The genotoxicity, metabolism and carcinogenicity of nitrated polycyclic aromatic hydrocarbons

Rosenkranz, Herbert S.; Mermelstein, Robert

doi:10.1080/10590508509373334

Cited by 74 publications

(51 citation statements)

References 163 publications

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“…Another predominant HA found in cooked meats, 2 -amino-3,8-dimethylimidazo [ 4,5-f] quinoxaline (MeIQx), causes tumors at multiple sites in rats and mice Bogen, 1994 ). HAs are metabolically activated by P450 and N -acetyltranserase enzymes, and activated forms are observed to bind covalently to DNA at sites including tissues (including prostate ) in which HAs induce cancer in rats (Thorgeirsson, 1984;Thorgeirsson et al, 1983;Rosenkranz and Mermeistein, 1985;Sato et al, 1986;Kato and Yamazoe, 1987;Snyderwine and Battula, 1989;McManus et al, 1990;Turesky et al, 1991;Davis et al, 1993;Kaderlik et al, 1994a,b;Takahashi et al, 1998;Schut and Snyderwine, 1999 ).…”

Section: Introductionmentioning

confidence: 99%

U.S. dietary exposures to heterocyclic amines*

Bogen

Keating

2001

J Expo Sci Environ Epidemiol

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Heterocyclic amines ( HAs ) formed in fried, broiled or grilled meats are potent mutagens that increase rates of colon, mammary, prostate and other cancers in bioassay rodents. Studies of how human dietary HA exposures may affect cancer risks have so far relied on fairly crudely defined HA -exposure categories. Recently, an integrated, quantitative approach to HA -exposure assessment ( HAEA ) was developed to estimate compound -specific intakes for particular individuals based on corresponding HA -concentration estimates that reflect their meat -type, intake -rate, cooking -method and meat -doneness preferences. This method was applied in the present study to U.S. national Continuing Survey of Food Intakes by Individuals ( CSFII ) data on meats consumed and cooking methods used by > 25,000 people, after adjusting for underreported energy intake and conditional on meat -doneness preferences estimated from additional survey data. The U.S. population average lifetime time -weighted average of total HAs consumed was estimated to be $9 ng / kg / day, with 2 -amino -1 -methyl -6 -phenylimidazo [ 4,5 -b ] pyridine ( PhIP ) estimated to comprise about two thirds of this intake. Pan -fried meats were the largest source of HA in the diet and chicken the largest source of HAs among different meat types. Estimated total HA intakes by male vs. female children were generally similar, with those by ( 0 -to 15 -year -old ) children $25% greater than those by ( 16 + -year -old ) adults. Race -, age -and sex -specific mean HA intakes were estimated to be greatest for African American males, who were estimated to consume $2 -and $3 -fold more PhIP than white males at ages < 16 and 30 + years, respectively, after considering a relatively greater preference for more well -done items among African Americans based on national survey data. This difference in PhIP intakes may at least partly explain why prostate cancer ( PC ) kills $2 -fold more African American than white men, in view of experimental data indicating that PhIP mutates prostate DNA and causes prostate tumors in rats. Journal of Exposure Analysis and Environmental Epidemiology ( 2001 ) 11, 155 ± 168.

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Section: Introductionmentioning

confidence: 99%

U.S. dietary exposures to heterocyclic amines*

Bogen

Keating

2001

J Expo Sci Environ Epidemiol

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“…1-Nitropyrene (1-NP) 1 , a representative of this class of compounds, is the most abundant nitroaromatic compound in the environment. 1-NP is mutagenic in many bacterial and mammalian assay systems and tumorigenic in experimental animals (5)(6)(7)(8). 1-NP is a major constituent in a mixture of more than 200 nitropolycyclic aromatic hydrocarbons in diesel exhaust (9).…”

Section: Introductionmentioning

confidence: 99%

Mutagenicity of the 1-Nitropyrene-DNA Adduct N-(Deoxyguanosin-8-yl)-1-aminopyrene in Mammalian Cells

Watt

Utzat

Hilario

et al. 2007

Chem. Res. Toxicol.

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The mutagenesis of the major DNA adduct N-(deoxyguanosin-8-yl)-1-aminopyrene (C8-AP-dG) formed by 1-nitropyrene was compared with the analogous C8-dG adducts of 2-aminofluorene (AF) and N-acetyl-2-aminofluorene (AAF) in simian kidney (COS-7) cells. The DNA sequence chosen for this comparison contained 5′-CCATCGCTACC-3′ that has been used for solution NMR investigations. The structural and conformational differences among these lesions are wellestablished (Patel et al., 1998). Accordingly, we found a notable difference in the viability of the progeny, which showed that the AAF adduct was most toxic and the AF adduct was least toxic with the AP adduct exhibiting intermediate toxicity. However, analysis of the progeny showed that translesion synthesis was predominantly error-free. Only low level mutations (<3%) were detected with G→T as the dominant type of mutation by all three DNA adducts. When C8-AP-dG was evaluated in a repetitive 5′-CGCGCG-3′ sequence, higher mutational frequency (~8%) was observed. Again, G→T was the major type of mutations in simian kidney cells, even though in bacteria CpG deletions predominate in this sequence (Hilario et al, 2002). Mutagenesis of C8-AP-dG in a 12-mer containing the local DNA sequence around codon 273 of the p53 tumor suppressor gene, where the adduct was located at the second base of this codon, was also investigated. In this 5′-GTGCGTGTTTGT-3′ site, the mutations were slightly lower but not very different from the progeny derived from the 5′-CGCGCG-3′ sequence. However, the mutational frequency increased by more than 50% when the 5′ C to the adduct was replaced with a 5-methylcytosine (5-MeC). With a 5-MeC, the most notable change in mutation was the enhancement of G→A, which occurred 2.5-times relative to a 5′ C. The C8-AP-dG adduct in codon 273 dodecamer sequence with a 5′ C or 5-MeC was also evaluated in human embryonic kidney (293T) cells. Similar to COS cells, targeted mutations doubled with a 5-MeC 5′ to the adduct. Except for an increase in G→C transversions, the results in 293T were similar to that in COS cells. We conclude that C8-AP-dG mutagenesis depends on the type of cell in which it is replicated, the neighboring DNA sequence, and the methylation status of the 5′ C.

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“…We were not able to separate In vitro studies were performed to gain insight into the nature of the binding and to provide ample material for spectral analysis. We incubated [3H] 1-NOP and 3[H] -NP-4,5-oxide with rat hemoglobin. 140 Both compounds bound to globin, the former more so (37% of the initial radioactivity) than the latter (25%).…”

Section: Analysis Of Hemoglobin Adducts Fliowig the Or Adnistration Omentioning

confidence: 99%

“…Mutagenic activities in bacterial and mammalian systems and tumorigenic activity in laboratory animals of several members of the class of NO2-PAH have been clearly documented (2)(3)(4)(5).…”

Section: Introductionmentioning

confidence: 99%

Development of Methods to Monitor Exposure to 1-Nitropyrene

El‐Bayoumy¹,

Johnson²,

Roy³

et al. 1994

Environmental Health Perspectives

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On the basis of 32P-postlabeling analysis, treatment of rats with 1-nitropyrene (1-NP) resulted in the formation of multiple DNA adducts in the liver, mammary glands, and peripheral lymphocytes. The one adduct resulting from nitroreduction, N-(deoxyguanosin-8-yl)-1-aminopyrene, constitutes only a minor component among the adducts. In the present study, incubation of calf thymus DNA with mutagenic ring-oxidized metabolites of 1-NP in vitro in the presence and absence of xanthine oxidase also resulted in the formation of multiple adducts. On the basis of their chromatographic behavior, it appears that DNA adducts derived from such metabolites may have been formed in vivo; however, this needs to be confirmed.[3H]1-NP was given to male and female F344 rats and Sprague-Dawley rats by gavage at five dose levels in the range of 0.1 to 1000 pg/kg bw. This led to stable hemoglobin adducts accounting for 0.08 ± 0.05% of the dose (n = 3 rats). The radioactivity associated with hemoglobin following administration of [3H]1-NP was cleared with a half-life of about 14 days, which is faster than that of unmodified erythrocytes in the rat (t1/2= 30 days).Treatment of the hemoglobin with 1% HCI in acetone, to precipitate the globin, released the radioactivity; it was all bound to the heme moiety. The structures of the heme adducts have not been elucidated; yet, because of their stability, they may be useful as dosimeters for human exposure to 1-NP. The results of this study demonstrate the potential of using hemoglobin adducts of 1-NP as dosimeters of uptake and metabolic activation of nitropolynuclear aromatic hydrocarbons (NO2-PAH). These indicators are a prerequisite for cancer risk assessment of N02-PAH. -Environ Health Perspect 102(Suppl 6): 31-37 (1994)

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The genotoxicity, metabolism and carcinogenicity of nitrated polycyclic aromatic hydrocarbons

Cited by 74 publications

References 163 publications

U.S. dietary exposures to heterocyclic amines*

U.S. dietary exposures to heterocyclic amines*

Mutagenicity of the 1-Nitropyrene-DNA Adduct N-(Deoxyguanosin-8-yl)-1-aminopyrene in Mammalian Cells

Development of Methods to Monitor Exposure to 1-Nitropyrene

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