Carcinogenicity in rats of a mutagenic compound, 2-amino-3,8-dimethylimidazo[4,5-<i>f</i>]quinoxaline

Kato, Tomokazu; Ohgaki, Hideaki; Hasegawa, Hirokazu; Sato, Shigeaki; Takayama, Seiji; Sügimura, Takashi

doi:10.1093/carcin/9.1.71

Cited by 137 publications

(58 citation statements)

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“…2). This finding is consistent with liver as the principal tumor target of MeIQx in the rat (Kato et al, 1988;Kushida et al, 1994) and mouse (Ohgaki et al, 1987). In a previous study in which MeIQx-induced DNA adducts were measured at very low doses in rodent and human tissues using accelerator mass spectrometry, MeIQx DNA adduct levels also were highest in liver and increased as a linear function of administered dose for a singledose exposure (Turteltaub et al, 1997).…”

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confidence: 86%

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Effect of N-Acetyltransferase 2 Polymorphism on Tumor Target Tissue DNA Adduct Levels in Rapid and Slow Acetylator Congenic Rats Administered 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine or 2-Amino-3,8-dimethylimidazo-[4,5-f]quinoxaline

Metry¹,

Neale²,

Bendaly³

et al. 2009

Drug Metab Dispos

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ABSTRACT:2-Amino-3,8-dimethylimidazo-[4,5-f ]quinoxaline (MeIQx) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) are suspected human carcinogens generated in well done meats. After N-hydroxylation, they are O-acetylated by N-acetyltransferase 2 (NAT2) to electrophiles that form DNA adducts. dG-C8-MeIQx and dG-C8-PhIP adducts have been identified in human tissues. In the female rat, administration of PhIP leads to mammary and colon tumors, whereas MeIQx induces liver tumors. Both humans and rats exhibit NAT2 genetic polymorphism yielding rapid and slow acetylator phenotypes. Because O-acetylation is an activation pathway, we hypothesized that MeIQx-and PhIP-induced DNA damage would be greater in tumor target tissues and higher in rapid than slow NAT2 acetylators. Adult female rapid and slow acetylator rats congenic at the Nat2 locus received a single dose of 25 mg/kg MeIQx or 50 mg/kg PhIP by gavage, and tissue DNA was isolated after 24 h. Deoxyribonucleoside adducts were identified and quantified by capillary liquid chromatography-tandem mass spectrometry using isotope dilution methods with deuterated internal standards. Major adducts were those bound to the C8 position of deoxyguanosine. dG-C8-PhIP DNA adducts were highest in colon, lowest in liver and did not significantly differ between rapid and slow acetylator congenic rats in any tissue tested. In contrast, dG-C8-MeIQx adducts were highest in liver and significantly (p < 0.001) higher in rapid acetylator liver than in slow acetylator liver. Our results are consistent with the tumor target specificity of PhIP and MeIQx and with increased susceptibility to MeIQx-induced liver tumors in rapid NAT2 acetylators. -3,8-dimethylimidazo-[4,5-f ]quinoxaline (MeIQx) and 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP) are potent and abundant mutagens in the human diet, formed during high temperature cooking of meats (Keating and Bogen, 2004). They also have been detected in processed food flavorings, beer, wine, cigarette smoke, smoke condensate formed during frying of beef patties and bacon, and in aerosol from cooking of stir-fried fish (National Toxicology Program, 2005). PhIP has been detected in airborne particles, diesel-exhaust particles, and incineration ash from garbage-burning plants (Manabe et al., 1993). 2-AminoBoth MeIQx and PhIP induce tumors in the rat (Sugimura et al., 2004) and are designated as "reasonably anticipated to be a human carcinogen" (National Toxicology Program, 2005). MeIQx induces liver tumors in mice (Ohgaki et al., 1987) and up to 100% incidence of hepatic tumors in rats (Kato et al., 1988;Kushida et al., 1994). PhIP target organ specificity differs from MeIQx in the rat because it induces tumors in colon, prostate, and mammary tissue (Sugimura et al., 2004). MeIQx-and PhIP-induced DNA adduct formation and carcinogenesis require N-hydroxylation, which occurs at relatively high rates in humans (Stil1well et al., 1999;Turesky 2002). N-Hydroxy-MeIQx and -PhIP are further O-acetylated by N-acetyltransferase 2 (NAT2) to a...

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confidence: 86%

“…MeIQx induces liver tumors in mice (Ohgaki et al, 1987) and up to 100% incidence of hepatic tumors in rats (Kato et al, 1988;Kushida et al, 1994). PhIP target organ specificity differs from MeIQx in the rat because it induces tumors in colon, prostate, and mammary tissue (Sugimura et al, 2004).…”

mentioning

confidence: 99%

Effect of N-Acetyltransferase 2 Polymorphism on Tumor Target Tissue DNA Adduct Levels in Rapid and Slow Acetylator Congenic Rats Administered 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine or 2-Amino-3,8-dimethylimidazo-[4,5-f]quinoxaline

Metry¹,

Neale²,

Bendaly³

et al. 2009

Drug Metab Dispos

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“…In addition, the tumors induced by IQ in nonhuman primates occurred in a high percentage of the treated animals in only about one-seventh of their life span. Furthermore, two of the other HAAs occurring in greater amounts in cooked meats, MeIQx and PhIP, are carcinogenic in rodents and are currently also under evaluation for carcinogenic activity in nonhuman primates (6,7,9,12). Thus, we conclude that the food mutagen IQ is a potent hepatocarcinogen when administered to nonhuman primates and is a potential carcinogen for humans.…”

Section: Discussionmentioning

confidence: 78%

Induction of Hepatocellular Carcinoma in Nonhuman Primates by the Food Mutagen 2-Amino-3-Methylimidazo[4,5-f]quinoline

Adamson¹,

Takayama²,

Sügimura³

et al. 1994

Environmental Health Perspectives

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2-Amino-3-methylimidazo[4,5-fiquinoline (IQ) is one of 19 heterocyclic aromatic amines (HAAs) formed during the cooking of fish, fowl, pork, and beef and isolated as mutagens using the Ames Salmonella typhimurium assay (1,2). Although the HAAs thus far identified are present in the Western diet in only small amounts (nanograms per gram), they are among the most potent mutagens identified and may be of importance in the etiology of some human cancers (3). Ten of these food mutagens including IQ have been shown to be carcinogenic when administered to mice and rats (4-8). IQ was found to induce tumors of the liver, lung, and forestomach in mice and of the small and large intestine, mammary gland, liver, oral cavity, and Zymbal gland in rats (4,5,8). Based on chemical structure, mutagenic activity in vitro, concentration in cooked foods, carcinogenic activity in rodents, and availability, we selected three compounds for study in nonhuman primates: IQ, 2-amino-3,8-dimethylimidazo [4,5-flquinoxaline (8-MeIQx), and 2-amino-1-methyl-6-phenylimidazo [4,5, b]pyridine (PhIP) (9). Our initial report described tumors induced in three macaques by IQ as part of an ongoing study (JO). This paper reports on hepatocellular carcinoma induced in a high percentage of macaques by IQ after oral administration. Materials and MethodsMacaques assigned to this study were born in a closed colony, reared by their mothers, and were assigned to this study as they became approximately 1 year of age. The monkeys were primarily cynomolgus (Macacafascularis), but two rhesus (M mulatto) were also used at the high dose. The animals were housed in individual stainlesssteel cages that were wall mounted and equipped with an automatic watering device. Purina High Protein Monkey Chow #5045 was offered twice daily, and the animals also received a vitamin sandwich and a portion of an apple daily. IQ was purchased from the Nard Institute Ltd. (Osaka, Japan) and kept refrigerated in a desiccator until use. IQ was prepared daily as a suspension in hydroxypropylcellulose (HPC) and administered by gavage five times a week (Monday-Friday) at a dose of 10 or 20 mg/kg body weight. Twenty animals were assigned to each dose. The monkeys receiving 10 mg/kg IQ were all cynomolgus and consisted of 12 males and 8 females. Two rhesus females and 18 cynomolgus (8 males and 10 females) monkeys received 20 mg/kg IQ.There were three sources of controls: 9 concurrent HPC cynomolgus monkeys dosed by gavage, 3 historical HPC cynomolgus monkeys fed HPC in a prune for over 16 years and still on HPC treatment, and 5 cynomolgus untreated concurrent controls.We observed all IQ treated and control animals daily and measured body weight weekly. Blood was drawn every 3 months for routine hematology and clinical chemistry values as well as a-fetoprotein (AFP) measurements, which were determined by radioimmunoassay using monkey AFP as antigen. Liver palpation and laparoscopy were performed at 3-to 6-month intervals. The tumor bearing animals were euthanized with an overdose of sodium pe...

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“…meiQx can be detected in the urine of healthy volunteers after eating cooked meat (18)(19)(20), and meiQx-dna adducts have been found in kidney and colon tissues in humans (21). in rats, meiQx induces dna adduct formation in the liver (22) and the development of hepatocellular carcinomas with treatment at high doses (23).…”

Section: Introductionmentioning

confidence: 99%

Sensitive quantitative assay for point mutations in the rat H-ras gene based on single nucleotide primer extension

Yano

Yano²,

Kinoshita³

et al. 2010

Experimental and Therapeutic Medicine

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Abstract. point mutations in oncogenes and tumor suppressor genes occur at early stages in the carcinogenic process. point mutations in ras family oncogenes are the most common mutational events in several types of human cancer, and are available as molecular markers for the detection of cancer cells in carcinogenicity bioassay systems as well as in clinical samples. although several techniques are utilized to detect point mutations in carcinogenicity bioassay systems, the sensitivity is too low to determine a small number of mutations. in order to overcome the disadvantage and to sensitively determine gene mutation rates for in vivo carcinogenicity bioassays of presumptive carcinogens, we established a thermosequenase cycle End labeling (tcEl) method, a sensitive approach based on single nucleotide primer extension. One of the characteristics of the method is a high sensitivity of 1:100,000, ten times the sensitivity of the mutant allele-specific amplification now commonly employed. Using TCEL, we here quantified h-ras mutations in the livers of rats treated with a genotoxic carcinogen, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline. Our findings suggest that this method may be applied for many genetic targets as a component in vivo.

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Carcinogenicity in rats of a mutagenic compound, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline

Cited by 137 publications

References 0 publications

Effect of N-Acetyltransferase 2 Polymorphism on Tumor Target Tissue DNA Adduct Levels in Rapid and Slow Acetylator Congenic Rats Administered 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine or 2-Amino-3,8-dimethylimidazo-[4,5-f]quinoxaline

Effect of N-Acetyltransferase 2 Polymorphism on Tumor Target Tissue DNA Adduct Levels in Rapid and Slow Acetylator Congenic Rats Administered 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine or 2-Amino-3,8-dimethylimidazo-[4,5-f]quinoxaline

Induction of Hepatocellular Carcinoma in Nonhuman Primates by the Food Mutagen 2-Amino-3-Methylimidazo[4,5-f]quinoline

Sensitive quantitative assay for point mutations in the rat H-ras gene based on single nucleotide primer extension

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