in these tissue. In the remaining organs, DNA alkylation was either considerably less (colon, glandular stomach, kidney) or not detectable (small intestine, spleen). These date indicate that following i.p. injection in mice, MBN is preferentially metabolised in a non-target organ (liver). Among the various other tissues investigated, highest levels of initial DNA methylation were present in forestomach and lung, i.e., the principal target organs of MBN for this route of application.

Animals↗
PubMed1981

[Carcinogenicity in BD-IX rats of 7 homologues of N-nitroso-N-n-alkylureas in different stages of postnatal development (author's transl)].

Carcinogenic activity of seven N-Nitroso-N-n-alkylureas was investigated in 679 BD-IX rates in different stages of postnatal development after administration of a single s.c. dose of the test compound. The results are compared with a former investigation using N-nitroso-N-ethylurea. The nitrosoureas in a series from the methyl- to the n-octyl derivative showed a pronounced neurotropic carcinogenic effect on treatment during the first ten days after birth. Malignant neurinomas of the heart, subcutaneous sarcomas at the site of injection and malignant tumors in other organs varied distinctly, depending mainly on the time of treatment. All observed effects were similar in all 7 alkylnitrosoureas investigated.

Animals↗
PubMed1980

Effect of disulfiram on the alkylation of rat liver DNA by nitrosodiethylamine.

The extent of ethylation of guanine in 7 N and O 6 position in rat liver DNA was studied after chronic feeding with unlabelled nitrosodiethylamine followed by a single application of the 14C labelled drug. Disulfiram inhibits the alkylation of rat liver DNA. It was also shown that a discontinuous dosage of disulfiram protects against the alkylating effect of 14C nitrosodiethylamine only for a distinct period of time.

Alkylation↗
PubMed1980

Preferential methylation of target organ DNA by the oesophageal carcinogen N-nitrosomethylbenzylamine.

Male Wistar rats received a single i.v. injection of the oesophageal carcinogen N-nitroso[methyl-14C]-methylbenzylnitrosamine (2.5 mg/kg body weight). Rapid distribution of the carcinogen occurred, with highest initial concentrations in liver and kidney. Within 10 min after the injection, 14C-labelled metabolites accounted for 50% of the total radioactivity present in the oesophagus, for approximately 25% in liver and forestomach, and for less than 20% in all other organs investigated. Decay of the carcinogen in rat serum followed first-order kinetics with a half-life of 35 min. Of the total radioactivity administered, 49% was exhaled as 14CO2 within 10 h and an additional 5-10% was excreted via urine and faeces. Four hours after a single i.v. injection of N-nitroso-[methyl-14C]benzylnitrosamine methylation of purine bases in DNA was most extensive in the oesophagus, followed by liver, lung and forestomach DNA. In the remaining tissues, DNA methylation was either considerably less (kidney, glandular stomach, spleen) or not at all detectable (ileum, colon, brain). At this time the concentration of the promutagenic base O6-methylguanine in oesophageal DNA was six times higher than in lung and nine times higher than in hepatic DNA. These data suggest that in the rat the selective induction of oesophageal tumours by N-nitrosomethylbenzylamine and related asymmetrical nitrosamines is mediated by a preferential bioactivation of the carcinogen in the target organ.

Animals↗
PubMed1979

Carcinogenicity of di(N-nitroso)-perhydropyrimidine (DNPP) after intraperitoneal application to rats.

Male Sprague-Dawley rats received 30 mg/kg body wt. (group I) or 15 mg/kg (group II) di(N-nitroso)-perhydropyrimidine (DNPP) by the intraperitoneal route once a week for life. The DNPP treatment significantly reduced the life expectancy in both groups. DNPP induced tumors of the esophagus (27% incidence in group I, 33% in group II) and possibly also of the liver (4% incidence in group I, 8% in group II).

Animals↗
PubMed1978

Carcinogenicity of acetoxymethyl-methyl-nitrosamine after subcutaneous, intravenous and intrarectal applications in rats.

In comparison to the known carcinogenic properties of Acetoxymethyl-Methyl-Nitrosamine (AMMN) after oral or intraperitoneal application the dimethylnitrosamine derivative was tested by subcutaneous, intravenous and intrarectal route in male Sprague-Dawley or Wistar rats. AMMN proved to be primarily a locally acting carcinogen. However, a second mode of action is indicated by systemic carcinogenic properties found after i.v. and s.c. applications. The lung and heart, and to a less extent the kidney and earduct were found as target organs of distant carcinogenic response.

Adenocarcinoma↗
PubMed1978

[On the carcinogenetic action of N-nitroso compounds. 7th communication: methyl-, trideuteromethyl-, ethyl-, n-propyl-, n-butyl-, acetoxymethyl-nitrosamine, and methyl-butyroxymethyl-nitrosamine (author's transl)].

The homologons alkyl-acetoxymethyl-nitrosamines were tested for carcinogenicity in SD rats. All compounds were found to be carcinogenic and induced within the same time carcinomas of the forestomach. The total doses necessary for induction of tumors are related to the length of the alkyl chain and hence to the watersolubility. These results are discussed.

Alkylation↗