3-amino-1-4-dimethyl-5h-pyrido(4-3-b)indole and 2-amino-3-4-dimethylimidazo(4-5-f)quinoline

Heterocyclic aromatic amines (HAAs) are process-induced food contaminants with high mutagenic and/or carcinogenic potential. Although the human gut microbiota is known to affect the metabolism of dietary constituents, its impact on HAA metabolism and toxicity has been little studied. Here, the glycerol-dependent metabolism of seven foodborne HAAs (AαC, Trp-P-1, harman, norharman, PhIP, MeIQx, and MeIQ) by the human fecal microbiota is investigated.. As analyzed by HPLC-DAD/FLD, the extent of conversion is strongly dependent on glycerol supplementation and HAA structure. AαC (60-100%) and the 2-aminoimidazoazarenes (up to 58%) are especially prone to microbial conversion. Based on high-resolution MS and/or NMR spectroscopy data, 70 fecal metabolites are identified in total, mainly formed by chemical reactions with one or two molecules of microbially derived reuterin. Moreover, it has been demonstrated that the human fecal microbiota can further transform reuterin adducts by reduction and/or hydroxylation reactions. Upon isolation, some reuterin-induced HAA metabolites appear to be partially unstable, complicating structural identification.. The formation of microbial metabolites needs to be incorporated into risk assessment considerations for HAAs in human health. In this study, several HAA metabolites, mainly reuterin-dependent, are identified in vitro, providing the basis for future human studies investigating microbial HAA metabolism.

Topics: Adult; Amines; Animals; Carbolines; Feces; Female; Food Contamination; Gastrointestinal Microbiome; Glyceraldehyde; Harmine; Heterocyclic Compounds, Fused-Ring; Humans; Male; Microsomes, Liver; Middle Aged; Propane; Quinolines; Quinoxalines; Rats, Wistar

The major pathway of bioactivation of procarcinogenic heterocyclic aromatic amines (HCAs) is cytochrome P450 1A2 (CYP1A2)-catalyzed N-hydroxylation and subsequent esterification by O-acetyltransferase (O-AT). We have previously reported that an umu tester strain, Salmonella typhimurium OY1001/1A2, endogenously coexpressing human CYP1A2 and NADPH-P450 reductase (reductase), is able to detect the genotoxicity of some aromatic amines [Aryal et al., 1999, Mutat Res 442:113-120]. To further enhance the sensitivity of the strain toward HCAs, we developed S. typhimurium OY1002/1A2 by introducing pCW"/1A2:hNPR (a bicistronic construct coexpressing human P450 1A2 and the reductase) and pOA102 (constructed by subcloning the Salmonella O-AT gene in the pOA101-expressing umuC"lacZ gene) in S. typhimurium TA1535. In addition, as an O-AT-deficient strain, we developed the OY1003/1A2 strain by introducing pCW"/1A2:hNPR and pOA101 into O-AT-deficient S. typhimurium TA1535/1,8-DNP. Strains OY1001/1A2, OY1002/1A2, and OY1003/1A2 expressed, respectively, about 150, 120, and 140 nmol CYP1A2/l culture (in whole cells), and respective cytosolic preparations acetylated 15, 125, and > or = 0 nmol isoniazid/min/mg protein as the O-AT activities of cytosolic preparations, respectively. We compared the induction of umuC gene expression as a measure of genotoxicity and observed that the OY1002/1A2 strain was more sensitive than OY1001/1A2 strain toward the genotoxicity of 2-amino-1,4-dimethylimidazo[4,5-f]quinol ine(MeIQ), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ),2-amino-3, 8-dimethylimidazo[4,5-f]quinoxaline (MeIQx),2-aminoanthracene, 2-amino-6-methyldipyrido[1,2-a::3,2'-d]i midazole,3-amino-1, 4-dimethyl-5H-pyrido[4,3-b]indole, and 3-amino-1-methyl-5H-pyrido[4, 3-a]indole. However, the genotoxicity of MeIQ, IQ, and MeIQx was not detected with the OY1003/1A2 strain. These results indicate that the newly developed strain OY1002/1A2 can be employed in detecting potential genotoxic aromatic amines requiring bioactivation by CYP1A2 and O-acetyltransferase.

Topics: Acetyltransferases; Bacterial Proteins; Carbolines; Carcinogens; Cytochrome P-450 CYP1A2; DNA-Directed DNA Polymerase; Escherichia coli Proteins; Genetic Engineering; Humans; Mutagenicity Tests; Mutagens; NADPH-Ferrihemoprotein Reductase; Quinolines; Salmonella typhimurium; SOS Response, Genetics

In order to study the mutagenic effects of heterocyclic aromatic amines (HAAs) in cells of human origin, five compounds, namely 2-amino-3-methyl-imidazo[4,5-f]quinoline (IQ), 2-amino-3, 4-dimethyl-imidazo[4,5-f]quinoline (MeIQ), 2-amino-3, 8-dimethyl-imidazo[4,5-f]quinoxaline (MeIQx), the pyridoimidazo derivative 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1), were tested in micronucleus (MN) assays with a human derived hepatoma (HepG2) cell line. All HAAs caused significant, dose-dependent effects. The activities of IQ, MeIQ, MeIQx and PhIP were similar (lowest effective concentrations 25-50 microM), whereas Trp-P-1 was effective at a dose of >/=2.1 microM. In addition, the HAAs were tested in MN assays with Chinese hamster ovary (CHO) cells and in Salmonella strain YG1024 using HepG2 cell homogenates as an activation mix. In the CHO experiments, positive results were obtained with Trp-P-1 and PhIP, whereas the other compounds were devoid of activity under all experimental conditions. The discrepancy in the responsivity of the two cell lines is probably due to differences in their acetylation capacity: enzyme measurements with 2-aminofluorene as a substrate revealed that the cytosolic acetyltransferase activity in the HepG2 cells is approximately 40-fold higher than that of the CHO cells. In the bacterial assays all five HAAs gave positive results but the ranking order was completely different from that seen in the HepG2/MN experiments (IQ > MeIQ > Trp-P-1 >/= MeIQx >> PhIP) and the mutagenic potencies of the various compounds varied over several orders of magnitude. The order obtained in bacterial tests with rat liver S9 mix was more or less identical to that seen in the tests with HepG2 cell homogenates but the concentrations of the amines required to give positive results were in general substantially lower (10(-5)-10(-1) microM). Overall, the results of the present study indicate that MN/HepG2 tests might reflect the mutagenic effects of HAAs more adequately than other in vitro mammalian cell systems due to the presence of enzymes involved in the metabolic conversion of the amines.

Topics: Amines; Animals; Arylamine N-Acetyltransferase; Carbolines; Carcinogens; Carcinoma, Hepatocellular; Cell Line; Cell Survival; CHO Cells; Cricetinae; Heterocyclic Compounds; Humans; Imidazoles; Liver Neoplasms; Mutagenicity Tests; Mutagens; Quinolines; Quinoxalines; Rats; Salmonella; Tumor Cells, Cultured

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 effects of dietary bioantimutagens (compounds which have been shown to inhibit mutagenesis via interaction with DNA repair processes) on spontaneous and heterocyclic amine (HCA)-induced micronucleus (MN) frequencies were studied in metabolically competent human hepatoma (Hep-G2) cells. All the compounds tested (coumarin, vanillin, caffeine, tannic acid and cinnamaldehyde) caused a moderate increase of MN numbers in Hep-G2 cells at high concentrations (500 microg/ml); only tannic acid was also active at lower dose levels. In combination experiments with the HCA 2-amino-3-methylimidazo-[3,4-f]quinoline (IQ), post-treatment of the cells with bioantimutagens resulted in a pronounced (75-90%) decrease in MN. The most drastic effects were seen with vanillin, coumarin and caffeine which were active at concentrations < or = 5 microg/ml. Further experiments indicated that these compounds also attenuate the mutagenic effects of other HCAs (PhIP, MeIQ, MeIQx, Trp-P-1).

Topics: Acrolein; Amines; Antimutagenic Agents; Benzaldehydes; Caffeine; Carbolines; Carcinoma, Hepatocellular; Coumarins; DNA Repair; Heterocyclic Compounds; Humans; Hydrolyzable Tannins; Imidazoles; Micronucleus Tests; Mutagens; Quinolines; Tumor Cells, Cultured

We investigated the enhancing effect of heterocyclic amines on base-substitution mutations with 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and 2-amino-3,4-dimethyl-imidazo[4,5-f]quinoline (MeIQ). We compared the mutagenicity of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) in the presence and absence of the heterocyclic amines in E. coli WP2 (trpE) and in excision repair-deficient strains WP2s (uvrA, trpE) and ZA500 (uvrA, rfa, trpE). Since the assay was performed without microsomal metabolic activation, Trp-P-1 and MeIQ alone were not mutagenic. In WP2, trp+ reversions induced by MX were greatly potentiated by Trp-P-1 and slightly potentiated by MeIQ. Mutation enhancement was not observed in strains WP2s and ZA500, suggesting that a functional DNA excision repair system is necessary for the combined action of MX and heterocyclic amines. Our finding implies that the combined effect of mutagens as well as the effect of individual mutagens, should be considered in risk evaluation.

Topics: Adenosine Triphosphatases; Bacterial Proteins; Carbolines; DNA Repair; DNA-Binding Proteins; Dose-Response Relationship, Drug; Escherichia coli; Escherichia coli Proteins; Furans; Mutagenicity Tests; Mutagens; Mutation; Quinolines

We used a modification of the alkaline single cell gel electrophoresis (SCG) (Comet) assay to test the in vivo genotoxicity of 6 heterocyclic amines, Trp-P-1 (25 mg/kg), Trp-P-2 (13 mg/kg), IQ (13 mg/kg), MeIQ (13 mg/kg), MeIQx (13 mg/kg) and PhIP (40 mg/kg), in mouse liver, lung, kidney, brain, spleen, bone marrow and stomach mucosa. Mice were sacrificed 1, 3, and 24 h after intraperitoneal injection. Trp-P-2, IQ, MeIQ, and MeIQx yielded statistically significant DNA damage in the stomach, liver, kidney, lung and brain; Trp-P-1 in the stomach, liver and lung; and PhIP in the liver, kidney and brain. None of the heterocyclic amines induced DNA damage in the spleen and bone marrow. Our results suggest that the alkaline SCG assay applied to multiple organs is a good way to detect organ-specific genotoxicity of heterocyclic amines in mammals.

Topics: Amines; Animals; Brain; Carbolines; DNA Damage; Electrophoresis; Imidazoles; Kidney; Liver; Male; Mice; Mice, Inbred Strains; Mutagens; Quinolines; Quinoxalines; Stomach

The heterocyclic amines (HA) 2-aminodipyrido[1,2-a:3',2-d]imidazole (Glu-P-2), 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) were mutagenic in V79 cells (Chinese hamster lung fibroblasts) using 6-thioguanine resistance as the marker of mutagenicity. Pancreas duct epithelial cells (DEC) from untreated hamsters, homogenates of pancreas ducts from untreated hamsters and those fed a high fat diet and human DEC were used to activate the heterocyclic amines. When hamster cells and tissues were used the optimum mutation frequencies (mutants/10(6) survivors) measured were: Glu-P-2, 10 +/- 1; MeIQ, 28 +/- 2 (DEC), 12 +/- 2 (control, duct homogenate), and 21 +/- 2 (high fat diet fed, duct homogenate); PhIP, 61 +/- 5. When human DEC were used the optimum mutation frequencies were: MeIQ, 32 +/- 4; PhIP, 35 +/- 3. 3,8-Dimethylimidazo[4,5-f]quinoxaline, 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole and 3-amino-1-methyl-5H-pyrido[4,3-b]indole were not mutagenic in this assay.

Topics: Adolescent; Adult; Amines; Animals; Carbolines; Cells, Cultured; Cricetinae; Heterocyclic Compounds; Humans; Imidazoles; Lung; Male; Mutagens; Pancreatic Ducts; Quinolines

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

Purified human red blood cell cytosol was used to activate the heterocyclic amines 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), 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) into mutagenic intermediate(s) in the Salmonella test. The liquid preincubation method in the presence of strain TA98 was utilized. In order to understand the mechanism involved in this metabolic activation, some modulators were incorporated in the medium. The results suggest that an oxygenated hemoprotein, probably oxyhemoglobin, is involved in the activation into genotoxic intermediate(s).

Topics: Biotransformation; Carbolines; Carcinogenicity Tests; Cytosol; Dose-Response Relationship, Drug; Erythrocytes; Humans; Kinetics; Mutagenicity Tests; Mutagens; Quinolines; Salmonella typhimurium

Potential synergism between five heterocyclic amines at low doses was evaluated in a medium-term liver bioassay system for carcinogens. F344 male rats were given a single i.p. injection of diethylnitrosamine (DEN, 200 mg/kg) and then received test compound(s) in their diet for 6 weeks beginning 2 weeks later. Control groups received DEN or test compound(s) alone. All rats were subjected to two-thirds partial hepatectomy at week 3 and killed at week 8. Compounds tested and reported positive were 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1, 150 p.p.m.), 2-aminodipyrido[1,2-a:3',2'-d]imidazole (Glu-P-2, 500 p.p.m), 2-amino-3-methylimidazo[4,5-f]quinoline (MeIQ, 300 p.p.m.), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx, 400 p.p.m.). Groups were given each chemical at the carcinogenic dose, or 1/5 or 1/25 of this. Other groups received the five chemicals in combination, each at the 1/5 or 1/25 levels. Enhancing activity was assessed by quantitative analysis of glutathione S-transferase placental form (GST-P) positive foci, the numbers being significantly increased with all chemicals at the highest dose. Trp-P-1, IQ and MeIQ also exerted positive influence even at the 1/5 dose level. Similar results were obtained regarding areas of foci at the highest dose levels, with the exception of Glu-P-2. An increase was also observed for MeIQ at the 1/5 dose. Additive or synergistic effects between the chemicals were evident in the groups given the five chemicals together at both the 1/5 and 1/25 dose levels, development of GST-P positive foic being increased over the sum totals of individual data for the 1/5 or 1/25 dose groups. Thus, carcinogenicity was predicted for all five heterocyclic amines tested in dose-dependent manner in the present system of 8 weeks duration, synergistic effects being apparent especially at the low dose level.

Topics: Animals; Body Weight; Carbolines; Carcinogens; Drug Synergism; Enzyme Induction; Glutathione Transferase; Imidazoles; Immunohistochemistry; Liver; Liver Neoplasms; Male; Organ Size; Quinolines; Quinoxalines; Rats; Rats, Inbred F344

The effect of chemically-induced diabetes on the hepatic microsomal mixed-function oxidase system and the activation of chemical carcinogens was investigated in animals treated with streptozotocin (STZ). In order to distinguish between the effects of the diabetogenic chemical per se and that of the diabetic state, groups of STZ-treated animals received either nicotinamide simultaneously with STZ to prevent the onset of diabetes, or daily treatment with insulin in order to reverse the effects of diabetes. STZ-treated animals exhibited higher pentoxyresorufin O-dealkylase, ethoxy-resorufin O-deethylase, ethoxycoumarin O-deethylase, aniline p-hydroxylase and NADPH-cytochrome c reductase activities; similarly, increases were seen in cytochrome P-450 and b5 levels. All of these effects were prevented by nicotinamide and, at least partly, antagonised by insulin therapy. Treatment of animals with STZ markedly increased the activation, by liver microsomes in vitro, of Trp-P-1 and Trp-P-2 to mutagens, the effect being totally preventable by nicotinamide and successfully antagonised with insulin therapy. The diabetic animals were similarly more efficient in activating MeIQ but the effect was not preventable by nicotinamide or reversed by insulin. In contrast no changes were seen in the activation of IQ and only a modest increase in the case of MeIQx. It is concluded that diabetes may modulate the metabolic activation of some chemical carcinogens, presumably by changing the ratio of the various cytochrome P-450 isoenzymes.

Topics: Animals; Biotransformation; Carbolines; Carcinogens; Cytochrome P-450 Enzyme System; Diabetes Mellitus, Experimental; Electrophoresis, Polyacrylamide Gel; Insulin; Isoenzymes; Male; Microsomes, Liver; Mixed Function Oxygenases; Molecular Weight; Mutagenicity Tests; Mutagens; Niacinamide; Quinolines; Quinoxalines; Rats; Rats, Inbred Strains

The genotoxicity of the cooked-food mutagens 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), 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 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) was studied by monitoring the induction of DNA repair (unscheduled DNA synthesis; UDS) in primary cultures of rodent hepatocytes. The hepatocytes were derived from male Sprague-Dawley rats or Syrian hamsters by collagenase perfusion and the cells were cultured for 4 hr before being exposed to various concentrations of the mutagens. DNA repair was determined by measuring incorporation of [3H]thymidine into extracted DNA over 17 hr using beta-scintillation counting. Dose-related increases in UDS were clearly seen in hamster hepatocytes treated with MeIQ, IQ and the positive control 2-acetylaminofluorene (AAF), and a weak response was induced by MeIQx and Trp-P-1. In the rat hepatocytes only MeIQ and AAF gave clear positive responses. Furthermore it was noted that all the mutagens displayed a more pronounced UDS response in hamster hepatocytes than in rat cells. Studies of the activation of MeIQ by hepatocytes to a bacterial mutagen suggest that this difference is probably a consequence of the greater capacity of hamster cells to activate the mutagens to genotoxic metabolites.

Topics: Animals; Biotransformation; Carbolines; Cricetinae; DNA; DNA Repair; Liver; Male; Mesocricetus; Mutagens; Quinolines; Quinoxalines; Rats; Rats, Inbred Strains; Species Specificity

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 heterocyclic amines 2-amino-3-methylimidazo-(4,5-f)-quinoline (IQ) and 2-amino-3,4-dimethylimidazo(4,5-f)-quinoline (Me-IQ) which are formed during broiling (grilling) and cooking of protein-rich food, have previously been shown to be both carcinogenic and mutagenic. In this work IQ and Me-IQ were found to be several hundred-fold more mutagenic in liver than in lung microsomal preparations from uninduced mice and rabbits. IQ has already been found to induce tumors at about the same frequency in liver and lung in mice. Obviously, the discrepancy between the data on carcinogenicity in vivo and mutagenicity in vitro with microsomal preparations from the two organs might in part be due to the lack of detoxification mechanisms in the latter system. Freshly isolated lung cells will better mimic the in vivo situation. With the metabolically active Clara cells, IQ was much more mutagenic than Me-IQ. It has previously been shown that the Clara cells have low capacity for DNA repair. It is tempting to speculate whether the situation in the mouse is in correspondence with that described in the rabbit, in which case the cell data fits well with the in vivo carcinogenesis data.

Topics: Animals; Biotransformation; Carbolines; Cytochrome P-450 CYP1A2; Cytochromes; In Vitro Techniques; Lung; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Microsomes; Microsomes, Liver; Mutagens; Quinolines; Rabbits