MeIQx-DNA adduct formation in rodent and human tissues at low doses

Turteltaub, Kenneth W.; Mauthe, Robert J.; Dingley, Karen H.; Vogel, John S.; Frantz, Christopher E.; Garner, R. Colin; Shen, Nancy H.

doi:10.1016/s0027-5107(97)00049-3

Cited by 75 publications

(42 citation statements)

References 30 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%

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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%

“…MeIQx-induced DNA adducts primarily form at the C8 position of deoxyguanosine (16) and deoxyguanosine (dG)-C8-MeIQx adducts have been identified in human tissues (17). Bulky DNA adducts such as these are recognized by the nucleotide excision repair pathway (18).…”

Section: Introductionmentioning

confidence: 99%

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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“…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).…”

Section: Metry Et Alsupporting

confidence: 86%

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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“…There are organ, species, and individual differences in P450 enzymes, so direct extrapolation from rodent experiments to human risks may be misleading. Using another heterocyclic amine, 2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline, which was radioisotopically labelled at low doses with 14 C, and accelerator mass spectrometry, deoxyguanosine adducts were shown in the human colon, but at approximately ten times greater levels than in rodents at the same dose and time point following exposure (Turteltaub et al 1997). The human colon, therefore, may be more susceptible to the effects of these compounds than the colon of rodents.…”

Section: Mechanisms Relating Meat To Cancermentioning

confidence: 99%

High-meat diets and cancer risk

Bingham

1999

Proc. Nutr. Soc.

118

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Up to 80 % of breast, bowel and prostate cancers are attributed to dietary practices, and international comparisons show strong positive associations with meat consumption. Estimates of relative risk obtained from cohort investigations are in the same direction, although generally weak, and red and processed meats rather than white meat seem to be associated with elevated risk of colon cancer. In breast cancer, there are consistent associations with total meat intake and there is evidence of a dose response. Despite these associations with meat, existing studies suggest that vegetarians do not have reduced risk of breast, bowel or prostate cancer, but there are no quantitative estimates of amounts of meat consumed by meat eaters in these cohort studies. Possible mechanisms underlying epidemiological associations include the formation of heterocyclic amines in meat when it is cooked. These heterocyclic amines require acetylation by P450 enzymes, and individuals with the fast-acetylating genotype who eat high amounts of meat may be at increased risk of large-bowel cancer. NH 3 and N-nitroso compounds (NOC) formed from residues by bacteria in the large bowel are probably also important. NH 3 is a promotor of large-bowel tumours chemically induced by NOC, and some of the chromosomal mutations found in human colo-rectal cancer are consistent with effects of NOC and heterocyclic amines. However, the type, amount, and cooking method of meat or protein associated with increased risk are not certain. The effects of high levels of meat on NH 3 and NOC output are not reduced by increasing the amount of fermentable carbohydrate in the diet, but interaction between meat, NSP and vegetable intakes on the risk of cancer has not been studied comprehensively. The interaction between dietary low-penetrance genetic polymorphic and somatic mutation factors has also been investigated to a limited extent. Current Department of Health (1998) recommendations are that meat consumption should not rise, and that consumers at the top end of the distribution should consider a reduction in intakes.

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MeIQx-DNA adduct formation in rodent and human tissues at low doses

Cited by 75 publications

References 30 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

High-meat diets and cancer risk

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