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PubMed1976

[Demonstration of the action of methyl benzimidazole 2 yl carbamate (MCB) and methyl(5(2 thienyl carbonyl) 1 H benzimidazole 2 yl carbamate) (R17934) on the nucleus of Physarum polycephalum (Myxomycetes)].

The toxicity of these compounds was determined in the amoebae and plasmodia. An electron microscopic study shows an increase in nuclear size which is in agreement with the increase of the total amount of DNA. Microtubules are present but they are not organized in a normal mitotic apparatus. Some other nuclear abnormalities are described.

Benzimidazoles↗
PubMed1987

NTP Toxicology and Carcinogenesis Studies of Methyl Carbamate (CAS No. 598-55-0) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Methyl carbamate is used as a chemical intermediate by the textile industry for the manufacture of dimethylol methyl carbamate-based resins that are applied on polyester/cotton blend fabrics as durable-press finishes. Experimental Design: Toxicology and carcinogenesis studies of methylyl carbamate (98% pure) were conducted by exposing groups of F344/N rats and B6C3F1 mice by gavage in water in a single dose and by repeated administration for 16 days, 13 weeks, 6 months, 12 months, 18 months, and 2 years. In addition, short-term mutagenicity studies in bacteria, mammalian cells, and Drosophila and of unscheduled DNA synthesis in rat liver cells were conducted. Single-Administration Studies: In the single-administration studies, 5/5 male and 5/5 female rats that received 8,000 mg/kg methyl carbamate and 2/5 male and 5/5 female that received 4,000 mg/kg died before the end of the 15-day observational period. Five of five male and 5/5 female mice that received 8,000 mg/kg and 1/5 females that received 4,000 mg/kg died before the end of the 15-day observational period. No compound-related morphologic effects were observed in rats or mice that received 2,000 mg/kg. Sixteen-Day Studies: In the 16-day studies, all rats dosed at 2,000 or 4,000 mg/kg died, and 3/5 male rats that received 1,000 mg/kg died. Male mice that received 2,000 or 4,000 mg/kg, female mice that received 4,000 mg/kg, and 1/5 female mice that received 2,000 mg/kg died. No compound-related gross pathologic or histopathologic effects were seen in male or female rats (groups of five each) that received 500 mg/kg or in mice that received 1,000 mg/kg. Thirteen-Week Studies: In the 13-week studies, groups of 10 male and 10 female rats and mice received up to 800 mg/kg (male rats), 1,000 mg/kg (female rats), 1,500 mg/kg (male mice), or 2,000 mg/kg (female mice). Four of 10 male rats that received 800 mg/kg and 1/10 female rats that received 1,000 mg/kg died of compound-related causes before the end of the studies. Toxic hepatitis, splenic pigmentation, bone marrow atrophy, and testicular atrophy were observed in the two highest dose groups of rats. One of the female mice that received 2,000 mg/kg died. The dosed female mice had significantly greater liver weights than did the vehicle controls. Experimental Design of Six-, Twelve-, and Eighteen-Month and Two-Year Studies: Based on the findings in the short-term studies, 2-year studies of methyl carbamate were conducted by administering 0, 100, or 200 mg/kg methyl carbamate in distilled water by gavage, 5 days per week for 103 weeks, to groups of 50 F344/N rats of each sex for 103 weeks. Groups of 50 B6C3F1 mice of each sex were administered 0, 500, or 1,000 mg/kg methyl carbamate on the same schedule. Additional groups of 30 rats of each sex were administered 0 or 400 mg/kg methyl carbamate, and additional groups of 30 mice of each sex were administered 0 or 1,000 mg/kg methyl carbamate in distilled water by gavage, 5 days per week. Ten animals from each group were killed at 6, 12, or 18 months so that the progression of lesions could be followed. Results of the Six-, Twelve-, and Eighteen-Month and Two-Year Studies: In the 6-month studies, all vehicle control and dosed (400 mg/kg) rats survived. Cytologic alterations and atypical proliferative changes were observed in the liver of all dosed male and female rats, and neoplastic nodules of the liver were observed in 6/10 dosed male and 5/10 dosed female rats. In the 12-month studies, all vehicle control male and female rats and dosed female rats survived. One of 10 dosed male rats died. Neoplastic nodules of the liver were observed in 7/10 dosed male and 9/10 dosed female rats, and hepatocellular carcinomas were observed in 8/10 dosed male and 6/10 dosed female rats. In the 18-month studies, 1/10 dosed male and 8/10 dosed female and all vehicle control rats survived. Hepatocellular carcinomas were observed in 9/10 dosed male and 8/10 dosed female rats. Compound-related neoplastic changes were not observed in mice in the 6-, 12-, or 18-month studies. In the 2-year studar studies, mean body weights of high dose (200 mg/kg) male rats were generally 5&percnt;-9&percnt; lower than those of the vehicle controls after week 20. Mean body weights of high dose female rats were 5&percnt;-8&percnt; lower than those of the vehicle controls after week 56. Survival of dosed and vehicle control rats was similar (male: vehicle control, 19/50; low dose, 26/50; high dose, 29/50; female: 29/50; 36/50; 35/50). The mean body weights of high dose (1,000 mg/kg) male mice were about 8&percnt;-18&percnt; lower than those of the vehicle controls after week 24. The mean body weights of high dose (1,000 mg/kg) female mice were about 16&percnt; lower than those of the vehicle controls after week 16 and 30&percnt; lower after week 64. Survival of dosed and vehicle control mice was similar (male: 28/50; 35/50; 28/50; female: 38/50; 36/50; 32/50). Chronic focal inflammation and cytologic alteration of the liver were observed at increased incidences in high dose rats of each sex. Hyperplasia of hepatocytes was observed atincreased incidences in dosed male and high dose female rats. Neoplastic nodules or hepatocellular carcinomas (combined) in female rats occurred with a significant positive trend (0/50; 0/50; 6/49; P<0.01); the incidence of neoplastic nodules or hepatocellular carcinomas (combined) in high dose female rats was greater (P<0.03) than that in the vehicle controls. Incidences of liver neoplasms in dosed male rats were not significantly increased (4/50; 0/50; 7/49). Inflammation of the harderian gland was observed at increased incidences in dosed rats (male: 4/50; 11/50; 16/50; female: 7/50; 16/50; 30/50). The lesions were considered to be chemically related. In the 2-year studies in rats, significant decreases in tumor incidences included the following: leukemia (both sexes), pituitary gland (male), adrenal gland (male), and mammary gland (female). In the 2-year mouse studies, multinucleate giant cells in the liver were observed at increased incidences in dosed male mice (14/50; 31/50; 31/49). Adenomatous hyperplasia and histiocytosis of the lung were observed at increased incidences in high dose mice (adenomatous hyperplasia--male: 13/50; 19/50; 24/49; female: 7/49; 10/50; 18/50; histiocytosis--male: 11/50; 7/50; 21/49; female: 9/49; 10/50; 21/50). Genetic Toxicology: Methyl carbamate was not mutagenic in Salmonella typhimurium strains TA97, TA98, TA100, or TA1535 when tested with or without metabolic activation in a preincubation protocol at doses up to 10 mg/plate. Methyl carbamate did not induce forward mutations in the mouse L5178Y/TK&plusmn; lymphoma assay with or without metabolicactivation at doses up to 5 mg/ml. Unscheduled DNA synthesis was not detected in rat hepatocytes after in vitro treatment with methyl carbamate at concentrations of 1.0-1,000 ug/ml. When tested in Drosophila at doses of 25,000-50,000 ppm, methyl carbamate did not induce sex-linked recessive lethal mutations. Results of tests for induction of chromosomal aberrations and sister chromatid exchanges by methyl carbamate in cultured Chinese hamster ovary cells were also negative at doses up to 5 mg/ml. Data Audit: An audit of the experimental data was conducted for the 6-, 12-, and 18-month and 2-year studies of methyl carbamate. No data discrepancies were found that influenced the final interpretation. Conclusions: Under the conditions of these 6-, 12-, and 18-month and 2-year gavage studies, there was clear evidence of carcinogenic activity for male and female F344/N rats given methyl carbamate as indicated by increased incidences of hepatocellular neoplastic nodules and hepatocellular carcinomas. There was no evidence of carcinogenic activity for male and female B6C3F1 mice given methyl carbamate at doses of 500 or 1,000 mg/kg. Methyl carbamate also induced inflammation of the harderian gland in male and female rats and adenomatous hyperplasia and histiocytosis of the lung in male and female mice. Synonyms: carbamic acid, methyl ester; methylurethan; methylurethane; urethylane

Journal Article↗
PubMed1976

The carbamate reaction of glycylglycine, plasma, and tissue extracts evaluated by a pH stopped flow apparatus.

We have used a stopped flow rapid reaction pH apparatus to investigate the carbamate equilibrium in glycylglycine solutions and in three biological tissues, human plasma, sheep muscle, and sheep brain, as well as to investigate the kinetics of carbamate formation in glyclyglycine solution and in human plasma. The rapid reaction apparatus was equipped with a pH sensitive glass electrode in order to follow the time course of pH from 0.005 to 100 s after rapid mixing of a solution of amine or protein and CO2. Two phases of the pH curve were observed: a fast phase representing carbamate formation, and a slow phase due to the hydration of CO2 which was uncatalyzed since a carbonic anhydrase inhibitor was added to the biological solutions. From the time course of pH change during the fast phase K2, the R-NH2 ionization constant, and Kc, the carbamate equilibrium constant as well as the velocity constant for the formation of carbamate, ka could be calculated from data at different pH and pCO2. The carbamate formed in glycylglycine solutions over a wide range of pH and pCO2 was found consistent with the theory of carbamate formation and with published data. At ionic strength 0.16 and 37 degrees pK is 7.67. pKc 4.58. The heat of the carbamate reaction (deltaH) was calculated to be -3.2 kcal/mol between 20 degrees and 37 degrees. Kt of glycylglycine depends quantitatively on ionic strength as predicted by the Debye-Huckel theory. With ionic strength 0.16 ku was found to be 2,500 M1 S1 at 37 degrees. The activation energy of carbamate formation is 6.7 kcal/mol. Carbamate measurements in human plasma at pCO2 from 38 to 359 Torr. pH from 6.9 to 8.3, temperature 37 degrees, and ionic strength 0.15 provided evidence that two kinds of amino groups participate in carbamate formation. From the equilibrium constants computed for the two species they could be identified as alpha- and epsilon-amino groups. On the basis of a protein molecular weight of 69.000. 0.6 alpha-amino groups/molecule with pKz=7.0 and pKc=4.2, and 5.9 epsilon-amino groups/molecule with pKz=9.0 and pKc=4.3 contribute to carbamate formation. The velocity constant ka was estimated to be 4,950 M1 S1 for the alpha-amino groups and 13,800 M1 S1 for the epsilon-amino groups. Under physiological conditions (pCO2=40 Torr. pH=7.4). The concentration of carbamate in plasma is 0.6 mM and the half-time of carbamate formation is 0.05 s. In extracts prepared from sheep brain at 37 degrees pH=7 and pCO2=35 Torr. the carbamate formation was estimated to be 0.8 mM. With pCO2=70 Torr and the same pH and temperature the carbamate concentration in muscle approximates 0.3 mM and increases to 7 mM as pH rises to 8. It is concluded that, as in plasma, a considerable number of epsilon-amino groups appear to be available for carbamate formation in these tissues.

Animals↗
PubMed1985

Computer-assisted structure--anticancer activity correlations of carbamates and thiocarbamates.

With the aid of the computer, approximately 8000 compounds that incorporate a carbamate or thiocarbamate moiety, which have been tested as potential anticancer agents at the National Cancer Institute (NCI), were classified and their structure-activity correlations against the in vivo P-388 and L-1210 leukemias were evaluated. Aromatic carbamates and thiocarbamates have shown good activity against P-388 and poor activity against L-1210. The majority of active compounds in this series of aromatic carbamates possess a 2- or 4-heteroatom-substituted phenyl attached to the carbamate oxygen atom or the thiocarbamate sulfur atom with the carbamate nitrogen atom as NHMe. The N-phenyl carbamates were much less active against P-388 than the phenyl carbamates; only bis-N-phenyl carbamates with a methylene bridge between the two phenyl groups showed good activity against both P-388 and L-1210 leukemias. Except for the mycophenolic acid carbamates, the fused phenyl carbamates showed poor activity against both P-388 and L-1210 leukemias. Certain nitrogen-heterocyclic carbamates and carbamates with heteroatom substituents have been selected by the NCI for development toward clinical trials. The nature of the heterocyclic carrier and the position of attachment to the carbamate moiety have a major role on the mode of action of the antitumor activity of these compounds.

Animals↗