Presence of N2-(deoxyguanosin-8-yl)-2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (dG-C8-MeIQx) in human tissues

Totsuka, Yukari; Fukutome, Kazuo; Takahashi, Mami; Takahashi, Satoru; Tada, Akihiro; Sügimura, Takashi; Wakabayashi, Keiji

doi:10.1093/carcin/17.5.1029

Cited by 91 publications

(57 citation statements)

References 22 publications

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“…Thus, these results confirm that metabolic O-acetylation by NAT2 substantially enhances DNA adduct formation and mutagenesis and that rapid acetylator NAT2 catalyzes this activation to a substantially greater extent than slow acetylator NAT2. The primary DNA adduct formed in our UV5/CYP1A1/NAT2*4 CHO cells was dG-C8-MeIQx, which is the primary adduct that has been identified in human tissues (17,39). The product ion fragmentation patterns for dG-C8-MeIQx and dG-C8-MeIQx-D3 were remarkably similar to those reported previously (19).…”

Section: Discussionsupporting

confidence: 83%

2-Amino-3,8-Dimethylimidazo-[4,5-f]Quinoxaline–Induced DNA Adduct Formation and Mutagenesis in DNA Repair–Deficient Chinese Hamster Ovary Cells Expressing Human Cytochrome P4501A1 and Rapid or Slow Acetylator N-Acetyltransferase 2

Bendaly

Zhao

Neale

et al. 2007

Cancer Epidemiology, Biomarkers &Amp; Prevention

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2- quinoxaline (MeIQx) is one of the most potent and abundant mutagens in the western diet. Bioactivation includes N-hydroxylation catalyzed by cytochrome P450s followed by O-acetylation catalyzed by N-acetyltransferase 2 (NAT2). In humans, NAT2*4 allele is associated with rapid acetylator phenotype, whereas NAT2*5B allele is associated with slow acetylator phenotype. We hypothesized that rapid acetylator phenotype predisposes humans to DNA damage and mutagenesis from MeIQx. Nucleotide excision repair -deficient Chinese hamster ovary cells were constructed by stable transfection of human cytochrome P4501A1 (CYP1A1) and a single copy of either NAT2*4 (rapid acetylator) or NAT2*5B (slow acetylator) alleles. CYP1A1 and NAT2 catalytic activities were undetectable in untransfected Chinese hamster ovary cell lines. CYP1A1 activity did not differ significantly (P > 0.05) among the CYP1A1-transfected cell lines. Cells transfected with NAT2*4 had 20-fold significantly higher levels of sulfamethazine N-acetyltransferase (P = 0.0001) and 6-fold higher levels of N-hydroxy-MeIQx O-acetyltransferase (P = 0.0093) catalytic activity than cells transfected with NAT2*5B. Only cells transfected with both CYP1A1 and NAT2*4 showed concentration-dependent cytotoxicity and hypoxanthine phosphoribosyl transferase mutagenesis following MeIQx treatment. Deoxyguanosine-C8-MeIQx was the primary DNA adduct formed and levels were dose dependent in each cell line and in the following order: untransfected < transfected with CYP1A1 < transfected with CYP1A1 and NAT2*5B < transfected with CYP1A1 and NAT2*4. MeIQx DNA adduct levels were significantly higher (P < 0.001) in CYP1A1/ NAT2*4 than CYP1A1/NAT2*5B cells at all concentrations of MeIQx tested. MeIQx-induced DNA adduct levels correlated very highly (r 2 = 0.88) with MeIQx-induced mutants. These results strongly support extrahepatic activation of MeIQx by CYP1A1 and a robust effect of human NAT2 genetic polymorphism on MeIQx-induced DNA adducts and mutagenesis. The results provide laboratory-based support for epidemiologic studies reporting higher frequency of heterocyclic amine-related cancers in rapid NAT2 acetylators. (Cancer Epidemiol Biomarkers Prev 2007;16(7):1503 -9)

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Section: Discussionsupporting

confidence: 83%

2-Amino-3,8-Dimethylimidazo-[4,5-f]Quinoxaline–Induced DNA Adduct Formation and Mutagenesis in DNA Repair–Deficient Chinese Hamster Ovary Cells Expressing Human Cytochrome P4501A1 and Rapid or Slow Acetylator N-Acetyltransferase 2

Bendaly

Zhao

Neale

et al. 2007

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…As reviewed previously (Turesky, 2002), glutathione S-transferases (Lin et al, 1994), sulfotransferases (Wu et al, 2000), and/or glucuronosyltransferases (Malfatti et al, 2005) also are important in the metabolic activation and deactivation of heterocyclic amine carcinogens, and differences in any of the metabolic pathways between organs and tissues could account for differences in DNA adduct formation and tumor incidence. PhIP and MeIQx are activated to electrophilic intermediates that form DNA adducts primarily at deoxyguanosine (dG) (Turesky, 2002 adducts have been identified in human tissues and cells (Totsuka et al, 1996;Gorlewska-Roberts et al, 2002 (Doll and Hein 1995). Because F344 and WKY inbred rats differ in genes other than NAT2, most likely including cytochrome P450s, glutathione S-transferases, sulfotransferases, glucuronyltransferase, and other enzymes important in the metabolism of heterocyclic amine carcinogens, we constructed congenic rat lines that are isogenic except for the Nat2 locus and very closely aligned loci .…”

Section: -Aminomentioning

confidence: 99%

“…PhIP and MeIQx are activated to electrophilic intermediates that form DNA adducts primarily at deoxyguanosine (dG) (Turesky, 2002). dG-C8-PhIP and dG-C8-MeIQx adducts have been identified in human tissues and cells (Totsuka et al, 1996;Gorlewska-Roberts et al, 2002).…”

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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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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“…The levels of MeIQx-DNA adducts in groups 3 and 4 were measured by the 32 P-postlabeling method under modified adduct intensification conditions using frozen samples, as previously reported (Totsuka et al, 1996). The number of samples/ group assayed was 5.…”

Section: Assessment Of Gst-p-positive Foci 8-ohdg and Meiqx-dna Addmentioning

confidence: 99%

“…Actually, 1.8 to 18 DNA adducts per 10 10 nucleotides have been detected in human organs such as the colon (Totsuka et al, 1996). In rats, MeIQx was reported to induce tumors of liver, lung, Zymbal's gland, clitoral gland, large intestine, oral cavity, mammary gland, and skin.…”

mentioning

confidence: 99%

Evidence of a Threshold-Effect for 2-Amino-3,8-dimethylimidazo-[4,5-f]quinoxaline Liver Carcinogenicity in F344/DuCrj Rats

et al. 2008

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To estimate potential human risk of exposure to a food-derived, genotoxic hepatocarcinogen, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), a 2-year carcinogenicity test was conducted using male F344 rats administered MeIQx-containing diet at doses of 0 (control), 0.001, 1, and 100 ppm. The lowest dose 0.001 ppm was established as equivalent to the daily intake of this carcinogen in humans (0.2 to 2.6 μg/man/day). Significant decreases of survival rate and body weight gain were observed in rats treated with 100 ppm MeIQx. Histopathological examination revealed significant induction of hepatocellular carcinomas, adenomas, and development of glutathione S-transferase placental form-positive foci with MeIQx at 100 ppm. Moreover, the incidences of Zymbal's glands carcinoma, mammary fibroadenoma, and subcutaneous fibroma were found significantly increased in a 100 ppm MeIQx group. However, no significant induction of altered preneoplastic hepatocellular foci was observed in 0.001 and 1 ppm groups as compared to the controls. 8-Hydroxy-2'-deoxyguanosine levels in the rat liver DNA of the 100 ppm-treated group were not elevated, but MeIQx-DNA adduct formation increased as compared with the 1 ppm case, albeit without significance. No significant induction of any other neoplastic lesions related to the carcinogen administration was found in MeIQx-administered groups except for 100 ppm. These results imply that 1 ppm may be a no-effect level for MeIQx carcinogenesis.

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Presence of N²-(deoxyguanosin-8-yl)-2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (dG-C8-MeIQx) in human tissues

Cited by 91 publications

References 22 publications

2-Amino-3,8-Dimethylimidazo-[4,5-f]Quinoxaline–Induced DNA Adduct Formation and Mutagenesis in DNA Repair–Deficient Chinese Hamster Ovary Cells Expressing Human Cytochrome P4501A1 and Rapid or Slow Acetylator N-Acetyltransferase 2

2-Amino-3,8-Dimethylimidazo-[4,5-f]Quinoxaline–Induced DNA Adduct Formation and Mutagenesis in DNA Repair–Deficient Chinese Hamster Ovary Cells Expressing Human Cytochrome P4501A1 and Rapid or Slow Acetylator N-Acetyltransferase 2

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

Evidence of a Threshold-Effect for 2-Amino-3,8-dimethylimidazo-[4,5-f]quinoxaline Liver Carcinogenicity in F344/DuCrj Rats

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