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S R Tannenbaum

Publications and source records attributed to S R Tannenbaum.

At least 127 records · Page 7Linked to original sources
PubMed1988

Hemoglobin adducts of aromatic amines: associations with smoking status and type of tobacco.

Hemoglobin adducts of 15 aromatic amines were determined in nonsmokers and smokers of blond- or black-tobacco cigarettes living in Turin, Italy. The subjects were all males age 55 or less and were representative of the population previously examined in a case/control study of bladder cancer. 4-Aminobiphenyl adduct levels were found to be significantly different in the three groups, and the differences were approximately proportional to the relative risk of each group. Adjustment for age and cigarette consumption did not materially influence the differences. A significant correlation of adduct levels with cigarette consumption was also observed for all smokers as well as for smokers of blond tobacco. Other amines for which significant differences between smokers and nonsmokers were observed were 3-aminobiphenyl, 2-naphthylamine, o- and p-toluidine, 2,4-dimethylaniline, and 2-ethylaniline. Some of these amines are human bladder carcinogens, and their occurrence in blood as hemoglobin adducts is evidence for their metabolic activation. Thus, by a combination of traditional epidemiological methods and modern chemical analyses, we have provided evidence for a biochemical basis for the often observed association between cigarette smoking and bladder cancer.

Adult↗
PubMed1988

Use of ascorbic acid to inhibit nitrosation: kinetic and mass transfer considerations for an in vitro system.

Ascorbic acid and ascorbate ion (denoted together as ASC) inhibit nitrosation by competing for the nitrosating agents formed from nitrite (e.g. N2O3, NO+ and NOSCN). ASC is oxidized irreversibly by this reaction and the nitrite equivalents are reduced to nitric oxide (NO). In open, aerobic systems the effective stoichiometry of the reaction between ASC and nitrite is not fixed, but is determined by a competition between the physical removal of NO (and NO2) from the system and the oxidation of NO by dissolved O2. The oxidation of NO reconverts it to a nitrosating agent which may react again with the remaining ASC. To determine the conditions under which ASC is most effective as a nitrosation inhibitor, we examined the kinetics of the reactions between nitrite and ASC and between nitrite and proline. These reactions were studied in open shaker flasks as functions of pH, anion composition (SCN- and Cl-), temperature, and gas-liquid mass transfer rate. At lower mass transfer rates, at lower pH and/or in the presence of SCN- or Cl-, relatively more ASC was consumed by a given amount of nitrite. Increased temperature caused more or less ASC to be consumed by a given amount of nitrite, depending on the conditions. A mathematical model of the reactions and mass transfer steps was developed which describes each of these features. The model predicts the variable stoichiometry of the reaction between nitrite and ASC in open, aerobic systems, and clarifies the mechanisms by which ASC inhibits nitrosation.

Ascorbic Acid↗
PubMed1988

Major routes of metabolism of the food-borne carcinogen 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline in the rat.

The metabolic fate of 2-amino-3,8-dimethylimidazo[4,5-f] quinoxaline (MeIQx), a carcinogen formed in cooked meat and fish, has been investigated in male Sprague-Dawley rats. Five metabolites were recovered from bile of animals given an intragastric dose of [2-14C]MeIQx. These accounted for nearly all of the radioactivity in bile. The chemical structures of these metabolites were elucidated by proton NMR, UV and mass spectroscopy. Three structures may be assigned unambiguously: two sulfamates, N-(3,8-dimethylimidazo [4,5-f]quinoxalin-2-yl)sulfamic acid and N-(8-hydroxy-methyl-3-methylimidazo[4,5-f]quinoxalin-2-yl) sulfamic acid, and one glucuronide, N2-(beta-1-glucosiduronyl)-2-amino-3,8-dimethylimidazo[4,5-f ]quinoxaline. In addition, an acetyl and a glucosiduronyl conjugate of 5-hydroxy-MeIQx were observed. The spectral evidence did not allow an unambiguous assignment of the site of conjugation. The two glucuronides were excreted in urine and the sulfamate of MeIQx was found in feces as well as urine. All five metabolites were found to be non-mutagenic to Salmonella typhimurium TA98 with or without metabolic activation. The glucuronide conjugates were found also to be non-mutagenic when beta-glucuronidase was incorporated with S-9 mixture in the mutation assay, and thus all appear to be detoxification products. The previously reported metabolite, 2-amino-8-hydroxymethyl-3-methylimidazo[4,5-f]quinoxaline which is mutagenic to Salmonella typhimurium TA98 with metabolic activation, was identified as a minor component in both urine and feces.

Animals↗
PubMed1988

Serum albumin adducts in the molecular epidemiology of aflatoxin carcinogenesis: correlation with aflatoxin B1 intake and urinary excretion of aflatoxin M1.

Aflatoxin-serum albumin adducts in the blood of 42 residents of Guangxi Province, People's Republic of China, were determined and compared with intake of aflatoxin B1 (AFB1) and excretion of aflatoxin M1 (AFM1) in urine. Blood specimens were obtained during the same period that urine was collected and that diet was sampled. Serum albumin was isolated from blood by affinity chromatography on Reactive Blue 2-Sepharose and subjected to enzymatic proteolysis using Pronase. Immunoreactive products were purified by immunoaffinity chromatography and quantified by competitive radioimmunoassay. A highly significant correlation (r = 0.60, P less than 0.00003) of adduct level with AFM1 excretion was observed. An equally highly significant correlation of adduct level with intake (r = 0.69, P less than 0.000001) was also observed. From the slope of the regression line for adduct level as a function of intake, it was calculated that 1.4-2.3% of ingested AFB1 becomes covalently bound to serum albumin, a value very similar to that observed when rats are administered AFB1.

Aflatoxin B1↗
PubMed1988

Bacterial catalysis of nitrosation: involvement of the nar operon of Escherichia coli.

We have developed a rapid and sensitive fluorimetric method, based on the formation of a fluorescent product from nitrosation of 2,3-diaminonaphthalene, for measuring the ability of bacteria to catalyze nitrosation of amines. We have shown in Escherichia coli that nitrosation can be induced under anaerobic conditions by nitrite and nitrate, that formate is the most efficient electron donor for this reaction, and that nitrosation may be catalyzed by nitrate reductase (EC 1.7.99.4). The narG mutants defective in nitrate reductase do not catalyze nitrosation, and the fnr gene is essential for nitrosation. Induction by nitrite or nitrate of nitrosation, N2O production, and nitrate reductase activity all require the narL gene.

2-Naphthylamine↗
PubMed1988

Haemoglobin adducts of aromatic amines in people exposed to cigarette smoke.

In a population-based study in Turin, Italy, smokers of blond tobacco showed 4-aminobiphenyl (4-ABP) adduct levels some three times higher than nonsmoking subjects, and smokers of black tobacco showed levels about five times greater than nonsmokers. A dose-response relationship between the number of cigarettes smoked per day and 4-ABP adduct level was observed, but did not account for the higher adduct levels observed in smokers of black tobacco. Smoking-related increases in haemoglobin adducts were also observed for o-toluidine, p-toluidine, 2,4-dimethylaniline and 2-ethylaniline. Smoking subjects showed 3-aminobiphenyl adduct levels about 12 times greater than those of nonsmokers, who rarely showed a detectable level. This may indicate that there are fewer sources of 3-aminobiphenyl exposure not related to tobacco smoke. Smokers of black tobacco showed higher adduct levels than smokers of blond tobacco for 4-ABP, p-toluidine and 2,4-dimethylaniline.

2-Naphthylamine↗
PubMed1987

Hemoglobin adducts of 4-aminobiphenyl in smokers and nonsmokers.

A quantitative method has been developed for the analysis of 4-aminobiphenyl (4-ABP) covalently bound as the sulfinic acid amide to the 93 beta cysteine of human hemoglobin. The method uses mild basic hydrolysis of hemoglobin to release the parent amine, derivatization to form the pentafluoropropionamide, and capillary gas chromatography with detection by negative-ion chemical ionization mass spectrometry. The method is precise and gives reproducible results on multiple blood samples taken from individuals over 48 h. Application of this method to blood samples from cigarette smokers and nonsmokers revealed consistently higher adduct levels in smokers. The mean value for smokers was 154 pg 4-ABP per g Hb compared to 28 pg/g Hb for nonsmokers, with no overlap of adduct levels between the two groups. Studies on quitting smokers revealed that adduct levels declined over a period of 6-8 weeks to nonsmoker levels. The finding of 4-ABP adducts in all nonsmokers was not anticipated but is consistent with low-level ubiquitous contamination of air, food, or water. In other animals sampled, rats and dogs had measurable adduct levels, but monkeys and fish did not. The hemoglobin adduct of 4-ABP is the product of a series of reactions between the hemoprotein and N-hydroxy-4-ABP. The formation of hydroxylamines from carcinogenic aromatic amines and their subsequent reactions with DNA are generally thought to be critical events in the initiation of bladder tumors. We suggest that the observed hemoglobin adduct levels formed by this proximate carcinogen will reflect the extent to which these steps have occurred. This is the first report of 4-ABP adducts in human blood.

Aminobiphenyl Compounds↗
PubMed1987

Genetic etiology of gastric carcinoma: II. Segregation analysis of gastric pH, nitrate, and nitrite.

A study of gastric pH, nitrate, and nitrite in 110 families collected as part of a cohort from the Narino region of Colombia is presented. All three traits are familial and have a significant linearly increasing age trend. Gastric pH has a clear bimodal distribution but does not show Mendelian segregation. The nitrate distribution is slightly skewed, but generational heterogeneity explains the data best. Gastric nitrite is also biomodal with a clear break at concentration 1.08 micrograms/ml, and 74% of the observations at zero concentration; it shows a recessive Mendelian segregation with significant residual spouse correlation. This model also fits the data best when nitrite is dichotomized into detected (measurable) and undetected values. The estimated frequency of the recessive allele is .57, so that an estimated 32% of the population sampled are recessives. Recessives whose spouses have measurable nitrite have an estimated penetrance of 99.3% at age 30 years, whereas those whose spouses have zero or undetected nitrite have a penetrance of only 8.8% at age 30 years. It appears that gastric nitrite, and, from our previous study of these families, chronic atrophic gastritis are important biologic markers for the early identification of persons predisposed to gastric cancer.

Adult↗
PubMed1987

Comparison of the mutagenic activity of various brands of food grade beef extracts.

The mutagenic activity of 9 brands of commercial meat extracts were compared using Ames tester strain TA 98 with hepatic S-9 activation prior to concentration by solvent extraction. In a preincubation test system where 20 mg of intact meat extract preparations were tested per plate, about half of the brands were non-mutagenic whereas the other half increased the spontaneous revertant number by a factor of 2.5-3 (MF). The mutagenic principals could be extracted into methylene chloride under alkaline conditions and the mutagenic activity of these basic organic extracts ranged in potency from a mutation factor of 7-40 (280-1600 revertants) per 2 g equivalents of intact meat extracts in the standard Ames test. A quantitative correlation was obtained between the two trials (intact and extracted samples). The commercial meat extract with the greatest activity contained approximately 70 ng/g of total amino-imidazoquinoline and amino-imidazoquinoxaline compounds while the weakest brand of meat extract contained less than 10 ng/g of these heterocyclic aromatic amines. The human intake of these heterocyclic amines from meat extract in bouillon soups was estimated at maximally 100 ng/day and is approximately 10(3) times less than the estimated total daily intake of all heterocyclic amines which are known to be formed in protein-rich heated foods.

Animals↗
PubMed1987

Binding of 2-amino-3-methylimidazo[4,5-f]quinoline to hemoglobin and albumin in vivo in the rat. Identification of an adduct suitable for dosimetry.

Blood protein binding by the food-borne carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) was investigated using male Sprague-Dawley rats. Among the many blood proteins modified in rats dosed intragastrically with [3H(G)]IQ, hemoglobin and albumin were modified in a dose dependent fashion. Albumin bound 3-5 times more IQ than hemoglobin at doses from 2 to 150 mumol. IQ-modified serum albumin was enzymatically digested using Pronase and analyzed by h.p.l.c. Many peptide fragments containing radioactivity were detected but the low level of protein modification (0.01-0.04% of dose) prevented spectroscopic analyses of these adducts. An in vitro system containing hepatic microsomes metabolized IQ to a reactive species which could bind to serum albumin. One major adduct was formed at the cysteine residue using this activation system and was identical to an adduct isolated from in vivo-modified albumin. Chemical and spectroscopic analyses of the Pronase fragment proved the adduct was a tripeptide containing N2-cysteinesulfinyl-IQ. A chemically identical adduct was formed in vitro when N-hydroxy-IQ was incubated with serum albumin. As much as 10% of the IQ bound to serum albumin in vivo was present as this sulfur-linked adduct based on h.p.l.c. analysis of the Pronase digest fragments and on the acid-labile activity which could be recovered as IQ.

Animals↗
PubMed1987

Isolation and characterization of the major serum albumin adduct formed by aflatoxin B1 in vivo in rats.

Aflatoxin B1 (AFB1) was shown to react primarily with one or more lysine residues in serum albumin (SA), accounting for more than half of the total binding to this protein. The radioactivity associated with SA following administration of [U-14C]AFB1 to rats was cleared with a half-life of 2.5 days, which is not significantly different from the half-life of unmodified albumin in the normal rat. The product isolated from a Pronase digest of in vivo-modified SA was identical by chromatographic retention time and u.v. and mass spectroscopy to the synthetic product obtained by the acylase-catalyzed deacetylation of the reaction product of N alpha-acetyl-L-lysine with 8,9-dihydro-8,9-dibromo-AFB1. The latter was characterized by u.v., fluorescence, 500 MHz 1H-n.m.r. and fast atom bombardment mass spectrometry. The spectral data strongly support a structure in which the terminal dihydrofuran ring of AFB1 has been converted to a pyrrolinone ring. It is proposed that the initial adduct is formed by condensation of the dialdehyde tautomer of 8,9-dihydro-8,9-dihydroxy-AFB1, with the epsilon-amino group of lysine, to form a Schiff base, and that the Schiff base undergoes an Amadori rearrangement to an alpha-amino ketone. The pyrrolinone ring is formed by condensation of the amino group with the remaining aldehyde to yield the final product. The purified product was relatively stable but was shown to decompose significantly under the conditions used to isolate it from modified SA.

Aflatoxin B1↗
PubMed1987

Nitrosation of amines by stimulated macrophages.

Rats and mice treated in vivo with Escherichia coli lipopolysaccharide (LPS) synthesize and excrete large quantities of nitrate. Murine peritoneal macrophages, elicited in vivo with thioglycolate and stimulated in vitro with LPS and/or gamma-interferon (IFN), produce copious amounts of nitrate and nitrite. We report here experiments showing N-nitrosamine formation by macrophages immunostimulated in vitro. Macrophage cell lines J774.1, PU5-1.8, WEHI-3 and RAW 264 and freshly isolated macrophages from C3H/He mice were used. Macrophages were cultured in Dulbecco's modified Eagle's medium (pH 7.5) supplemented with calf serum (10%). Supernatant NO2- and NO3- were measured. N-Nitrosamines were extracted with dichloromethane and the extracts analyzed by a gas chromatography--thermal energy analyzer. Cells (1.5 X 10(6)/ml) were incubated with LPS (10 micrograms/ml) and morpholine (15 mM) for 72 h at 37 degrees C. Under these conditions, all of the cell types listed above produced nitrite (40-70 microM) and N-nitrosomorpholine (NMOR; 114-940 nM). LPS was required for both processes, and this effect was enhanced by IFN. Nitrite (150 microM) incubated with morpholine in cell-free medium did not form NMOR nor did cells plus morpholine and NO2-. The rate of NMOR formation in the J774.1 cell line was highest in the middle incubation period (24-36 h) although [NO2-] was highest in the final incubation period (48-72 h). Thus, the cells do not catalyze nitrosamine formation per se, rather the amine traps out a reactive nitrosating species prior to the formation of NO2- and NO3-. These results suggest that immunostimulated macrophages may be capable of nitrosamine formation under physiological conditions.

Animals↗
PubMed1987

The ferret as a model for endogenous synthesis and metabolism of N-nitrosamines.

We have begun to evaluate the ferret as a model for studying gastric nitrosation and nitrosamine metabolism. Jugular cannulation allows convenient dosing and sampling of blood, and this technique has been used to study clearance of N-nitrosodimethylamine (NDMA) after intravenous, intraperitoneal and intragastric administration. NDMA metabolism can be inhibited by 4-methylpyrazole for up to 24 h; the accumulation of endogenously-synthesized NDMA can therefore be observed in animals following pretreatment with this compound. We have studied endogenous NDMA synthesis in animals dosed with dimethylamine and nitrite and in animals to which no NDMA precursors were administered.

Animals↗
PubMed1987

Endogenous formation of N-nitroso compounds: a current perspective.

Exposure of people to nitrosating agents occurs through multiple pathways, ranging from nitrogen dioxide reactions in the lung to acid-catalysed nitrosation in the stomach to nitrosation mediated by macrophages or bacteria. The use of N-nitrosoproline (NPRO) as an index of endogenous nitrosation has proved to be especially valuable for some of these pathways but may not be universally indicative. Since the development of the NPRO test by Ohshima and Bartsch in 1981, several forms of the test have been used for different purposes. This paper examines some of the issues related to endogenous nitrosation and NPRO and attempts to view the immediate future.

Bacteria↗
PubMed1987

N-nitrosamine formation by macrophages.

Nitrate biosynthesis is a known mammalian process, and macrophages from mice treated with Escherichia coli lipopolysaccharide (LPS) have been shown to be capable of nitrate synthesis. Cell culture studies showed that macrophages produce nitrite as well as nitrate. We report here N-nitrosamine formation by stimulated macrophages. Experiments were carried out with the macrophage cell lines, J774.1, WEHI-3 and RAW 264. Macrophages were cultured in Dulbecco's modified Eagle's medium (pH 7.5) supplemented with calf serum (10%). The concentration of nitrate in the supernatant was measured. N-nitrosamines were extracted with dichloromethane and the extracts were analysed by gas chromatography-thermal energy analysis. When J774.1 (1.5 X 10(6) cells/ml) were incubated with LPS (10 micrograms/ml) and morpholine (15 mM) for 72 h at 37 degrees C, N-nitrosomorpholine (NMOR) was produced (0.8 microM). The amount of nitrite produced was 50 microM. RAW 264 and WEHI-3 also produced NMOR; LPS was required for nitrite and NMOR formation. gamma-Interferon (IFN) promoted both NMOR (2.5 microM) and nitrite (70 microM) formation. Nitrite (150 microM) incubated with morpholine and the medium did not form NMOR. Kinetics of LPS-induced nitrite and NMOR formation in J774.1 showed that the rate of NMOR formation was highest in the middle incubation period (24-36 h), although the nitrite concentration was highest in the latter incubation period (48-60 h). Our results showed that macrophages may be capable of nitrosamine formation under physiological conditions that do not normally permit this reaction.

Animals↗
PubMed1986

Mechanisms for nitrite loss from the stomach.

Nitrite loss from the stomach was studied using dogs equipped with Thomas cannulas for direct access to the stomach lumen. Solutions containing sodium nitrite and non-absorbable volume marker (polyethylene glycol, PEG) were infused into the stomach, and samples were taken over 60 min to determine the concentration of 'total nitrite' (including NO2-, HNO2 and other species in equilibrium with NO2-) and rate of dilution of the stomach contents as a function of time. Changes in stomach volume were also measured. Nitrite loss was found to be very rapid, with total nitrite concentrations declining to less than half the initial levels in 10 min. The decay in total nitrite concentrations was due predominantly to gastric absorption, with small additional contributions from dilution of the stomach contents (inferred from PEG concentrations) and chemical reactions (from in vitro kinetic data). Results for initial nitrite concentrations varying over a range of 0.15-4.5 mM showed absorption to be first order in total nitrite. The permeability-area product for nitrite absorption (PA) was about 0.6 l/h, and was unaffected by the addition of 1 mM SCN- or Cl-. All of these results are consistent with nitrite absorption in the form of NO2- or HNO2. Buffering the infusate with HCO3- to increase luminal pH from approximately 2 to 7 caused a three-fold reduction in the apparent value of PA. When pentagastrin was used to stimulate acid secretion, nitrite absorption was only half as fast as when acid secretion was inhibited with cimetidine, or when no drug was given. This effect could not be explained by variations in luminal pH, and suggests that acid secretion either decreases PA or is accompanied by active secretion of nitrite. Based on these data, a mathematical model was developed to stimulate the physical and chemical factors governing nitrite concentrations in the stomach.

Animals↗