Nitropyrene: DNA Binding and Adduct Formation in Respiratory Tissues

Jackson, M. A.; King, L. C.; Ball, L. M.; Ghayourmanesh, S.; Jeffrey, A. M.; Lewtas, J.

doi:10.2307/3430114

Cited by 2 publications

(1 citation statement)

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“…In the mammalian system, 1-NP is metabolized by nitroreduction, ring oxidation, and a combination of both pathways ( Figure 1). Studies in our laboratory and elsewhere indicate that simple nitroreduction of 1-NP to yield N-(deoxyguanosin-8-yl)-1-aminopyrene (N-dG-AP) cannot account for the observed DNA adducts in vivo and in vitro (7)(8)(9)(10)(11)(12). To more clearly define the metabolic activation of 1-NP, structural elucidation of DNA adducts is required.…”

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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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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Lung retention and binding of [¹⁴c]‐1‐nitropyrene when inhaledby f344 rats as a pure aerosol or adsorbed to carbon black particles

Wolff

Sun²,

Barr³

et al. 1989

Journal of Toxicology and Environmental Health

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1-Nitropyrene (NP), as found in the environment, is more typically associated with carbonaceous particles than found as an aerosol of the pure compound. To determine whether (and why) an association with particles resulted in prolonged lung retention of NP, rats were exposed to 14C-NP as a pure aerosol or adsorbed on carbon black particles. Total 14C retained in the lung was greater at all times from 0.5 h to 30 d after exposure to 14C-NP adsorbed to carbon black particles than after exposure to pure 14C-NP (p less than .05). The fraction of total 14C in lung bound to carbon black particles decreased steadily with time after exposure, indicating in vivo removal of NP from the particles. At 0.5 h after exposure, the fraction of the estimated deposited 14C that was covalently bound to lung macromolecules was twofold greater for NP adsorbed on carbon black than for pure NP. Covalently bound 14C in lungs increased with time after exposure to 14C-NP adsorbed to carbon black, reaching levels of approximately 1% of the deposited radioactivity at 7-30 d after exposure, whereas levels of covalently bound 14C declined with time after exposure to pure NP. Thus, at 30 d after exposure, the amount of 14C covalently bound to lung macromolecules was approximately 10-fold greater (p less than .05) in rats that inhaled 14C-NP adsorbed on carbon black particles than in rats that inhaled pure 14C-NP aerosols. These results suggest that association of NP with carbon black particles augments the interaction of reactive metabolites of NP with target macromolecules. This phenomenon is thought to be related to the slow release of NP from carbon black particles, and may augment the biological effects of inhaled NP when adsorbed on carbon black or similar particles in the environment.

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Nitropyrene: DNA Binding and Adduct Formation in Respiratory Tissues

Cited by 2 publications

References 21 publications

Development of Methods to Monitor Exposure to 1-Nitropyrene

Development of Methods to Monitor Exposure to 1-Nitropyrene

Lung retention and binding of [¹⁴c]‐1‐nitropyrene when inhaledby f344 rats as a pure aerosol or adsorbed to carbon black particles

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Nitropyrene: DNA Binding and Adduct Formation in Respiratory Tissues

Cited by 2 publications

References 21 publications

Development of Methods to Monitor Exposure to 1-Nitropyrene

Development of Methods to Monitor Exposure to 1-Nitropyrene

Lung retention and binding of [14c]‐1‐nitropyrene when inhaledby f344 rats as a pure aerosol or adsorbed to carbon black particles

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Lung retention and binding of [¹⁴c]‐1‐nitropyrene when inhaledby f344 rats as a pure aerosol or adsorbed to carbon black particles