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Biomedical subjects

S R Tannenbaum

Publications and source records attributed to S R Tannenbaum.

At least 145 records · Page 8Linked to original sources
PubMed1986

Sulfamate formation is a major route for detoxification of 2-amino-3-methylimidazo[4,5-f]quinoline in the rat.

The major biliary metabolite of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) in the rat was identified as the sulfamate derivative, N-[3-methylimidazo[4,5-f]quinolin-2-yl] sulfamic acid. Identification was accomplished primarily by u.v., 1H-n.m.r. and mass spectrometry of the material isolated from bile and confirmed by comparison with material synthesized by reaction of chlorosulfonic acid with IQ. The sulfamate was shown to be non-mutagenic in bacterial forward mutation assays. Greater than 20% of an administered dose of IQ could be recovered from feces (17%) and urine (5%) as the sulfamate. Very little unmetabolized IQ was recovered in bile, urine, or feces. Thus, the unusual process of N-sulfation is a major contributor to the detoxification and elimination of IQ in the rat.

Animals↗
PubMed1986

Diet and chronic atrophic gastritis: a case-control study.

A hospital-based case-control study of gastric cancer precursor lesions was conducted in a high-risk black population in southern Louisiana. Ninety-three subjects with biopsy-proved advanced chronic atrophic gastritis were compared to two control series: a gastroscopy clinic series and a general hospital-admission series. Dietary case-control differences indicated a protective effect associated with fruit and vegetable intake and with dietary vitamin C and a risk elevation associated with milk consumption. The protective effect associated with consumption of fruits, vegetables, and vitamin C is consistent with findings for gastric cancer and with the etiologic hypothesis of intragastric nitrosation. A twofold increased risk was associated with cigarette smoking. Gastric juice pH, NO3-, and NO2- were determined for subjects undergoing gastroscopy, and comparisons were made between this high-risk U.S. group and a Colombian population with a much greater magnitude of risk; the latter had higher NO3- and NO2- levels. An increase in pH was associated with increasing severity of gastric lesions. Levels of pH and NO2- concentration were significantly correlated (P less than .0005); however, in Louisiana the large difference in NO2- concentration associated with pH elevation is not associated with histopathologic severity. Divergent trends with severity of lesions for NO3- concentration were seen in the two populations.

Adult↗
PubMed1986

Analytical methods for assessing exposure to 4-aminobiphenyl based on protein adduct formation.

Past studies with animals have demonstrated that 4-aminobiphenyl (ABP) administration results in the formation of appreciable amounts of adducts between the carcinogen and both serum albumin and hemoglobin. The hemoglobin adduct is relatively stable in vivo, but may be readily hydrolyzed in vitro to regenerate ABP. The formation of this adduct reflects a mixed-function oxidase-mediated metabolic pathway operating directly on the amine. The predominant albumin adduct, 3-(tryptophan-N1-yl)-4-acetylaminobiphenyl, reflects the contribution of N-acetyltransferase activity as well as mixed function oxidase activity to the overall metabolism. The simultaneous measurement of these two different adducts thus offers an opportunity to investigate the role of both ABP and acetylator phenotype in bladder carcinogenesis. An analytical method, using gas chromatography coupled with electron capture detection, was developed to quantitate ABP adducted to hemoglobin.

Aminobiphenyl Compounds↗
PubMed1985

Nitrate biosynthesis in the rat. Precursor-product relationships with respect to ammonia.

The endogenous biosynthesis of nitrate in rats was investigated by using 15NH3 administered as a continuous intravenous infusion for as long as 96 h. A comparison of the enrichment of 15N in urinary nitrate after a 24 h infusion revealed that it was 36% of the enrichment of plasma NH3 and about 50% of the enrichment of plasma urea and urinary NH3. Continuous infusion of 15NH3 for 96 h showed that a plateau for the incorporation of NH3 into nitrate is reached by 24 h, whereas the enrichment of urinary NH3 and urea increase during the 96 h. After the infusion of progressively larger doses of 15NH3, the concentration of nitrate synthesized de novo increased. Although there was a significant correlation between plasma 15NH3 concentration and 15NO3- appearance, a given change in plasma NH3 concentration does not produce a direct proportional change in nitrate synthesis. Our findings indicate that NH3 is a quantitatively significant nitrogen precursor for nitrate, but that approx. 50% of nitrate nitrogen is derived from other, as yet unidentified, sources.

Ammonia↗
PubMed1985

Pharmacokinetics of nitrate in humans: role of gastrointestinal absorption and metabolism.

A model to describe the response of the blood pool to an oral dose of nitrate in humans has been developed. The permeability-area product of the small intestine to nitrate was estimated by comparing simulations from a three-compartment model with published data for blood nitrate concentration following nitrate ingestion. The transport of nitrate from the bloodstream to the lumen of the large intestine and the metabolism of nitrate by enteric bacteria were examined by including an additional compartment representing the large bowel. The simulations indicate that the bacteria of the large intestine may be responsible for about half of the extrarenal removal of nitrate from the body. This prediction was tested experimentally by comparing the urinary recoveries of 15NO3- in conventional and germfree rats following an i.p. dose of Na15NO3. The mean urinary recovery in germfree rats (71% of dose) substantially exceeded that in rats with conventional bacterial flora (54%). This suggests that of the 40-45% of a nitrate dose that is metabolized in the body rather than excreted in urine as nitrate, approximately half is metabolized by mammalian processes and approximately half by enteric bacteria. This conclusion is consistent with that obtained from our pharmacokinetic model of nitrate in humans.

Animals↗
PubMed1985

Attempts to isolate N-nitroso compounds from Chinese-style salted fish.

Various types of salted fish have been collected from Hong Kong and analyzed for volatile nitrosamines and bacterial mutagenicity. Both of these parameters were low in the samples as collected. Exposure of these samples to nitrite yields substantial quantities of nitrosamines and mutagenic activity.

Animals↗
PubMed1985

Diet and exposure to N-nitroso compounds.

The hypothesis linking nitrate and increased risk of cancer rests on the proposition that nitrate is endogenously reduced to nitrite by bacteria and that carcinogenic N-nitroso compounds are formed. A large number of foods and biological material have been examined for their ability to generate mutagens or carcinogens under simulated gastric conditions in the presence of nitrite. Only a limited number of foods qualify under these conditions for consideration as potential sources of genotoxic agents. Foods that have generated mutagens following nitrosation include beans, salt-preserved fishery products, fermented soy products, and certain moldy foods. In each case there appears to be a potential link between formation of the nitroso compound and epidemiological evidence of increased risk for specific cancers. The present state of knowledge is reviewed and the chemistry of the nitrosation of specific chemicals of interest is discussed. A major problem for the future will be to demonstrate that these N-nitroso compounds form in the population at risk and react with cellular nucleophiles to produce genetic damage.

Bacteria↗
PubMed1985

Carcinogenicity in rats of the nitrosated bile acid conjugates N-nitrosoglycocholic acid and N-nitrosotaurocholic acid.

Two nitrosated bile acid conjugates, N-nitrosoglycocholic acid and N-nitrosotaurocholic acid, were examined for carcinogenicity in a 2-year study with male Fischer rats using a 6-week p.o. dosing protocol with a total of 300 mg compound/rat. Both compounds were approximately equally carcinogenic and induced significant levels of hepatocellular carcinoma in 54 to 70% of the animals at risk. Gastric tumors of the glandular and aglandular stomach were observed in 12 to 13% of the treated rats. Although the incidence was not significant, these levels were much higher than those in historic controls. Malignant liver and gastric tumors were not detected in vehicle control rats. Alkaline phosphatase-positive foci, putative early mucosal alterations which may precede neoplasia, were found in approximately 35% of the glandular stomachs of compound-treated rats but not in those of control rats.

Alkaline Phosphatase↗
PubMed1985

Identification of the major serum albumin adduct formed by 4-aminobiphenyl in vivo in rats.

Serum albumin was isolated from rats at 27 h after administration of the carcinogen [2,2'-3H]-4-aminobiphenyl. Pronase digestion of the purified albumin yielded a mixture of radiolabeled materials which was resolved into 5 major components by reverse-phase liquid chromatography. From detailed UV, 1H-NMR, and mass spectral analyses, four of these were determined to be 4-aminobiphenyl, 4'-hydroxy-4-acetylaminobiphenyl, and two other metabolites, all of which are presumed to be non-covalently associated with the serum albumin. The fifth component, however, resulted from covalent bond formation and was identified as a tetrapeptide containing 3-tryptophanyl-4-acetylaminobiphenyl, the amino acid sequence of which was H2N-ala-trp-ala-val. Since rat serum albumin contains only a single tryptophan residue in a hydrophobic drug binding site, its high selectivity for carcinogen binding suggests a unique role for this protein in the detoxification and/or transport of ultimate carcinogenic metabolites.

Amino Acids↗
PubMed1985

Flow cytometric analysis of the effect of sodium chloride on gastric cancer risk in the rat.

Dietary sodium chloride has been identified, both experimentally and epidemiologically, as a risk factor for gastric cancer. In order to elucidate the manner in which salt increases gastric tumor incidence in N-methyl-N'-nitro-N-nitrosoguanidine-treated animals, flow cytometric cell cycle analyses were performed on rats which had been treated with 1 ml of a solution of saturated NaCl by gavage and sacrificed 0, 1, 6, 12, 24, or 48 h after treatment. The gastric antra were excised, disaggregated, and stained with propidium iodide for cell cycle analysis. Results showed that there is a reduction in cell yield at early time points due to the toxicity of NaCl, followed by a net increase in the number of cells in the S phase of the cell cycle at 24 h. Treatment of rats with NaCl 24 h prior to a dose of 10 micrograms of 3H-labeled N-methyl-N'-nitro-N-nitrosoguanidine did not lead to an increase in alkylation of DNA isolated from mucosal cells. Therefore, the hypothesis that salt enhances gastric cancer risk from N-methyl-N'-nitro-N-nitrosoguanidine by disruption of the "mucosal barrier" leading to an increased effective dose to target cells is not supported by the results of these experiments. Several studies have shown that cells in S phase are the most susceptible to mutagenesis and that increasing the number of cycling cells in a target organ will increase tumor incidence (e.g., partial hepatectomy). Thus it is possible that NaCl increases gastric cancer risk through the mitogenesis which results from the damage caused to the mucosa by this agent.

Animals↗
PubMed1985

Effect of vitamins C and E on endogenous synthesis of N-nitrosamino acids in humans: precursor-product studies with [15N]nitrate.

The endogenous formation of nitrosoproline (NPRO) following administration of nitrate and proline is reported in ten healthy young adults. There was a relatively constant basal excretion of NPRO, 26 +/- 10 (SD) nmol/day, in excess of amounts found in the diet. This basal synthesis of NPRO was not reduced by ascorbic acid (2 g/day) or alpha-tocopherol (400 mg/day). A significant rise in the excretion of NPRO was observed following the administration of nitrate and proline, ranging from 29 to 318 nmol/24 h with a mean of 100 nmol/24 h. [15N]Nitrate was used as a tracer to study the observed excess excretion of NPRO in urine. The data revealed that urinary NPRO excretion as a result of endogenous synthesis is not totally derived from ingested nitrate as its precursor. The ingestion of ascorbic acid and alpha-tocopherol inhibited the incorporation of [15N]nitrate into NPRO by 81 and 59%, respectively. An additional nitrosamino acid, N-nitrosothiazolidine-4-carboxylic acid, was present in the urine. It was found that N-nitrosothiazolidine-4-carboxylic acid increased 6-fold upon ingestion of nitrate. Ascorbic acid and alpha-tocopherol blocked this nitrate induced synthesis.

Adult↗
PubMed1984

Inhibition of N-nitrosodimethylamine metabolism by ethanol and other inhibitors in the isolated perfused rat liver.

The effects of several potential inhibitors of N-nitrosodimethylamine (NDMA) metabolism have been studied in isolated perfused rat livers. Low concentrations of ethanol (less than 0.5 mM) were found to strongly inhibit hepatic metabolism of NDMA. This effect does not require the metabolism of ethanol. The metabolism and toxicity of NDMA may therefore be influenced by the intake of alcohol as well as by ethanol produced endogenously by the intestinal flora. Other compounds found to inhibit NDMA metabolism include n-propanol, tert-butanol, 4-methylpyrazole, amino-triazole and acetaldehyde.

1-Propanol↗
PubMed1984

4-Chloro-6-methoxyindole is the precursor of a potent mutagen (4-chloro-6-methoxy-2-hydroxy-1-nitroso-indolin-3-one oxime) that forms during nitrosation of the fava bean (Vicia faba).

Fava beans (Vicia faba) upon treatment with nitrite under simulated gastric conditions, form a direct-acting bacterial mutagen, comparable in specific activity to the most potent known mutagens for several strains of Salmonella typhimurium. The precursor of the mutagen was isolated and identified as 4-chloro-6-methoxyindole by u.v., i.r., m.s. and n.m.r. The precursor was dechlorinated with NaBH4 and PdCl2 as the catalyst and the product obtained from this reaction was identified as 6-methoxyindole. Since synthetic 4-chloro-6-methoxyindole was not available, structure activity studies were conducted on substituted indoles. Nitrosation of 4-chloroindole closely follows the results for nitrosation of 4-chloro-6-methoxyindole. The major product of nitrosation of 4-chloroindole is 4-chloro-2-hydroxy-N1-nitroso-indolin-3-one oxime. Thus, it appears that the major nitrosation product of 4-chloroindole and of 4-chloro-6-methoxyindole is a stable alpha-hydroxy N-nitroso compound. This is the first reported case of stable alpha-hydroxy N-nitroso compounds. In the presence of N-(1-naphthyl)ethylenediamine dihydrochloride (NEDD), the alpha-hydroxy N-nitroso compound rearranges to an aromatic diazonium ion which couples with the diamine to form an azo dye. Studies on nitrosation kinetics indicate that the nitrosation of indoles are relatively fast reactions. Both the structural and rate studies give strong support to the hypothesis that intragastric nitrosation of fava beans yield the putative gastric carcinogen in the high-risk area in Colombia.

Fabaceae↗
PubMed1984

In vivo dosimetry of 4-aminobiphenyl in rats via a cysteine adduct in hemoglobin.

The feasibility of monitoring doses of 4-aminobiphenyl (ABP) via adduction to hemoglobin was investigated. Rats dosed with ABP (from 0.5 micrograms/kg to 5 mg/kg) formed a stable covalent hemoglobin:ABP adduct. Approximately 5% of a single dose was bound as hemoglobin:ABP; chronic dosing led to an accumulation of the adduct to a level 30 times greater than that found after a single dose. Facile in vitro hydrolysis of the adduct regenerated ABP, allowing detection at the sub-ng level. Human hemoglobin was also readily adducted, using N-hydroxy-ABP in vitro. The predominant site of adduction appeared to be the cysteine residue in hemoglobin. The use of such adducts as dosimeters for arylamine exposures in humans is discussed.

Aminobiphenyl Compounds↗
PubMed1984

Modulation of endogenous synthesis of N-nitrosamino acids in humans.

Endogenous production of N-nitrosoproline (NPRO) was demonstrated in human subjects ingesting a diet low in nitrate and NPRO. The daily endogenous synthesis of NPRO was 26 +/- 10 nmol/day (mean +/- SD). Upon administration of nitrate and proline, the NPRO excreted in urine ranged from 50-318 nmol/24 h. It was found that ascorbic acid and alpha-tocopherol did not lower the background endogenous synthesis of NPRO; however, ascorbic acid was very effective in preventing the nitrate-induced synthesis of NPRO in all subjects, while alpha-tocopherol was less effective in some subjects. Furthermore, it was demonstrated that administered 15N-nitrate could be incorporated into NPRO, suggesting clearly that nitrosation reactions indeed occur in humans. Ascorbic acid significantly inhibited the incorporation of 15N-nitrate into NPRO. The presence of another N-nitrosamino acid, N-nitrosothiazolidine-4-carboxylic acid (NTCA), was detected in the urine of many subjects even without nitrate intake. However, upon ingestion of nitrate, there was a six-fold increase in mean NTCA synthesis (25 +/- 16 nmol/24 h), and all subjects had detectable levels of NTCA in the urine. Ascorbic acid completely blocked the nitrate-induced synthesis of NTCA, while alpha-tocopherol was not as effective.

Adult↗