3-amino-1-4-dimethyl-5h-pyrido(4-3-b)indole and 2-amino-6-methyldipyrido(1-2-a-3--2--d)imidazole

Topics: Animals; Breast Neoplasms; Carbolines; Carcinogens, Environmental; Cattle; Colonic Neoplasms; Cooking; Food; Harmine; Head and Neck Neoplasms; Humans; Imidazoles; Male; Meat; Mutagens; Neoplasms; Nitrates; Nitrites; Nitrosamines; Prostatic Neoplasms

Antigenotoxic properties and the possible mechanisms of water extracts from Cassia tora L. (WECT) treated with different degrees of roasting (unroasted and roasted at 150 and 250 degrees C) were evaluated by the Ames Salmonella/microsome test and the Comet assay. Results indicated that WECT, especially unroasted C. tora (WEUCT), markedly suppressed the mutagenicity of 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). In the Comet assay performed on human lymphocytes, WECT exhibited significant protective effect on Trp-P-1-mediated DNA damage followed the order of unroasted (55%) > roasted at 150 degrees C (42% ) > roasted at 250 degrees C (29%). Pre-treatment of the lymphocytes with WEUCT resulted in 30% repression of DNA damage. However, no significant effect on excision-repair system was found during DNA damage expression time in post-treatment scheme (p>0.05). WEUCT showed 84% scavenging effect on oxygen free radicals generated in the activation process of mutagen detected by electron paramagentic resonance system. Two possible mechanisms were considered: (1) neutralization the reactive intermediate of Trp-P-1; and (2) protecting cells directly as an antioxidant that scavenge the oxygen radicals from the activation process of mutagen. The individual anthraquinone content in extracts of C. tora was measured by HPLC. Three anthraquinones, chrysophanol, emodin and rhein, have been detected under experimental conditions. The anthraquinone content decreased with increased roasting temperature. Each of these anthraquinones demonstrated significant antigenotoxicity against Trp-P-1 in the Comet assay. In conclusion, our data suggest that the decrease in antigenotoxic potency of roasted C. tora was related to the reduction in their anthraquinones.

Topics: Analysis of Variance; Anthraquinones; Beverages; Carbolines; Cassia; Chromatography, High Pressure Liquid; Comet Assay; Cooking; DNA Damage; Free Radicals; Humans; Imidazoles; Lymphocytes; Microscopy, Fluorescence; Microsomes; Plant Extracts

We have found that the exhaust gas from many incineration plants of municipal solid wastes (MSW) show significant mutagenic activities. The mutagenic activities of exhaust gas from incineration plants of the other wastes have not been studied in detail. Here, we analyzed the mutagenic activities and compounds in exhaust gas and ash from seven sludge incineration plants. Some samples of the exhaust gas from the sludge incineration plants showed high mutagenic activities; although, none of the ash residues showed mutagenic activities. There was no relationship between the mutagenic activities and furnace types, the plant size or the apparent residence time of the gas in the furnace. The mutagenic activities of the exhaust gas were produced during incomplete combustion at lower temperatures. Direct mutagenic activities without S9 mix were higher than indirect mutagenic activities with S9 mix which was made from rat liver homogenate and was used to test mutagenic activity after metabolism. These results are different to those of MSW incineration plants. We analyzed the mutagenic compounds in the exhaust gas by GC/MS after fractionation by HPLC, but they could not be identified. We found that the mutagenic compounds in the exhaust gas were different from the compounds that were produced from the MSW incineration plants. We believed that these mutagenic compounds might be non-volatile and more polar than the heterocyclic amines, Trp-P-2, Trp-P-1 and Glu-P-1, which are typical mutagenic compounds in sewage and sludge.

Topics: Animals; Carbolines; Carcinogens; Chemical Fractionation; Imidazoles; Incineration; Liver; Mutagenicity Tests; Rats; Refuse Disposal; Sewage; Vehicle Emissions

Precision-cut liver slices were prepared from male Fischer 344 rats, female CDF1 mice and humans (both male and female subjects). Liver slices were cultured for 24 hr in medium containing [3H]thymidine and either PhIP, IQ, MeIQ, MeIQx, Glu-P-1 or Trp-P-1, and then processed for auto-radiographic evaluation of unscheduled DNA synthesis (UDS). All six cooked food mutagens examined produced concentration-dependent increases in UDS in human liver slices. PhIP was the most potent compound examined, followed by MeIQx, IQ and then MeIQ, Glu-P-1 and Trp-P-1. Significant increases in UDS were observed with PhIP, IQ and MeIQx at concentrations as low as 5 microM in the culture medium. The same rank order of potency was not apparent in either rat or mouse liver slices. In rat liver slices only MeIQ significantly induced UDS, although positive results were obtained with two other genotoxins, namely 2-acetylaminofluorene and aflatoxin B1. Apart from MeIQx, all the cooked food mutagens produced significant increases in UDS in mouse liver slices. This study demonstrates the usefulness of precision-cut liver slices to evaluate species differences in xenobiotic-induced genotoxicity. Both marked compound and species differences in induction of UDS were observed. The data provide further evidence that dietary cooked food mutagens are potential human carcinogens.

Topics: 2-Acetylaminofluorene; Aflatoxin B1; Animals; Autoradiography; Carbolines; Cooking; Culture Techniques; DNA; Dose-Response Relationship, Drug; Female; Humans; Imidazoles; Liver; Male; Mice; Mutagens; Quinolines; Quinoxalines; Rats; Rats, Inbred F344; Structure-Activity Relationship

Antimutagenic and binding properties of 28 strains of Lactobacillus gasseri and 2 strains of Bifidobacterium longum on the mutagenicity of amino acid pyrolysates were investigated in vitro using a streptomycin-dependent (SD510) strain of Salmonella typhimurium TA 98. Four strains of L. acidophilus (SBT0274, SBT1703, SBT10239, and SBT10241) and 1 strain of B. longum (SBT 2928) exhibited the highest percentage of antimutagenicity and binding. These 5 strains were further optimized for other physical factors influencing the mechanism of binding, such as cell and mutagen concentration, pH, and incubation time. In all of the selected strains, 2 mg of cells bound with 88 to 95% of 0.2 mg of 3-amino-1,4 dimethyl-5H-pyrido[4,3-b]indole in 30 min at pH 7.0. Other amino acid pyrolysates, such as 3-amino-1-methyl-5H-pyrido[4,3-b]indole, 2-amino-6-methyldi-pyrido[1,2-a:3',2'-d]imidazole, 2-amino-3-methyl-imidazo[4,5,f]quinoline, and 2-amino-3,4-dimethyl-imidazo[4,5,f]quinoline were also tested for the binding ability of these strains. We observed that the complexity of the mutagens greatly influenced the binding properties. The binding of 3-amino-1,4 dimethyl-5H-pyrido[4,3-b]indole to the purified cell walls was very high compared with that of the crude cell wall, peptidoglycan, or the cell extract. Binding was inhibited when the cell walls were subjected to treatment with metaperiodate or trichloroacetic acid but not when they were subjected to treatment with lysozyme, trypsin, or proteinase K, reflecting the role of the carbohydrate component as a binding site.

Topics: Amino Acids; Antimutagenic Agents; Bifidobacterium; Binding Sites; Carbolines; Cell Wall; Chemical Phenomena; Chemistry, Physical; Hydrogen-Ion Concentration; Imidazoles; Lactobacillus; Mutagens; Periodic Acid; Quinolines; Time Factors; Trichloroacetic Acid

The antimutagenic effects of methanolic extracts of peanut hulls (MEPH) were evaluated by the Ames test. MEPH inhibited the mutagenicity of 4-nitroquinoline-N-oxide (NQNO), a direct-acting mutagen. MEPH also inhibited the mutagenicity of some indirect-acting mutagens and decreased in the order of 2-amino-3-methyl-imidazo(4,5-f)quinoline (IQ) > aflatoxin B1 (AFB1) > 2-amino-6-methyldipyrido(1,2-a:3',2'-d)imidazole (Glu-P-1) > 3 amino-1,4-dimethyl-5H-pyridol(4,3-b)indole (Trp-P-1) > benzo(a)pyrene (B(a)P for S. typhimurium TA98, and IQ > Trp-P-1 > Glu-P-1 > AFB1 > B(a)P for S. typhimurium TA100.

Topics: 4-Nitroquinoline-1-oxide; Aflatoxin B1; Animals; Antimutagenic Agents; Arachis; Benzo(a)pyrene; Carbolines; Imidazoles; Male; Methanol; Mutagenicity Tests; Mutagens; Plant Extracts; Quinolines; Rats; Rats, Sprague-Dawley; Salmonella typhimurium

The ability of phthalic acid, phthalic acid anhydride, and various phthalate esters to enhance the mutagenicity of many amino acid pyrolysates was observed with the Ames test (Salmonella typhimurium TA98), but not the SOS Chromotest. Phthalate enhancement of the mutagenicity of 4-nitroquinoline-1-oxide, 2-nitrofluorene, and benzo[a]pyrene was not observed with either test. The mutagenicity-enhancing ability may be related to the induction of enzymes such as P450IIB, that metabolize amino acid pyrolysates. By quantitative structure activity relationship (QSAR) analysis, a good correlation was observed between the mutagenicity-enhancing activity of phthalates and their octanol-water partition coefficients.

Topics: 1-Octanol; 4-Nitroquinoline-1-oxide; Benzo(a)pyrene; Carbolines; Cytochrome P-450 CYP2B1; Cytochrome P-450 Enzyme System; Drug Synergism; Enzyme Induction; Esters; Fluorenes; Imidazoles; Mutagenesis; Mutagenicity Tests; Mutagens; Octanols; Oxidoreductases; Phthalic Acids; Quinolines; Structure-Activity Relationship; Water

The inactivation of 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and 2-amino-6-methyldipyrido[1,2-a: 3',2'-d]imidazole (Glu-P-1) by binding of mutagenic pyrolysate to fractions of microorganisms (their desmutagenic and bio-antimutagenic activity) was investigated. All strains bound Trp-P-1 effectively, but Glu-P-1 to a lesser extent. The Gram-negative bacteria (GNB) could bind about 10-20 micrograms/mg of Trp-P-1 more than the Gram-positive bacteria (GPB), and about 50-60 micrograms/mg more than the yeasts. The cell wall skeletons of all strains tested had great binding ability, but in the cytoplasm of all strains tested it was lower. The peptidoglycan, outer membrane, and glucan isolate from the cell wall skeletons showed the highest binding ability to Trp-P-1. The cell wall skeletons of the tested strains greatly inhibited the mutagenicity induced by Trp-P-1, and to a lower extent that of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx). Although the cultured broth and solution of cells extracted by phosphate buffer (pH 7.0) showed antimutagenicity against Trp-P-1, this activity was lower than the binding of Trp-P-1 to the cells. The cultured broth and freeze-dried cytoplasms of yeast cells showed bio-antimutagenicity towards Trp-P-1, but those of all bacteria tested did not.

Topics: Amines; Antimutagenic Agents; Bacterial Outer Membrane Proteins; Binding Sites; Carbolines; Cell Fractionation; Cell Wall Skeleton; Chromatography, High Pressure Liquid; Cytoplasm; Glucans; Gram-Negative Bacteria; Gram-Positive Bacteria; Heterocyclic Compounds; Hot Temperature; Imidazoles; Mannans; Mutagenicity Tests; Mutagens; Peptidoglycan; Salmonella typhimurium; Yeasts

The binding of mutagenic pyrolyzates to cell fractions from some gram-negative intestinal bacteria and to thermally treated bacterial cells was investigated. 3-Amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) were effectively bound by several of the bacterial cells. The cell wall skeletons of all bacteria effectively bound Trp-P-1 and Trp-P-2. Their cytoplasmic fractions retained Trp-P-1 and Trp-P-2, but to a lesser extent than the cell wall skeletons. 2-Amino-3-methylimidazo[4,5-f]quinoline (IQ) was not found in their cytoplasmic fractions. These cell wall skeletons also bound 2-amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole (Glu-P-1), 2-amino-5-phenylpyridine (Phe-P-1), IQ, 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQX). The amount of each mutagen bound differed with the type of mutagen and the bacterial strain used. The outer membrane of Escherichia coli IFO 14249 showed binding of about 123.7 micrograms/mg of Trp-P-2, and its cytoplasmic membrane bound 57.14 micrograms/mg. Trp-P-2 bound to the bacterial cells was extracted with ammonia (5%), methanol, and ethanol but not with water.

Topics: Bacteroides fragilis; Carbolines; Cell Wall; Chromatography, High Pressure Liquid; Citrobacter freundii; Escherichia coli; Gram-Negative Bacteria; Hot Temperature; Imidazoles; Mutagens; Pseudomonas putida; Quinolines

The binding ability of bovine milk caseins with mutagenic heterocyclic amines was investigated. Binding was determined with 2 mg of casein and 20 micrograms of heterocyclic amine in .40 ml of pH 7.4, 50 mM phosphate buffer, at 37 degrees C, in a shaker for 10 min. The unbound heterocyclic amine in protein-free ultrafiltrate was analyzed by HPLC. The binding ability of whole casein, alpha s-casein, beta-casein, and kappa-casein, respectively, was 90.08, 83.06, 90.92, and 96.70% with 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole; 85.48, 51.54, 63.62, and 82.71% with 3-amino-1-methyl-5H-pyrido[4,3-b]indole; and 87.03, 59.77, 97.04, and 88.30% with 2-amino-6-methyldipyrido[1,2-a:3',2'-d]-imidazole. Higher binding of 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole and 3-amino-1-methyl-5H-pyrido[4,3-b]indole to alpha s-casein, beta-casein, and kappa-casein was observed at pH above 7.4, and the binding was inhibited at pH below 6.5. The maximum binding of 2-amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole to these caseins was at pH 6.6 and 7.4. The binding was inhibited at alkaline pH above 8.5 and acidic pH below 6.5.

Topics: Animals; Carbolines; Caseins; Cattle; Hydrogen-Ion Concentration; Imidazoles; Mutagens

Most heterocyclic amines formed during the cooking of meat and fish have been shown to form adducts in the livers of rats. Recently, however, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), administered in the diet to Fischer 344 (F344) rats for 4 weeks, was shown to produce the highest levels of adducts in the heart. In the present study 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,8-dimethylimidazo [4,5-f]quinoxaline (MeIQx), 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and 2-amino-6-methyldipyrido[1,2-a:1',2'-d]imidazole (Glu-P-1) were given to F344 rats at carcinogenic dose levels (IQ 0.03%, MeIQx 0.04%, Trp-P-1 0.015%, Glu-P-1 0.05%) in the diet for 4 weeks. DNA adducts in the liver and heart were analyzed by 32P-postlabeling. DNA adducts were demonstrated to appear in the hearts of all animals exposed to heterocyclic amines at the following levels: IQ, 1.8 adducts/10(7) nucleotides, MeIQx, 3.8/10(7) ntd, Trp-P-1, 20/10(7) ntd and Glu-P-1, 7.2/10(7) ntd. Values for the heart were 10-20% of the respective liver adduct levels. Heart adducts increased linearly throughout the observed period when MeIQx was administered for up to 40 weeks. When MeIQx feeding was discontinued after 20 weeks and the animals subsequently given the basal diet, the adduct level at 20 weeks did not change during the following 20 weeks. A possible role for heart DNA alterations caused by food-borne heterocyclic amines in the development of age-related myopathies and cardiovascular disease is not inconceivable.

Topics: Administration, Oral; Aging; Amines; Animals; Carbolines; Diet; DNA; DNA Damage; Heart; Imidazoles; Kinetics; Liver; Male; Myocardium; Quinolines; Quinoxalines; Rats; Rats, Inbred F344

The presence of 2 kinds of components in brewed and instant coffee that could remove and destroy heterocyclic amine mutagens was demonstrated. The component that could remove the mutagens was insoluble fiber composed of hemicellulose. The fiber could tightly adsorb the mutagens Trp-P-1, Trp-P-2, Glu-P-1 and A alpha C, and those generated in roasted coffee beans. The component that could destroy the mutagens was high-molecular-weight soluble polyphenolics. They might be converted into quinone derivatives in the presence of molecular oxygen. The quinone derivatives might destroy the mutagens. The fibers and the polyphenolics in one cup of brewed or instant coffee had the capacity to remove and destroy a substantial amount of the mutagens in pyrolysates of foodstuffs.

Topics: Amines; Anisoles; Benzoquinones; Caffeic Acids; Carbolines; Chlorogenic Acid; Coffee; Coumaric Acids; Gallic Acid; Hydrogen-Ion Concentration; Hydrolyzable Tannins; Imidazoles; Mutagenicity Tests; Mutagens; Phenols; Polysaccharides; Salmonella typhimurium

The binding of mutagenic pyrolyzates to freeze-dried cells of Streptococcus cremoris Z-25 was investigated in human gastric juice and compared with the ability of these pyrolyzates to bind in distilled water (pH 6.30). The pH of donated gastric juice ranged from 1.2 to 7.8. Binding that occurred in gastric juice was pH dependent, and binding was affected by NaCl, CaCl2, and MgCl2. Les sof Trp-P-2 was bound in gastric juice at low pH (1.2, 1.48, and 2.1) than at pH 4 to 8. The strain bound simultaneously Trp-P-1, Trp-P-2, and Glu-P-1. The maximum amounts of Trp-P-2 bound to S. cremoris Z-25 were approximately 47.50 micrograms/mg of cells. Freeze-dried cells treated at 120 degrees C for 15 min or 80 degrees C for 3 h showed increased binding of Trp-P-2. However, binding decreased 10% after heating at 120 degrees C for 15 min. Cells nonthermally killed by gastric juice (pH 1.5) had the same Trp-P-2 binding capacity as viable cells. Lactobacillus acidophilus IFO 13951 and Bifidobacterium bifidum IFO 14252 representation of the intestinal bacteria nonthermally killed by gastric juice also showed larger binding of Trp-P-2.

Topics: Calcium Chloride; Carbolines; Freeze Drying; Gastric Juice; Hot Temperature; Humans; Hydrogen-Ion Concentration; Imidazoles; Magnesium Chloride; Mutagens; Sodium Chloride; Streptococcus

In order to evaluate the effect of carcinogenic heterocyclic amines on the stimulus-reaction system of human cells, we examined the effect of 5 kinds of carcinogenic heterocyclic amines including 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole (Glu-P-1), 2-amino-dipyrido[1,2-a:3',2'-d]imidazole (Glu-P-2), 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) on human lymphocyte (4 x 10(5) cells/ml) blast transformation induced by 0.125% phytohemagglutinin (PHA). Both Trp-P-1 and Trp-P-2 exhibited an inhibitory effect on the lymphocyte proliferation stimulated by PHA at the final concentration of 1.0-5.0 and 1.0-10 microM, respectively. The concentrations of Trp-P-1 and Trp-P-2 causing 50% inhibition were 3.1 and 5.1 microM, respectively. However, the other carcinogenic heterocyclic amines examined did not show any inhibitory effect on lymphocyte mitogenesis even at a final concentration of 10 microM. Viabilities of lymphocytes were more than 90% (n = 3 x 5) when 5 kinds of carcinogenic heterocyclic amines (0.1 ml) were respectively added at the final concentration of 10 microM to the lymphocyte culture medium (4 x 10(5) cells/0.9 ml).

Topics: Amines; Carbolines; Carcinogens; Dose-Response Relationship, Drug; Hot Temperature; Humans; Imidazoles; Lymphocyte Activation; Lymphocyte Culture Test, Mixed; Mathematics; Phytohemagglutinins; Tryptophan

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.

Topics: Animals; Binding Sites; Carbolines; Carcinogens; DNA; Hydroxylamines; Imidazoles; In Vitro Techniques; Liver; Male; Mutagens; Quinoxalines; Rats; Rats, Inbred F344

Trp-P-1, Trp-P-2, MeA alpha C, A alpha C, Glu-P-1, Glu-P-2, Lys-P-1, IQ and Phe-P-1 were tested for tumour initiating activity in a two-stage skin carcinogenesis model using 12-O-tetradecanoylphorbol-13-acetate (TPA) as the promoter. The total initiating doses were 20 mg for Trp-P-1, Trp-P-2, Glu-P-1 and Glu-P-2, 40 mg for MeA alpha C and A alpha C, 5 mg for Lys-P-1, 7.5 mg for IQ and 100 mg for Phe-P-1. 7,12-Dimethylbenz[a]anthracene was used as a positive control compound at a total dose of 100 micrograms. All compounds were topically applied twice weekly for 5 weeks on the dorsal skin, and then followed by similar TPA administration for 47 weeks. Trp-P-2 induced skin tumours in 30% of the mice (0.35 tumours/mouse), and Trp-P-1, MeA alpha C and Phe-P-1 in 10-20% (0.20-0.25 tumours/mouse). The smaller amounts of Lys-P-1 and IQ applied induced tumours at an incidence of 10 and 5% respectively. No tumours appeared in the groups treated with test chemicals alone or TPA alone. Statistical analysis according to either the Fisher exact test or Peto trend test revealed significant differences for tumour appearance in the Trp-P-1, Trp-P-2, MeA alpha C and Phe-P-1 followed by TPA groups as compared with that given TPA alone. The data were used to generate ID50 (50% initiating dose) values for each of the compounds.

Topics: Animals; Carbolines; Female; Imidazoles; Mice; Mutagens; Quinolines; Skin Neoplasms; Tetradecanoylphorbol Acetate

Carcinogenicities of mutagenic heterocyclic amines in cooked foods have been tested in CDF1 mice and F344 rats of both sexes. Eight heterocyclic amines--Trp-P-1, Trp-P-2, Glu-P-1, Glu-P-2, MeA alpha C, A alpha C, IQ, and MeIQ--were given to mice and/or rats at 0.02 to 0.08% in the diet continuously. In mice, all heterocyclic amines tested were demonstrated to be carcinogenic. Hepatocellular carcinomas were induced in a high incidence in all groups treated with heterocyclic amines. Hemangioendothelial sarcomas were also induced by Glu-P-1, Glu-P-2, MeA alpha C, and A alpha C. Most hemangioendothelial sarcomas were located in the interscapular brown adipose tissue. In mice given IQ, forestomach and lung tumors were also observed in a high incidence. Carcinogenicity tests on MeIQ are ongoing, and interim data by week 83 show that MeIQ also induces forestomach tumors in addition to liver tumors. In rats, hepatocellular carcinomas were induced by Trp-P-1, Glu-P-1, Glu-P-2, and IQ. In rats given Glu-P-1, Glu-P-2, and IQ, adenocarcinomas in the small and large intestines, squamous cell carcinomas in the Zymbal gland and clitoral gland were also observed in a high incidence.

Topics: Animals; Carbolines; Carcinogens; Female; Food Contamination; Heterocyclic Compounds; Hot Temperature; Imidazoles; Male; Mice; Neoplasms, Experimental; Quinolines; Rats

The activities of pyrolysis products for initiating or promoting preneoplastic lesions were tested. In experimental series I, N-2-fluorenylacetamide (2-FAA) was used as an initiator or a promoter and 3-amino-1,4-dimethyl-5H-pyrido-[4, 3-b] indole (Trp-P-1), 3-amino-1-methyl-5H-pyrido [4, 3-b] indole (Try-P-2), 2-amino-6-methyldipyrido [1,2-a:3', 2'-d] imidazole (Glu-P-1) or 2-amino-dipyrido [1, 2-a:3', 2'] imidazole (Glu-P-2) was administered at a fixed dose and for the same period in the initiation stage or the promotion stage. Animals were subjected to partial hepatectomy or treated with carbon tetrachloride (CCl4) to increase the induction of gamma-glutamyl transpeptidase (gamma-GT) positive foci. Trp-P-1 and Glu-P-2 administered in either the initiation or promotion stage significantly increased the induction of gamma-GT positive foci (p less than 0.001). Glu-P-1 increased the induction of gamma-GT positive foci (P less than 0.001) when administered in the initiation stage but it was not effective when administered during the promotion stage. In experimental series II, animals were given a single dose of these chemicals at one of three different dose levels with partial hepatectomy and then were fed with 2-FAA and given a single dose of CCl4. Trp-P-1, Glu-P-1 and Glu-P-2 caused dose-dependent inductions of gamma-GT positive foci.

Topics: 2-Acetylaminofluorene; Animals; Carbolines; Enzyme Induction; gamma-Glutamyltransferase; Imidazoles; Liver; Liver Regeneration; Male; Mutagens; Rats; Rats, Inbred F344

The mutagenic aromatic amines Trp-P-1, Trp-P-2 and Glu-P-1, isolated frm pyrolysates of tryptophan and glutamic acid, at the concentration of 0.025 mM were treated with 0.05 mM nitrite at various pH values at 37 degrees C. The resulting reaction mixtures were tested for mutagenicity towards Salmonella typhimurium TA98 and TA100. When treated with nitrite at this physiologically realistic concentration, these mutagenic aromatic amines were readily converted to extremely weak or non-mutagenic deaminated compounds. These deaminated products were identified as the corresponding hydroxy compounds by mass and proton magnetic resonance spectroscopies. Comparative kinetic studies were made on the disappearance of the mutagenic aromatic amines. The half-life (t1/2 of Glu-P-1 on treatment with nitrite at pH 1.6 was less than 5 min, and those of Trp-P-1 and Trp-P-2 were 95 and 105 min, resp.

Topics: Amines; Animals; Carbolines; Deamination; Glutamates; Imidazoles; Mutagenicity Tests; Mutagens; Nitrites; Rats; Salmonella typhimurium; Tryptophan