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S Grivas

Publications and source records attributed to S Grivas.

35 records · Page 2Linked to original sources
PubMed1988

Oxidation of the 2-hydroxyamino derivative of 2-amino-6-methyl-dipyrido[1,2-a: 3',2'-d] imidazole (Glu-P-1) to its 2-nitroso form, an ultimate form reacting with hemoglobin thiol groups.

The binding to hemoglobin of synthetic 2-hydroxyamino-6-methyldipyrido[1,2-a: 3',2'-d] imidazole from the carcinogenic product of L-glutamic acid pyrolysis 2-amino-6-methyldipyrido[1,2-a: 3',2'-d] imidazole were investigated in vitro. The hydroxylamine required oxidation to its nitroso derivative to bind to rat hemoglobin through thiol groups. Oxidation of the hydroxylamine to the nitroso form was found to be enhanced by oxyhemoglobin and superoxide dismutase at pH 7.4 under aerobic conditions. Since these conditions might also enhance this oxidation in vivo, the conversion of the DNA-reactive arylhydroxylamines to the DNA-non-reactive nitroso compounds and their subsequent binding to highly abundant thiol groups of proteins could be considered as a process for detoxification of toxic arylhydroxylamines.

Animals↗
PubMed1988

Non-enzymatic glutathione conjugation of 2-nitroso-6-methyldipyrido [1,2-a: 3',2'-d] imidazole (NO-Glu-P-1) in vitro: N-hydroxy-sulfonamide, a new binding form of arylnitroso compounds and thiols.

In order to study the possible detoxification mechanisms of the carcinogenic arylamine, 2-amino-6-methyldipyrido[1,2-a: 3',2'-d]imidazole (Glu-P-1), the in vitro non-enzymatic reaction of 2-nitroso-6-methyldipyrido[1,2-a: 3',2'-d]imidazole (NO-Glu-P-1) with reduced glutathione (GSH) was examined at pH 7.4 under both aerobic and anaerobic conditions. Two GSH-arylamine adducts were isolated and found to contain the Glu-P-1 and GSH moieties in a 1:1 molar ratio via an N-S linkage. Their structures were assigned as sulfinamide (-NH-SO-) and N-hydroxy-sulfonamide (-N(OH)-SO2-) by their behaviour under acidic and basic conditions and by UV-VIS, 1H-NMR, infrared and mass spectrometries. Also, a N-hydroxy-sulfonamide adduct was produced when NO-Glu-P-1 and cysteine were reacted at pH 7.4. The N-hydroxy-sulfonamide structure is a new binding form between arylnitroso compounds and thiols. The formation of these adducts may also take place in vivo as a detoxification of toxic arylamines since GSH is abundant in organs such as liver or kidney.

Chromatography, High Pressure Liquid↗
PubMed1988

In vitro reaction of hydroxyamino derivatives of MeIQx, Glu-P-1 and Trp-P-1 with DNA: 32P-postlabelling analysis of DNA adducts formed in vivo by the parent amines and in vitro by their hydroxyamino derivatives.

The synthetic hydroxyamino derivatives of three mutagenic and carcinogenic heterocyclic amines present in cooked foods and amino acid pyrolysates, 2-amino-3,8-dimethylimidazo-[4,5-f]quinoxaline (MeIQx), 2-amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole (Glu-P-1) and 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1), were reacted with DNA in vitro. Their reactivities were increased by addition of 10-fold excess of acetic anhydride. 32P-Postlabelling analysis of the adducts formed in these in vitro reactions revealed that almost all the adducts of the hydroxyamino derivatives of MeIQx and Glu-P-1 were the same as those formed in liver DNA of rats intragastrically treated with the parent amines. In contrast, analysis of Trp-P-1--DNA adducts showed that the adducts formed in vitro were minor components of those formed in vivo; the two main adducts formed in vivo were not formed in vitro. Thus, MeIQx and Glu-P-1 may be metabolized in vivo to hydroxyamino derivatives and/or their esterified forms, such as N-acetoxy derivatives that form DNA adducts. Formation of adducts by Trp-P-1, however, may occur through more complicated metabolic pathways. Elucidation of the structures of DNA adducts in vivo is necessary to clarify this problem.

Animals↗
PubMed1988

Heterocyclic amine-DNA adducts analyzed by 32P-postlabeling method.

DNA adducts formed by 12 heterocyclic amines were analyzed by 32P-postlabeling method. Several DNA adducts were detected in rat liver by administration of each heterocyclic amine. Total adduct levels ranged from 0.5 for 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) to more than 250 for 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) per 10(7) nucleotides 24 hr after intragastric administration of these compounds. The N-hydroxy derivative of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) was reactive toward DNA in vitro to form adducts. Addition of acetic anhydride to N-OH-MeIQx greatly enhanced its reactivity to DNA. 32P-Postlabeling analysis revealed that the MeIQx-DNA adducts formed in vivo and in vitro were identical. Thus, MeIQx would be metabolized in vivo to N-hydroxy form and further esterified to produce more reactive species, such as N-acetoxy form, which modify DNA to form adducts.

Amines↗
PubMed1986

Formation of 4,8-DiMeIQx from the model system fructose, alanine and creatinine. Comparison with the isomeric 5,8-DiMeIQx.

In a previous paper, the main mutagenic compound isolated from the model reaction system D-fructose, DL-alanine and creatinine was tentatively identified as 4,8-DiMeIQx. Its mutagenic activity and spectral characteristics have now been compared with those of the isomer 5,8-DiMeIQx. The comparison clearly demonstrates that the isolated compound was indeed 4,8-DiMeIQx. This finding is in agreement with the hypothesis that sugars, amino acids and creatinine present in meat may be the precursors of the mutagenic imidazoquinolin- and imidazoquinoxalin-2-amines (IQ compounds).

Alanine↗
PubMed1985

Formation of a new mutagenic DiMeIQx compound in a model system by heating creatinine, alanine and fructose.

A mixture of creatinine, D-fructose and DL-alanine was heated in diethylene glycol containing 14% water for 2 h at ca. 128 degrees C. The mutagens formed were extracted with 1-butanol, and purified by cation-exchange column chromatography, C18 reversed-phase Sep-Pak treatment and reversed-phase HPLC. According to its UV absorption, mass and 1H NMR spectra, one isolated fraction was tentatively assigned the chemical name, 3,4,8-trimethyl-3H-imidazo[4,5-f]quinoxalin-2-amine (4,8-DiMeIQx). This finding is in agreement with the suggestion that sugars, amino acids and creatinine present in meat may be the precursors of the mutagenic imidazoquinolin- and imidazoquinoxalin-2-amines (IQ compounds).

Alanine↗
PubMed1985

The synthesis and mutagenicity of the 3-ethyl analogues of the potent mutagens IQ, MeIQ, MeIQx and its 3,7-dimethyl isomer.

The title compounds were synthesized and tested for mutagenicity on Salmonella typhimurium TA98 in the presence of S9 mix. All test compounds showed lower activity than their respective 3-methyl analogues (IQ compounds). The replacement of the 3-methyl by an ethyl group should not alter the chemistry of these compounds; hence, their lower mutagenic activity could merely be of steric origin.

Imidazoles↗
PubMed1985

An improved synthesis of 3,8-dimethyl-3H-imidazo[4,5-f]quinoxalin-2-amine ("MeIQx") and its 2-14C-labelled analogue.

The highly mutagenic title compound (MeIQx) was prepared in 21% overall yield from 4-fluoro-o-phenylenediamine. The 3,7-dimethyl isomer may be obtained as a minor by-product. The 14C-label was introduced in the last step through cyclization with [14C]cyanogen bromide. An alternative synthesis of MeIQx from p-fluoroaniline avoided the separation of isomers but gave poorer yield.

Chemical Phenomena↗
PubMed1985

Effects of meat composition and cooking conditions on the formation of mutagenic imidazoquinoxalines (MeIQx and its methyl derivatives).

In recent years it has been shown that certain methyl derivatives of 3H-imidazo[4,5-f]quinoxaline-2-amine are responsible for a major part of the mutagenicity formed during frying, broiling or baking of meat, and also formed in the preparation of meat extracts. The present study describes the precursors of these compounds and their formation with participation of Maillard or nonenzymatic browning reactions. The formation of these IQ-type mutagens was shown to occur when model systems of creatin(in)e, reducing monosaccharides, and certain amino acids were heated at 128 degrees C for 2 hr. In meat experiments, the mutagenicity was found to be significantly correlated with the presence of creatin(in)e in the meat samples. The same conditions that are favorable for Maillard reactions, such as supply of starting materials, high temperature, and a suitable water concentration, also increased the yield of mutagenicity during cooking. Fats seemed to act as regulators of the amount of heat transferred into the product rather than as reactants in the formation of mutagenicity.

Amino Acids↗
PubMed1984

Formation of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline in a model system by heating creatinine, glycine and glucose.

A mixture of creatinine, glucose and glycine was heated in diethylene glycol containing 14% water for 2 h at 128 degrees C, and the mutagens formed were purified by XAD-2 column chromatography, acid-base partition, Sephadex LH-20 column chromatography, 'blue cotton' treatment and HPLC. Two mutagenic substances were isolated by HPLC. The major mutagen was identified by its UV absorption and mass and NMR spectra as 2-amino-3,8- dimethylimidazo [4,5-f]quinoxaline, which was originally isolated from fried beef. This finding supported the idea that creatinine, amino acids and sugars present in meat are precursors in the formation of the mutagenic imidazoquinoxaline derivative.

Chemical Phenomena↗
PubMed1984

Mutagenicity of some synthetic quinolines and quinoxalines related to IQ, MeIQ or MeIQx in Ames test.

3-Methyl- and 3,4-dimethyl-3H-imidazo[4,5-f]quinoline, 3,8-dimethyl-3H-imidazo[4,5-f]quinoxaline, N6-methyl- and N6,7-dimethylquinoline-5,6-diamine, as well as N6,3-dimethylquinoxaline-5,6-diamine, have been synthesized. Only the first-mentioned compound was active in Ames test; the response was equal for Salmonella typhimurium TA98 and TA100, regardless of enzymatic activation (S9). However, its mutagenicity to TA98 + S9 was 300-1300 times smaller than the values reported for the related compounds, 3-methyl- and 3,4-dimethyl-3H-imidazo[4,5-f]quinolin-2-amine ('IQ' and 'MeIQ'), and for 3,8-dimethyl-3H-imidazo[4,5-f]quinoxalin-2-amine ('MeIQx'). Hence, the presence of the imidazole ring and the 2-amino group in the molecule seems to be important for the high mutagenicity of the latter compounds.

Animals↗
PubMedDate not supplied

Formation of heterocyclic amines using model systems.

Initially, modeling was used to identify the mutagenic heterocyclic amines and their precursors. Major precursors have been shown to be single amino acids or amino acids together with creatine or creatinine. There is also evidence that Maillard reactions are involved since heating sugar and amino acids together with creatine or creatinine has been shown to produce several of the mutagenic heterocyclic amines, especially the aminoimidazoazaarenes (AIA compounds), e.g., IQ, MeIQ, MeIQx, DiMeIQx and PhIP. Due to a low yield in the model systems, the mechanisms behind the formation of the mutagenic heterocyclic amines are still unclear and need further substantiation. The fact that some AIA compounds are also produced in the absence of sugar casts some doubts on an obligatory participation of the Maillard reaction; alternative routes might exist. Further work using isotopically labeled precursors needs to be done and so far such work has only been performed for PhiP. The formation of mutagenic heterocyclic amines is dependent on time, temperature, pH, concentration of the precursors, type of amino acid, and the presence of certain divalent ions. Water may have an impact both as a temperature regulator and as a solvent medium for the reactants.

Amines↗
PubMedDate not supplied

Analysis of mutagenic imidazo[4,5-f]quinolines and -quinoxalines (IQ compounds). Comparison of electrochemical and ultraviolet detection.

Two synthetic imidazoquinolin-2-amines (IQ and MeIQ) and two imidazoquinoxalin-2-amines (MeIQx and 4,8-DiMeIQx), all known potent mutagens, have been separated by reversed-phase HPLC and detected by two methods - UV detection and electrochemical (EC) detection. The limits of detection were found to be 2.5 pmoles for UV detection and 0.5-1.5 pmoles for electrochemical detection.

Chromatography, Liquid↗