Genotoxicity of compounds from cooked beef in repair-deficient CHO cells versus Salmonella mutagenicity

Thompson, Larry H.; Tucker, James D.; Stewart, S. A.; Christensen, Mari; Salazar, Edmund P.; Carrano, A.V.; Felton, James S.

doi:10.1093/mutage/2.6.483

Cited by 125 publications

(53 citation statements)

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“…54 High sensitivity LC/ESI-MS 55 has measured several adducts per 10 7 nucleotides in animal tissues. 19,56 The levels of C8 and N 2 -dG IQ adducts measured in tissues of rats and primates using mass spectrometry 57,58 are in agreement with data obtained by 32 P postlabeling.…”

Section: F]quinoline (Iq) 1-4supporting

confidence: 59%

Base-Displaced Intercalated Structure of the Food Mutagen 2-Amino-3-methylimidazo[4,5-f]quinoline in the Recognition Sequence of the NarI Restriction Enzyme, a Hotspot for −2 bp Deletions

et al. 2006

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The solution structure of the oligodeoxynucleotide 5′-d(CTCGGCXCCATC)-3′·5′-d (GATGGCGCCGAG)-3′ containing the heterocyclic amine 8- [(3-methyl-3H-imidazo[4,5-f] quinolin-2-yl)amino]-2′-deoxyguanosine adduct (IQ) at the third guanine in the NarI restriction sequence, a hot spot for −2 bp frameshifts, is reported. Molecular dynamics calculations restrained by distances derived from 24 1 H NOEs between IQ and DNA, and torsion angles derived from 3 J couplings, yielded ensembles of structures in which the adducted guanine was displaced into the major groove with its glycosyl torsion angle in the syn conformation. One proton of its exocyclic amine was approximately 2.8 Å from an oxygen of the 5′ phosphodiester linkage, suggesting formation of a hydrogen bond. The carcinogen-guanine linkage was defined by torsion angles α′ [N9-C8-N(IQ)-C2(IQ)] of 159 ± 7° and β′ [C8-N(IQ)-C2(IQ)-N3(IQ)] of −23 ± 8°. The complementary cytosine was also displaced into the major groove. This allowed IQ to intercalate between the flanking C·G base pairs. The disruption of Watson-Crick hydrogen bonding was corroborated by chemical-shift perturbations for base aromatic protons in the complementary strand opposite to the modified guanine. Chemical-shift perturbations were also observed for 31 P resonances corresponding to phosphodiester linkages flanking the adduct. The results confirmed that IQ adopted a base-displaced intercalated conformation in this sequence context but did not corroborate the formation of a hydrogen bond between the IQ quinoline nitrogen and the complementary dC.

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Section: F]quinoline (Iq) 1-4supporting

confidence: 59%

Base-Displaced Intercalated Structure of the Food Mutagen 2-Amino-3-methylimidazo[4,5-f]quinoline in the Recognition Sequence of the NarI Restriction Enzyme, a Hotspot for −2 bp Deletions

et al. 2006

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“…Thus, the mutation frequency is directly proportional to the number of adducts formed. This appears to be related to the number of active intermediates formed, but could also be related to repair of specific DNA (23). Again, Trp-P-2 appears to be more potent in mammalian systems.…”

Section: In Vitro Mammalian Toxicologymentioning

confidence: 95%

“…Trp-P-2 and PhIP showed cytotoxic, mutagenic (hprt and aprt loci), and chromosome damage (SCEs and aberrations) at doses as low as 1 pg/ml in CHO cells treated in the presence of liver S9 from PCB-induced hamsters (23). An excision-repair-deficient cell line (UV5) was more than twice as sensitive as the parental line (AA8) for both mutagens.…”

Section: In Vitro Mammalian Toxicologymentioning

confidence: 99%

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Mutagenic activity of heterocyclic amines in cooked foods.

Felton

Knize

Dolbeare

et al. 1994

Environ Health Perspect

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Mutagenic heterocyclic amines are generated in foods when they are cooked at temperatures over 1 50°C. These compounds are present from 0.1 to 50 ppb, depending on the food and cooking conditions. These heterocyclic amines are not only present in cooked red meat, fish, and chicken, but are also present at lower levels in baked and fried foods derived from grain. Mutagenicity of fried beef hamburgers cooked at 230°C is 800 ± 37 TA98 revertants per gram cooked weight. We measured 2-amino-3,8-dimethylimidazo[4,5-flquinoxaline (MelQx), 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMelQx), and 2-amino-3-methylimidazo[4,5-flquinoline (IQ) formation at this temperature and found 3.0 ± 2.0, 1.0 ± 0.18, and 0.06 ± 0.03 ng/g, respectively. 2-amino-1-methyl--phenylimidazo[4,5-blpyridine (PhIP) was found at a higher concentration of 9.6 ng/g. In our laboratory we have shown these heterocyclic amines are capable of producing both reverse and forward mutations in Salmonella bacteria and forward mutations in Chinese hamster ovary cells (CHO). We have also been able to show a statistically significant increase in mutations in the pancreas of the "mutamouse" following PhIP exposure. The pancreas also shows relatively high DNA binding compared to other organs in the mouse. The number and type of mutations depend on the repair capacity of the cells for both Salmonella and CHO. In Salmonella the mutations are primarily 2-base deletions when the cells lack uvrB repair, but mutations are more complex (larger deletions and insertions) but lower in frequency when repair is functional. Efforts are now under way to assess specific sequence changes in the aprt gene in mutant CHO cells. -Environ Health Perspect 102 (Suppl 6):201-204 (1994)

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“…Although PhIP is less potent in the Salmonella test than the quinoline-and the quinoxaline-AIA compounds, it has been shown to be an equally potent genotoxin in mammalian cells both in vitro and in vivo (7)(8)(9)(10) in rats (11) and abdominal lymphomas in mice (12). In a series of previous studies, we have characterized the metabolic pathways of PhIP leading to mutagenic activation and detoxification (10,(13)(14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

Metabolism of the Food Mutagen 2-Amino-1-Methyl-6-Phenylimidazo[4,5-b]pyridine (PhIP) in Isolated Liver Cells from Guinea Pig, Hamster, Mouse, and Rat

Alexander¹,

Fossum²,

Holme³

1994

Environmental Health Perspectives

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The metabolism of 2-amino-1-methyl-6-phenylimidazo [4,, the most abundant compound of the aminoimidazoazaarens (AIA) group of mutagens/carcinogens isolated from the crust of fried and broiled meat, was examined in freshly isolated hepatocytes from untreated rat, mouse, hamster, and guinea pig. Activation was evaluated by the total level of covalent binding of PhIP to macromolecules. Rat hepatocytes had the lowest rate of metabolism, both to reactive and detoxified metabolites. The products were identified as 4'-PhIP-sulfate, PhIP-glucuronide, and N(OH)-PhIPglucuronide. The ring hydroxylation rate was much greater in mouse hepatocytes, the main products being 4'-PhIP-sulfate and 4-hydroxy-PhIP. The level of covalent binding in the mouse hepatocytes exceeded those of the rat and guinea pig at high doses of PhIP. An extensive metabolism was seen in guinea pig hepatocytes, the major products being 4'-PhIP-sulfate, 4'-O-PhIP glucuronide, PhIP-glucuronide, and N(OH)-PhIP-glucuronide. In addition, several other unknown metabolites were formed. However, the amount of covalent binding in guinea pig hepatocytes was similar to that in rat hepatocytes. Covalent binding of PhIP metabolites was highest in hamster hepatocytes. Three of the main metabolites were identified as 4'-PhIP-sulfate, 4'-O-PhIP-glucuronide, and PhIP-glucuronide, but several unknown PhIP metabolites also were formed. Only minor amounts of N(OH)-PhIP-glucuronide were produced in the hamster. The present study shows that both the direct detoxification of PhIP and further conjugation of the 2-hydroxylamino-PhIP to reactive and/or detoxifie,d metabolites are important for the resulting covalent binding. -Environ Health Perspect 102(Suppl 6):109-114 (1994)

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Genotoxicity of compounds from cooked beef in repair-deficient CHO cells versus Salmonella mutagenicity

Cited by 125 publications

References 0 publications

Base-Displaced Intercalated Structure of the Food Mutagen 2-Amino-3-methylimidazo[4,5-f]quinoline in the Recognition Sequence of the NarI Restriction Enzyme, a Hotspot for −2 bp Deletions

Base-Displaced Intercalated Structure of the Food Mutagen 2-Amino-3-methylimidazo[4,5-f]quinoline in the Recognition Sequence of the NarI Restriction Enzyme, a Hotspot for −2 bp Deletions

Mutagenic activity of heterocyclic amines in cooked foods.

Metabolism of the Food Mutagen 2-Amino-1-Methyl-6-Phenylimidazo[4,5-b]pyridine (PhIP) in Isolated Liver Cells from Guinea Pig, Hamster, Mouse, and Rat

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