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PubMed1996

Thiocyanate-independent nitrosation in humans with carcinogenic parasite infection.

Infection with the liver fluke, Opisthorchis viverrini, is a causative agent of cholangiocarcinoma. One possible contributing factor in this carcinogenesis is the chronic, local generation of nitric oxide by inflammatory cells expressing inducible nitric oxide synthase and the production of N-nitroso compounds via the reaction between amines and nitrosating agents derived from nitric oxide. Our previous studies provided evidence that nitric oxide synthesis is elevated during human liver fluke infection. Here we present data on the same sample of men which definitively demonstrates increased nitrosation of proline and thioproline (thiazolidine-4-carboxylic acid) among infected men compared to uninfected control subjects on a low nitrate diet. This difference was specifically abolished by co-administration of ascorbic acid with proline and by elimination of parasites by praziquantel treatment. Multivariate statistical models demonstrate the importance of salivary thiocyanate levels to variation in the nitrosation of proline among uninfected individuals, but not among those with current fluke infection. This suggests that considerable generation of nitrosating agents (N203/N204) in infected people may be occurring via oxidation of arginine by nitric oxide synthase in inflamed tissue which is thiocyanate insensitive. Analyses revealed positive associations between N-nitrosoproline excretion and nitrate/nitrite levels in urine, plasma and saliva and with usual alcohol intake; with variation in these trends between groups. In conclusion, we have confirmed the relationship between O.viverrini infection and enhanced endogenous nitrosation, showing evidence of its extragastric site. New information is also provided on the determinants of N-nitrosamino acid excretion in men on a controlled low nitrate diet without smoking, conditions which reduce exogenous sources of nitrosating agents.

Adult↗
PubMed1987

Bacterially catalysed N-nitrosation reactions and their relative importance in the human stomach.

Human exposure to endogenously formed N-nitroso compounds has frequently been suggested as a causative factor in carcinogenesis where this is related to chronic bacterial infection such as is seen in gastric achlorhydria. At least two distinct mechanisms of endogenous formation have been identified. The first, a direct chemical reaction between secondary amino compounds and nitrite, is strongly pH dependent and does not proceed rapidly at neutral pH even in the presence of chemical catalysts. The second depends on the direct bacterial catalysis of N-nitrosation. The data presented demonstrate that the bacterially mediated reaction is catalysed by bacterial enzyme systems and proceeds much more rapidly at neutral pH than the chemical reaction. This suggests a particular relevance to the in vivo situation where neutral pH, bacteria and elevated nitrite concentrations are found. Drawing on the kinetic information presented regarding the bacterially mediated nitrosation reaction, the known kinetics of the chemical reaction and the published values for the relevant substrate concentrations in both the colonised and the normal acid stomach the bacterial and chemical reactions have been compared. Using these criteria, and assuming the presence of bacteria with the appropriate metabolic activity, it may be predicted that N-nitroso compounds may be formed in the colonized stomach at much higher concentrations than in the normal acid stomach. The difference in yield may be by two to four orders of magnitude. Different bacterial species and different isolates of the same species show considerable variation in their abilities to catalyse N-nitrosation reactions. The most rapid catalysis is associated with those bacteria capable of reducing nitrate and nitrite by the process of denitrification. The most significant clinical corollary of these studies is that although bacterial catalysis of N-nitrosation has been demonstrated unequivocally, bacterial colonization of the stomach may not itself necessarily result in elevated endogenous N-nitroso compound exposure despite the elevated nitrite concentrations normally associated with such colonization. An increase in exposure to endogenously formed N-nitroso compounds would only be predicted in those individuals where a significant proportion of the colonizing bacteria expressed significant N-nitrosation activity. As a consequence the carcinogenic risk may be restricted to only a small proportion of colonized individuals depending on the prevalence of sustained infection by bacteria with significant N-nitrosation activity, particularly denitrifiers.

Humans↗
PubMed1980

Effects of ergothioneine, cysteine, and glutathione on nitrosation of secondary amines under physiologic conditions.

The effects of ergothioneine, cysteine, and glutathione, which are naturally occurring sulfhydryl compounds, on the aerobic and anaerobic nitrosation of dimethylamine were studied at pH 2.0-7.0 and at 37 degrees C. Under aerobic conditions, ergothioneine increased the formation of dimethylnitrosamine (DMN) at all pH values tested, cysteine and glutathione had the same effect at pH 4.0-6.0, and cysteine formed DMN at pH 7.0. However, as compared to controls cysteine showed no increased effect in an O2 atmosphere at pH 6.0. The effects of sulfhydryl compounds on anaerobic nitrosation were more significant (p < 0.001) than on aerobic nitrosation, probably because these sulfhydryl compounds, except ergothioneine, are easily oxidized. Ergothioneine increased aerobic nitrosation almost as strongly as anaerobic nitrosation. The effects of sulfhydryl compounds, especially ergothioneine, on nitrosation at physiologic pH and temperature might be significant in the in vivo formation of N-nitrosamines in the hemorrhage or ulcerous gastrointestinal tract or injured organs.

Animals↗
PubMed1984

Nitrosating properties of bis-methylthio-diiron-tetranitrosyl (Roussin's red methyl ester), a nitroso compound isolated from pickled vegetables consumed in northern China.

Bis-methylthio-diiron-tetranitrosyl (Roussin's red methyl ester, RRME), recently identified in pickled vegetables consumed in a high incidence area of oesophageal cancer in Northern China, was examined for its activity as a nitrosating agent in vivo and in vitro. Freshly synthesized RRME nitrosated secondary amines (morpholine and pyrrolidine) slowly in the presence of air; it failed to nitrosate these amines under strictly anaerobic conditions. In experiments in rats, a fresh sample of RRME was found to be a weak nitrosating agent, whereas partially decomposed RRME showed a strong nitrosating activity comparable to that of nitrite. Possible mechanisms for nitrosation by RRME are discussed.

Animals↗
PubMed1996

Mutagenic activity of glycine upon nitrosation in the presence of chloride and human gastric juice: a possible role in gastric carcinogenesis.

The mutagenic activity of glycine upon nitrosation was studied in the Ames tester strains TA98, TA100, TA102, and TA104. The results obtained show that glycine at acidic pH values and in the presence of Cl- can react with nitrite giving rise to genotoxic compounds to the tester strains used. When these experiments were carried out in the presence of gastric juice the genotoxicity observed was associated with the Cl- concentration in the different gastric juice samples. The nature and the mechanism of genetic lesion induced by the ultimate genotoxicant arising from the nitrosation of glycine are not fully understood. Primary amines (e.g., amino acids) have been described as potential alkylating agents after nitrosation. However, in our experimental conditions these alkylating activities were not detected, suggesting that other mechanisms could be involved in the genetic lesion induced by nitrosated glycine. The influence of Cl- in the genotoxic activity of glycine and other primary amines upon nitrosation and its possible involvement in the etiology of gastric cancer are discussed.

Chlorides↗
PubMed2000

Genotoxicity of instant coffee and of some phenolic compounds present in coffee upon nitrosation.

Instant coffee exhibits genotoxic activity upon nitrosation at acidic pH values in the Ames tester strain TA100. Using adsorption chromatography (Amberlit XAD-2) it was observed that the major fraction of molecules responsible for the genotoxic activity upon nitrosation was not retained on this resin, suggesting that the polar molecules present in instant coffee could be responsible for the genotoxicity observed upon nitrosation. Some phenolic molecules present in instant coffee (catechol, caffeic acid, and chlorogenic acid) were also genotoxic upon nitrosation under the same experimental conditions. The concentrations of nitrosatable phenolic compounds in the studied coffee were determined by HPLC and their contributions to the total genotoxicity observed were studied. The results obtained suggest that besides phenolic compounds other molecules were also involved in the genotoxicity of this beverage upon nitrosation. Teratogenesis Carcinog. Mutagen. 20:241-249, 2000.

Adsorption↗
PubMed2005

Evidence of nitrosative damage in the brain white matter of patients with multiple sclerosis.

Nitric oxide (NO) has been implicated in the pathophysiology of both experimental autoimmune encephalomyelitis and multiple sclerosis (MS). NO-mediated protein damage in MS appears to be confined to large plaques where 3-nitrotyrosine has been detected. To determine whether nitrosative damage takes place beyond visible MS plaques, the occurrence of various NO-triggered protein modifications in normal-appearing white matter (NAWM) of eight MS brains was assessed and compared to that in white matter (WM) of four control brains. As determined by amino acid analysis and western blotting, no evidence of tyrosine nitration was found in the MS samples studied, suggesting that they did not contain appreciable amounts of plaque-derived material. The amino acid composition of total myelin proteins and proteolipid protein (PLP) was also unaltered in the diseased tissue, as was the fatty acid composition of PLP. In addition, we detected no changes in the number of protein free thiols suggesting that oxidation do not occur to any appreciable extent. However, the levels of nitrite in MS-NAWM were higher than those in control WM, while in the MS-gray matter (GM) the concentration of this ion was unaltered. Furthermore, five of the MS samples analyzed, and the same as those with high levels of glial fibrilary acidic protein, showed increased amounts of protein nitrosothiols as determined by the "biotin switch" method. S-nitrosation of GM proteins was again normal. There was no indication of N-nitrosation of tryptophan and N-terminal amino groups in both control and MS tissue. Overall, the data suggests that WM, but not GM, from MS brains is subjected to considerable nitrosative stress. This is the first report to present direct evidence of increased protein S-nitrosation and nitrite content in the brain parenchyma of MS patients.

Adult↗
PubMed1992

Genotoxicity and cell proliferative activity of a nitrosated Oroxylum indicum Vent fraction in the pyloric mucosa of rat stomach.

In vivo genotoxic activity and cell proliferative activity were examined in the stomach mucosa of male F344 rats by in vivo short-term methods after oral administration of a nitrosated Oroxylum indicum Vent (OiV) fraction, which had been found to be mutagenic without S9 mix to Salmonella typhimurium TA98 and TA100. Administration of the nitrosated OiV fraction at doses of 1 and 2 g/kg body weight induced dose-dependent DNA single-strand scission (p less than 0.02), determined by the alkaline elution method, in the stomach pyloric mucosa 2 h after its administration: a dose of 2 g/kg body weight induced an 18-fold increase in the DNA elution rate constant. Administration of the nitrosated OiV fraction at doses of 0.7-2.8 g/kg body weight also induced dose-dependent increases, up to 11-fold (p less than 0.05), in replicative DNA synthesis in the stomach pyloric mucosa 16 h after its administration. Moreover administration of the nitrosated OiV fraction at doses of 0.25-2.0 g/kg body weight induced dose-dependent increases, up to 100-fold, in ornithine decarboxylase activity in the stomach pyloric mucosa with a maximum 4 h after its administration. These results demonstrate that the nitrosated OiV fraction has genotoxic and cell proliferative activity in the pyloric mucosa of rat stomach in vivo.

Administration, Oral↗
PubMed1993

Genotoxicity of nitrosated red wine and of the nitrosatable phenolic compounds present in wine: tyramine, quercetin and malvidine-3-glucoside.

Phenolic compounds and biogenic amines are known to be present in some foodstuffs which become directly genotoxic after nitrosation in vitro. Red wine has previously been shown to be genotoxic and this activity has been attributed mainly to flavonoids. Besides flavonoids, red wine contains a multiplicity of compounds, including biogenic amines. Using the Ames assay and the SOS chromotest, this study has shown that red wine and some of the nitrosatable molecules present in wine become directly genotoxic on nitrosation in vitro: these include the phenolic molecules tyramine, quercetin and malvidine-3-glucoside, whereas phenylethylamine and histamine were negative on nitrosation. Interestingly, quercetin had been predicted to be negative after nitrosation, using the CASE methodology. The concentrations of these three positive nitrosatable compounds in wine were determined by HPLC. Comparison of these concentrations and their respective levels of genotoxicity suggests that the genotoxicity after nitrosation is probably attributable to other molecules. It is also possible that synergistic effects may occur between various nitrosatable compounds in wine.

Anthocyanins↗
PubMed1992

Nitrosating activity in Escherichia coli.

Nitrosation activity was measured in Escherichia coli isolates and a range of nitrite reductase (nir) mutants. Activity was only detected in intact cells and could be inhibited by a number of treatments such as sonication and osmotic shock. Aerobically-grown cells had highest nitrosation activity compared to oxygen-limited ones. Inclusion of nitrite in growth media induced high activities of nitrite reductase and for some isolates, nitrosation. Analysis of nir mutants identified two which were unable to nitrosate. This result suggested that NADH-dependent nitrite reductase was implicated either directly or indirectly in nitrosation.

Aerobiosis↗
PubMed2005

Inhibition of the transcription factor Yin Yang 1 activity by S-nitrosation.

Treatment of several prostate cancer (CaP) cell lines (PC-3, CL-1, and DU-145) with the nitric oxide (NO) donor DETA/NONOate upregulated Fas expression and sensitized the CaP cells to the Fas ligand CH-11 agonist monoclonal antibody-induced apoptosis. Previous findings demonstrated that the transcription repressor Yin Yang 1 (YY1), which is inhibited by NO, negatively regulates Fas transcription [H.J. Garban, B. Bonavida, Nitric oxide inhibits the transcription repressor Yin-Yang 1 binding activity at the silencer region of the Fas promoter: a pivotal role for nitric oxide in the upregulation of Fas gene expression in human tumor cells, J. Immunol. 167 (2001) 75-81]. YY1 is a zinc finger protein and thus, we hypothesized that NO inhibits YY1 activity via S-nitrosation of critical cysteines residues coordinated by Zn2+. Treatment of PC-3 cells with DETA/NONOate inhibited the constitutive DNA-binding activity of YY1 as assessed by EMSA. Further, treatment with DETA/NONOate resulted in S-nitrosation of YY1 as detected by two different methods. The DAN-based method examined NO-treated tumor-derived cell lysates that were immunoprecipitated with an anti-YY1 specific antibody and the NO released was determined quantitatively by fluorometry. The second method consisted of immunoprecipitation of the tumor cell lysates by an anti-SNO cysteine antibody and the immunoprecipitate was immunoblotted with anti-YY1 antibody. Both methods revealed significant S-nitrosation of YY1 by DETA/NONOate treatment over control untreated cells. The S-nitrosation of YY1 was further corroborated by immunohistochemistry using dual color immunofluorescence. The direct role of YY1 in the negative regulation of Fas expression was demonstrated by transfection of cells with siRNA YY1. The transfectants exhibited upregulation of Fas expression in the absence of treatment with DETA/NONOate and were sensitized to CH-11-induced apoptosis. Altogether, these findings reveal that NO inhibits YY1 DNA-binding activity through S-nitrosation and consequently results in upregulation of Fas expression and tumor cell sensitization to Fas-induced apoptosis.

Apoptosis↗
PubMed2004

Processing of protein glycation, oxidation and nitrosation adducts in the liver and the effect of cirrhosis.

BACKGROUND/AIMS: Plasma proteins are modified non-enzymatically in vivo by glycation, oxidation and nitrosation processes. Hepatic extraction of albumin glycated in vitro was reported but it is not clear if plasma proteins glycated in vivo also undergo hepatic extraction. We investigated the hepatic extraction of glycated, oxidised and nitrosated proteins in vivo. METHODS: Protein glycation, oxidation and nitrosation marker residues and free adducts were determined in portal, hepatic and peripheral venous blood plasma of cirrhotic patients and hepatic and peripheral venous blood plasma (as a surrogate of portal venous blood) of control subjects by liquid chromatography-mass spectrometry. RESULTS: There was no evidence for extraction of glycated, oxidised or nitrosated proteins or related free adducts by the liver in control subjects. There was limited extraction of methylglyoxal-modified proteins in cirrhotic patients and twofold increases in the concentrations of fructosyl-lysine and advanced glycation endproduct residues of plasma protein, with respect to controls. Remarkably, glyoxal-derived hydroimidazolone free adduct was increased 14-16-fold probably as a consequence of hepatic lipid peroxidation. CONCLUSIONS: We found no evidence for hepatic extraction of glycated, oxidised and nitrosated proteins or related free adducts in subjects with normal liver function and limited extraction of methylglyoxal-modified protein in cirrhotic subjects.

Adult↗
PubMed2005

Development of enzymatic probes of oxidative and nitrosative DNA damage caused by reactive nitrogen species.

Chronic inflammation is associated with a variety of human diseases, including cancer, with one possible mechanistic link involving over-production of nitric oxide (NO*) by activated macrophages. Subsequent reaction of NO* with superoxide in the presence of carbon dioxide yields nitrosoperoxycarbonate (ONOOCO2-), a strong oxidant that reacts with guanine in DNA to form a variety of oxidation and nitration products, such 2'-deoxy-8-oxoguanosine. Alternatively, the reaction of NO and O2 leads to the formation of N2O3, a nitrosating agent that causes nucleobase deamination to form 2'-deoxyxanthosine (dX) and 2'-deoxyoxanosine (dO) from dG; 2'-deoxyinosine (dI) from dA; and 2'-deoxyuridine (dU) from dC, in addition to abasic sites and dG-dG cross-links. The presence of both ONOOCO2- and N2O3 at sites of inflammation necessitates definition of the relative roles of oxidative and nitrosative DNA damage in the genetic toxicology of inflammation. To this end, we sought to develop enzymatic probes for oxidative and nitrosative DNA lesions as a means to quantify the two types of DNA damage in in vitro DNA damage assays, such as the comet assay and as a means to differentially map the lesions in genomic DNA by the technique of ligation-mediated PCR. On the basis of fragmentary reports in the literature, we first systematically assessed the recognition of dX and dI by a battery of DNA repair enzymes. Members of the alkylpurine DNA glycosylase family (E. coli AlkA, murine Aag, and human MPG) all showed repair activity with dX (k(cat)/Km 29 x 10(-6), 21 x 10(-6), and 7.8 x 10(-6) nM(-1) min(-1), respectively), though the activity was considerably lower than that of EndoV (8 x 10(-3) nM(-1) min(-1)). Based on these results and other published studies, we focused the development of enzymatic probes on two groups of enzymes, one with activity against oxidative damage (formamidopyrimidine-DNA glycosylase (Fpg); endonuclease III (EndoIII)) and the other with activity against nucleobase deamination products (uracil DNA glycosylase (Udg); AlkA). These combinations were assessed for recognition of DNA damage caused by N2O3 (generated with a NO*/O2 delivery system) or ONOOCO2- using a plasmid nicking assay and by LC-MS analysis. Collectively, the results indicate that a combination of AlkA and Udg react selectively with DNA containing only nitrosative damage, while Fpg and EndoIII react selectively with DNA containing oxidative base lesions caused by ONOOCO2-. The results suggest that these enzyme combinations can be used as probes to define the location and quantity of the oxidative and nitrosative DNA lesions produced by chemical mediators of inflammation in systems, such as the comet assay, ligation-mediated polymerase chain reaction, and other assays of DNA damage and repair.

Animals↗
PubMed2006

Nitrosation of uric acid induced by nitric oxide under aerobic conditions.

Uric acid is a well-established scavenger of reactive oxygen and nitrogen species such as hydroxyl radical and peroxynitrite. However, little attention has been paid to the relationship between uric acid and nitric oxide. This paper reports the identification and characterization of a reaction product of uric acid induced by nitric oxide. When uric acid was treated with nitric oxide gas in a neutral solution under aerobic conditions, uric acid was consumed, yielding an unknown product. The product was identified as nitrosated uric acid from mass spectrometric data, although the position of the nitroso group on the molecule was not determined. The nitrosated uric acid decomposed to several compounds including uric acid with a half-life of 2.2 min at pH 7.4 and 37 degrees C. The incubation of nitrosated uric acid with glutathione resulted in the formation of S-nitrosoglutathione. Nitrosated uric acid was also formed in the reaction with nitric oxide donors, but not with peroxynitrite. Nitrosated uric acid was detected in human serum and urine by in vitro treatment with a nitric oxide donor. In the reaction of glutathione with the nitric oxide donor, the addition of uric acid caused an increase in the yield of S-nitrosoglutathione. These results indicate that under aerobic conditions nitric oxide can convert uric acid into its nitroso derivative, which can give a nitroso group to glutathione. Uric acid may act as a vehicle of nitric oxide in humans.

Aerobiosis↗
PubMed2003

S-nitrosation of Cys-800 of HIF-1alpha protein activates its interaction with p300 and stimulates its transcriptional activity.

Hypoxia inducible factor 1 (HIF-1) is a heterodimeric transcriptional complex that plays pivotal role in the regulation of cellular utilization of oxygen as well as glucose and is an essential regulator of angiogenesis in solid tumor and ischemic disorders. Recently HIF-1alpha, a subunit of HIF-1 complex, was characterized as a potential target for S-nitrosation, providing no information about the impact of this posttranslational modification on the protein transactivation. Cys-800 of HIF-1alpha protein has reactive SH-group, which is critical for the recruitment of p300 co-activator that is necessary for transcriptional activity of HIF-1 complex. Here we report that S-nitrosation of Cys-800 activates HIF-1alpha-p300 interaction and stimulates protein transactivation. We have found that S-nitrosation of the HIF-1alpha C-terminal domain by nitric oxide derived from donors and nitric oxide synthase increases protein transcriptional activity. The increase of HIF-1 transcriptional activity was not observed in the case of Cys-800 substitution to Ala, though other protein thiol groups were nitrosated. Experiments with GST pull-down assay suggest that S-nitrosation of Cys-800 stimulates the recruitment of p300 co-activator protein to the HIF-1alpha C-terminal domain.

Binding Sites↗
PubMed2002

Nitrosation of dietary myosmine as risk factor of human cancer.

The tobacco alkaloid myosmine was detected in nut and nut products [J. Agric. Food Chem. 46 (1998) 2703]. Upon nitrosation, myosmine yields 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB) and N-nitrosonornicotine (NNN) [J. Agric. Food Chem. 48 (2001) 392]. NNN is a strong oesophageal carcinogen in rats. Metabolic activation of NNN leads to formation of DNA and protein adducts which release HPB upon hydrolysis. In the present study the time, pH and dose-dependent nitrosation of myosmine and its covalent binding to DNA was investigated. [5-(3)H]myosmine was incubated with nitrite for 1-24 h in buffer solutions adjusted to pH 1-6. At pH 2-4 myosmine was easily nitrosated and gave rise to two major products, HPB and NNN, and five minor not yet identified products. Maximal formation was achieved for HPB at pH 2 after 8 h (72% of total radioactivity) and for NNN at pH 3 after 8 h (16%). For DNA binding studies labeled myosmine was incubated under nitrosation conditions with calf thymus DNA. Within 3 h up to 0.1% of the radioactivity was covalently bound to DNA. Endogenous nitrosation of myosmine, present in nuts and other dietary components could constitute a significant risk factor for tumours in the upper intestinal tract such as oesophageal adenocarcinoma, which are unrelated to tobacco smoking and alcohol abuse.

Adenocarcinoma↗
PubMed2001

Endonuclease V of Escherichia coli prevents mutations from nitrosative deamination during nitrate/nitrite respiration.

Endonuclease V (Endo V) of Escherichia coli participates in the excision repair of hypoxanthine and xanthine (deaminated adenine and guanine) in DNA. It thereby reduces the mutagenic effects of nitrous acid by attacking lesions caused by nitrosative deamination. Nitrosating agents may be produced endogenously when E. coli is grown in oxygen-poor cultures, during which nitrate and nitrite replace oxygen as preferred electron acceptors. In this study, the protective effect of Endo V was observed under such conditions. During micro-aerobic growth, an nfi (Endo V) mutation enhanced the frequency of nitrate- and nitrite-induced A:T-->G:C and G:C-->A:T transition mutations, which are consistent with a defect in the removal of DNA hypoxanthine and xanthine, respectively. Similar effects were observed in saturated, aerobic cultures but not in well-aerated, logarithmically growing ones. A narG (nitrate reductase) mutation blocked the mutagenesis of the nfi mutant by nitrate but not by nitrite. These results differed from those of previous studies in which cell suspensions generated an exogenous nitrosating agent from nitrite, but not from nitrate, in a reaction that was narG-dependent. Nitrate/nitrite metabolism is also known to generate endogenous alkylating agents through N-nitrosation. However, an nfi mutation did not appreciably enhance mutagenesis by N-methyl-N-nitrosourea, suggesting that the mutator effect of nfi is not due to a defect in alkylation repair. The overall results indicate that Endo V functions during normal growth by helping to repair nitrosatively deaminated bases in DNA, which are by-products of anaerobic nitrate/nitrite respiration.

Aerobiosis↗
PubMed2001

Effects of mono-, di- and tri-hydroxybenzoic acids on the nitrosation of propranolol: structure-activity relationship.

Nitrosation of propranolol under standard conditions recommended by the World Health Organization (10mM propranolol hydrochloridre, 40mM sodium nitrite, pH 3.5) was performed in the absence and in the presence of benzoic acid and of twelve mono-, di- and tri-hydroxybenzoic acids, added to the nitrosation mixture in concentrations ranging from 2 to 40mM, in order to examine their effect on the nitrosation reaction. The yield of N-nitrosopropranol (NOP) was reduced by benzoic acid and, with potency decreasing in the following order, by 2,3,4-tri-hydroxybenzoic acid>/=3,4-tri-hydroxybenzoic acid>2,5-di-hydroxybenzoic acid>2,3-di-hydroxybenzoic acid>3-hydroxybenzoic acid>2-hydroxybenzoic acid>3,4,5-tri-hydroxybenzoic acid>4-hydroxybenzoic acid; their inhibiting effect was concentration-dependent. In contrast, 2,4-di-hydroxybenzoic acid, 2,6-di-hydroxybenzoic acid and 2,4,6-tri-hydroxybenzoic acid caused an increase in the yield of NOP that was inversely related to their concentration. 3,5-Di-hydroxybenzoic acid was substantially inactive. These findings indicate that, depending on the positions of carboxyl group and hydroxyl groups on the benzene ring, mono-, di- and tri-hydroxybenzoic acids may inhibit or hasten nitrosation reactions. As compared with benzenediols and benzenetriols [Mutat. Res. 398 (1998) 75], hydroxybenzoic acids inhibit the nitrosation of propranolol to a greater extent and have the advantage of being nonmutagenic and less toxic.

Area Under Curve↗