Biomedical subjects

N Frank

Publications and source records attributed to N Frank.

At least 73 records · Page 4Linked to original sources

PubMed1988

pH-dependent degradation of nitrosocimetidine and its mechanisms.

The degradation of nitrosocimetidine (NC) and its mechanism were found to be strongly dependent upon pH by monitoring NC and its degradation products by high-performance liquid chromatography (HPLC). NC was relatively stable at neutral pH, but it degraded rapidly under both acidic and alkaline conditions. In a strongly acidic solution, the degradation was shown to be entirely by denitrosation, but under alkaline conditions scarcely any denitrosation was observed and various other degradation products were found. At neutral pH, both these degradation mechanisms were observed. In neutral solution, the presence of thiol compounds greatly shortened the half life of NC, and enhanced its denitrosation. The high degradation rate in acidic solution, the strong influence of thiol groups, and the preference of denitrosation at pH 0.3-5 can explain the discrepancy between the in vitro genotoxicity and the lack of carcinogenicity of NC.

Acetylcysteine↗

PubMed1988

Effects of potassium ethylxanthogenate on nitrosodiethylamine-induced DNA damage and on liver carcinogenesis.

BD-6 rats were injected with 80 mg/kg N-nitroso-diethylamine weekly for 10 weeks. Addition of 270 mg/kg potassium ethylxanthogenate weekly reduced significantly the number of rats developing NDEA-induced malignant liver tumors. Ethylxanthogenate decreased the total number of liver tumors induced by the carcinogen to 6 as compared to a total of 29 neoplasms in animals treated only with NDEA. In acute experiments potassium ethylxanthogenate markedly decreased the exhalation of 14CO2 derived from 14C-NDEA. The amount of the nonmetabolized carcinogen increased in the urine of ethylxanthogenate protected rats only 4% of the given dose. Initial DNA damage, single strand breaks and alkali-labile sites, was determined by alkaline sucrose gradients and in protected animals was minimal for at least 24 hours after NDEA administration. It appears that the production of less initial DNA damage may be important for the further course of liver carcinogenesis induced by relatively large doses of nitrosodiethylamine.

Animals↗

PubMed1987

Locoregional application of 5-fluorouracil to the liver: alteration of pharmacokinetics and bone marrow toxicity in rats with thioacetamide-induced cirrhosis.

Pharmacokinetics and toxicity of 5-fluorouracil (5-FU) applied intra-arterially into the liver were studied in control and cirrhotic rats. Cirrhosis was induced by administering thioacetamide (4.5 mg/rat X day) over 6 months. 5-FU was administered into the hepatic artery at 30 mg/kg b.w. by bolus injection followed by infusion of 0.63 mg/kg X min for 40 min. Pharmacokinetics of 5-FU in plasma was studied by HPLC analysis. 5-FU induced toxicity was examined in a second group of control and cirrhotic rats at 48 and 168 hours after treatment with 5-FU (31.4 mg/kg b.w.) infused into the liver artery for 1 h. Analysis of toxicity was carried out by determining liver enzymes in plasma, bone marrow cellularity and colony forming units in vitro (CFU-C) and in vivo (CFU-S). The results indicate that during the period investigated (85 min) 5-FU was not eliminated from the plasma of cirrhotic rats in contrast to controls. The constant level of 5-FU in the plasma of cirrhotic rats induced a considerably higher myelosuppression in these animals, than the short-lived 5-FU peak in controls.

Alanine Transaminase↗

PubMed1987

Could N-nitrosamino phosphates be transport forms of activated N-nitrosamines?

The stability of N-nitroso-N-methylamine-N-ethyl phosphate (NMEP) and N-nitroso-N-ethylamine-N-ethyl phosphate (NEEP) was studied in rat serum and in rat liver homogenate and found to be sufficiently high for the phosphates to be transported in vivo. In liver homogenates, the cleavage was more efficient, and a higher phosphatase activity was found in liver microsomal and cytosolic fractions than in serum. The substances exert a distinct activity in the Salmonella typhimurium mutagenicity test.

Alkaline Phosphatase↗

PubMed1986

Influence of the carboxylesterase inhibitor bis-p-nitrophenylphosphate on the rates of hydrolysis of various alpha-esters of 1-(N-methyl-N-nitrosamino)-methanol in vitro and in vivo and on the acute toxicity and carcinogenicity of 1-(N-methyl-N-nitrosamino)-methylacetate.

The effect of an in vivo treatment with the carboxylesterase inhibitor bis-p-nitrophenylphosphate (BNPP) on the hydrolysis of 1-(N-methyl-N-nitrosamino)-methylacetate (NNMA), 1-(N-methyl-N-nitrosamino)-methylbutyrate (NNMB), 1-(N-methyl-N-nitrosamino)-methylbenzoate (NNMBz) and 1-(N-methyl-N-nitrosamino)-methylpivaloate (NMMP) in rat tissue homogenates was studied. The rates of hydrolysis were specific for each compound and different in every organ tested; the extent of inhibition of the hydrolysis by BNPP was also substrate and organ specific. In some cases no inhibition at all was observed. The rate of elimination of NNMA, NNMB, and NNMP from blood was not influenced by BNPP pretreatment. The LD50 of NNMA after i.v. application showed a rise of 85% with a BNPP pretreatment. BNPP also influenced the carcinogenicity of NNMA, whereby the total carcinogenic potency was not altered, but the organotropism had changed slightly.

Animals↗

PubMed1986

N-nitroso-hydroxyalkyl-alkylamine phosphate esters--a new class of N-nitroso compounds.

A new class of phosphate-esterified alpha-hydroxyalkyl-alkyl-nitrosamines is described. Here we report the synthesis of these compounds. The mechanism of their formation from the corresponding alpha-acetoxy compounds, and starting from alpha-hydroperoxy compounds is studied by monitoring the reactions in the u.v.-spectrophotometer, by reaction with alkaline phosphatase and by determination of aldehydes generated during degradation of the N-nitrosoacetylesters. Their stability in aqueous solution and their phosphatase-induced degradation was determined. It was found that alpha-phosphate-nitrosamines are more stable in aqueous solution than the alpha-acetates or the parent alpha-hydroxy compounds. Therefore their role as intermediates in nitrosamine metabolism is discussed.

Alkaline Phosphatase↗

PubMed1986

Inhibition of the metabolism of N-nitrosoacetoxymethylmethylamine in the rat by disulfiram.

The stability of N-nitrosoacetoxymethylmethylamine (NAMM) in rat serum in vitro, the half-life in blood in vivo and the exhalation rate of 14CO2 after the application of 14C-labelled NAMM were studied with and without disulfiram (DSF) pre-treatment. It was found that the metabolism of NAMM is inhibited by DSF in vitro as well as in vivo. The influence is thought to be due to inhibition of esterase activity, as shown by comparing the kinetics of the degradation of NAMM with those of p-nitrophenylacetate. In contrast to this result the exhalation of 14CO2 does not seem to be influenced by the esterase inhibiting effect of DSF.

Animals↗

PubMed1984

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↗

PubMed1984

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↗

PubMed1984

Influence of diet on 1,2-dimethylhydrazine metabolism in rat liver.

The metabolism of 1,2-dimethylhydrazine (DMH) was investigated in isolated perfused livers excised from Sprague-Dawley rats fed four semisynthetic diets over two generations. The diets were varied within normal physiological limits, without producing specific deficiencies. Diet was shown to have an influence on the growth of animals and on the cholesterol content and beta-glucuronidase activity in the blood serum. However, diet did not influence the rate of metabolism of DMH or the concentration of metabolites.

Animals↗

PubMed1984

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↗

PubMed1984

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↗

PubMed1983

Nitrosamine metabolism in kwashiorkor rats.

The in vitro metabolism of nitrosodimethylamine (NDMA) was studied in liver tissue obtained from male weanling kwashiorkor wistar rats. The elimination of this compound and that of nitrosomorpholine (NMOR) from the blood, after a single intravenous dose, was also investigated. N-demethylase activity in liver microsomes of the test animals was not significantly different from that of the controls although the activity of this enzyme per gram wet liver tissue was considerably reduced in the model animals. On the other hand, the glutathione (GSH) content in liver cytosol of the kwashiorkor animals was much higher than that of the controls. The elimination of NDMA and NMOR from the blood of the experimental animals over 8 hr following i.v. administration of the carcinogens, showed that the clearance rate of each nitrosamine was significantly lower in the kwashiorkor rats.

Animals↗

PubMed1983

Computational methods for the screening of pharmacokinetic parameters in metabolism experiments.

A computational strategy is presented which is useful for the qualitative and quantitative assessment of reaction-kinetic parameters in a one-compartment open model for the metabolism of substances in a biological system, especially the metabolism of dialkylnitrosamines to the ultimate carcinogen. The mathematical model used is that of first order kinetics and results in Bateman-functions. The strategy allows to decide about stability or instability of a substance occurring in a chain of transformations. In the case of stability quantitative estimates of the half life are provided. The procedure compares parameter estimates from models of different qualitative nature. These estimates are derived by linear or non-linear regression methods.

Biotransformation↗

PubMed1983

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↗

PubMed1982

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↗

PubMed1982

Metabolism of 1,2-dimethylhydrazine in isolated perfused rat liver.

The metabolism of 1,2-dimethylhydrazine (DMH) was investigated in isolated perfused rat liver. The separation of [14C]DMH and its metabolites azomethane (AM), azoxymethane (AOM) and methylazoxymethanol (MAM) was performed by high pressure liquid chromatography (HPLC). The fractions were quantitatively detected by liquid scintillation counting of the radioactivity. It was demonstrated that DMH is highly metabolized by the liver. After 1 h of perfusion, the median amounts of DMH and its metabolites in the medium were: DMH, 16%; AM, 3%; AOM, 42%; MAM, 30% of the given dose. During this time 9.9% and 0.7% of the total radioactivity were eliminated as AM and CO2 in the oxygen stream of the perfusion apparatus; 0.6% were excreted by bile and 12.3% stored in hepatic tissue. The reaction rate (t1/2) of each individual metabolic step was estimated by means of a mathematical kinetic model as follows: DMH leads to AM, 21.8 min; AM leads to AOM, 1.5 min; AOM leads to MAM, 41.5 min; MAM leads to, 611 min. The results are discussed in comparison to in vivo experiments.

1,2-Dimethylhydrazine↗

PubMed1982

[Diagnostic value of sigmoidoscopic examination in diseases of the colon (author's transl)].

215 Cases out of 400 colosopic and 300 sigmoidoscopic examinations showed polypi and carcinomas. The polypi of 170 patients were located at a rate of 63,5% in the rectum and sigma area and of 36,5% in the proximal colon sections. Out of 45 carcinomas 80% could be localized in the rectum and sigma area and 20% in the further parts of the colon. Patients, if only sigmoidoscopically examined, showed polypi at a rate of 4,7% and carcinomas of 1,3%. For patients coloscopically examined polypi were found at a rate of 23,5% and carcinomas of 8% in the rectum and sigma area. 66% of all polypous changes and 82% of carcinomas were found with patients beyond 60 years of age. In 17 cases colitis ulcerosa, in 3 cases Morbus Crohn and in 3 cases of lipom could be established. The relatively high rate of pathological abnormities found in the upper colon section proves the diagnostic value of a total coloscopic examination. The recto-sigmoidoscopic examination therefore should be restricted to provisionary tests only.

Adult↗