Metabolism and DNA Binding of 2-Nitropyrene in the Rat

Pramod Upadhyaya, Ajit K. Roy, Peter P. Fu, Karam El-Bayoumy

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

2-Nitropyrene (2-NP), a contaminant of ambient air, is a potent bacterial mutagen in the Ames assay and induces leukemia/lymphoma in female Sprague-Dawley rats. To understand the mechanistic basis for its tumorigenic activity, it is essential to elucidate the metabolic pathways of 2-NP in vivo. Such knowledge will also assist in developing analytical methods for monitoring human exposure to nitropolynuclear aromatic hydrocarbons in ambient air. Thus, 2-nitro(£/-4,5,9,10-14C]pyrene was synthesized and administered to male F344 rats by intragastric gavage at a dose of 30 mg (0.4 mO/ mM)/kg body weight. During the first 48 h, 57.5% of the dose was eliminated in the feces and 9.7% was eliminated in the urine. Correspondingly, after 168 h, 58.9 and 10.6% were excreted in feces and urine, respectively. Fecal metabolites (isolated amounts) included 6-hydroxy-2-acetylaminopyrene (19.5%), 6-hydroxy-2-aminopyrene (10.4%), 2-aminopyrene (10.0%), 2-acetylaminopyrene (0.8%), and unmetabolized 2-nitropyrene (10.0%). 6-Hydroxy-2-acetylaminopyrene, 6-hydroxy-2-aminopyrene, and 2-aminopyrene were identified as their acetyl derivatives by comparison of their chromatographic retention times, mass spectra, and UV spectra to those of synthetic standards. Urinary metabolites included 6-hydroxy-2-acetylaminopyrene (2.0%); glucuronide conjugates were tentatively identified (3.2%). The results of this study indicate that nitroreduction and ring oxidation are metabolic pathways in vivo. For DNA binding studies, rats were treated with 2-nitro[4,5,9,10-3H] pyrene [1.6 mg (598 mCi/mM)/kg body weight). The levels of binding (pM bound/mg DNA) were as foUows: 13, liver; 1.14, mammary tissue; 0.65, lung; 1.67, kidney; and 1.8, bladder. Upon high-performance liquid chromatographic analysis of the DNA hydrolysate (liver, mammary, and kidney), approximately 2.0% of the radioactivity coeluted with the synthetic markers derived from nitroreduction, AKdeoxyguanosin-8-yl)-2-aminopyrene and ^V-(deoxyadenosin-8-yl)-2-aminopyrene. Thus, simple nitroreduction of 2-NP does not significantly contribute to the total DNA binding of 2-NP metabolites in vivo. The significance of each pathway for the tumorigenic effects of 2-NP remains to be examined.

Original languageEnglish (US)
Pages (from-to)1176-1181
Number of pages6
JournalCancer Research
Volume52
Issue number5
StatePublished - Mar 1992

Fingerprint

DNA
Metabolic Networks and Pathways
Feces
Breast
Air
Body Weight
Urine
Kidney
Aromatic Hydrocarbons
Liver
Glucuronides
Inbred F344 Rats
Mutagens
Radioactivity
Sprague Dawley Rats
2-nitropyrene
Lymphoma
Leukemia
Urinary Bladder
High Pressure Liquid Chromatography

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Upadhyaya, P., Roy, A. K., Fu, P. P., & El-Bayoumy, K. (1992). Metabolism and DNA Binding of 2-Nitropyrene in the Rat. Cancer Research, 52(5), 1176-1181.
Upadhyaya, Pramod ; Roy, Ajit K. ; Fu, Peter P. ; El-Bayoumy, Karam. / Metabolism and DNA Binding of 2-Nitropyrene in the Rat. In: Cancer Research. 1992 ; Vol. 52, No. 5. pp. 1176-1181.
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abstract = "2-Nitropyrene (2-NP), a contaminant of ambient air, is a potent bacterial mutagen in the Ames assay and induces leukemia/lymphoma in female Sprague-Dawley rats. To understand the mechanistic basis for its tumorigenic activity, it is essential to elucidate the metabolic pathways of 2-NP in vivo. Such knowledge will also assist in developing analytical methods for monitoring human exposure to nitropolynuclear aromatic hydrocarbons in ambient air. Thus, 2-nitro(£/-4,5,9,10-14C]pyrene was synthesized and administered to male F344 rats by intragastric gavage at a dose of 30 mg (0.4 mO/ mM)/kg body weight. During the first 48 h, 57.5{\%} of the dose was eliminated in the feces and 9.7{\%} was eliminated in the urine. Correspondingly, after 168 h, 58.9 and 10.6{\%} were excreted in feces and urine, respectively. Fecal metabolites (isolated amounts) included 6-hydroxy-2-acetylaminopyrene (19.5{\%}), 6-hydroxy-2-aminopyrene (10.4{\%}), 2-aminopyrene (10.0{\%}), 2-acetylaminopyrene (0.8{\%}), and unmetabolized 2-nitropyrene (10.0{\%}). 6-Hydroxy-2-acetylaminopyrene, 6-hydroxy-2-aminopyrene, and 2-aminopyrene were identified as their acetyl derivatives by comparison of their chromatographic retention times, mass spectra, and UV spectra to those of synthetic standards. Urinary metabolites included 6-hydroxy-2-acetylaminopyrene (2.0{\%}); glucuronide conjugates were tentatively identified (3.2{\%}). The results of this study indicate that nitroreduction and ring oxidation are metabolic pathways in vivo. For DNA binding studies, rats were treated with 2-nitro[4,5,9,10-3H] pyrene [1.6 mg (598 mCi/mM)/kg body weight). The levels of binding (pM bound/mg DNA) were as foUows: 13, liver; 1.14, mammary tissue; 0.65, lung; 1.67, kidney; and 1.8, bladder. Upon high-performance liquid chromatographic analysis of the DNA hydrolysate (liver, mammary, and kidney), approximately 2.0{\%} of the radioactivity coeluted with the synthetic markers derived from nitroreduction, AKdeoxyguanosin-8-yl)-2-aminopyrene and ^V-(deoxyadenosin-8-yl)-2-aminopyrene. Thus, simple nitroreduction of 2-NP does not significantly contribute to the total DNA binding of 2-NP metabolites in vivo. The significance of each pathway for the tumorigenic effects of 2-NP remains to be examined.",
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Upadhyaya, P, Roy, AK, Fu, PP & El-Bayoumy, K 1992, 'Metabolism and DNA Binding of 2-Nitropyrene in the Rat', Cancer Research, vol. 52, no. 5, pp. 1176-1181.

Metabolism and DNA Binding of 2-Nitropyrene in the Rat. / Upadhyaya, Pramod; Roy, Ajit K.; Fu, Peter P.; El-Bayoumy, Karam.

In: Cancer Research, Vol. 52, No. 5, 03.1992, p. 1176-1181.

Research output: Contribution to journalArticle

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T1 - Metabolism and DNA Binding of 2-Nitropyrene in the Rat

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AU - Roy, Ajit K.

AU - Fu, Peter P.

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N2 - 2-Nitropyrene (2-NP), a contaminant of ambient air, is a potent bacterial mutagen in the Ames assay and induces leukemia/lymphoma in female Sprague-Dawley rats. To understand the mechanistic basis for its tumorigenic activity, it is essential to elucidate the metabolic pathways of 2-NP in vivo. Such knowledge will also assist in developing analytical methods for monitoring human exposure to nitropolynuclear aromatic hydrocarbons in ambient air. Thus, 2-nitro(£/-4,5,9,10-14C]pyrene was synthesized and administered to male F344 rats by intragastric gavage at a dose of 30 mg (0.4 mO/ mM)/kg body weight. During the first 48 h, 57.5% of the dose was eliminated in the feces and 9.7% was eliminated in the urine. Correspondingly, after 168 h, 58.9 and 10.6% were excreted in feces and urine, respectively. Fecal metabolites (isolated amounts) included 6-hydroxy-2-acetylaminopyrene (19.5%), 6-hydroxy-2-aminopyrene (10.4%), 2-aminopyrene (10.0%), 2-acetylaminopyrene (0.8%), and unmetabolized 2-nitropyrene (10.0%). 6-Hydroxy-2-acetylaminopyrene, 6-hydroxy-2-aminopyrene, and 2-aminopyrene were identified as their acetyl derivatives by comparison of their chromatographic retention times, mass spectra, and UV spectra to those of synthetic standards. Urinary metabolites included 6-hydroxy-2-acetylaminopyrene (2.0%); glucuronide conjugates were tentatively identified (3.2%). The results of this study indicate that nitroreduction and ring oxidation are metabolic pathways in vivo. For DNA binding studies, rats were treated with 2-nitro[4,5,9,10-3H] pyrene [1.6 mg (598 mCi/mM)/kg body weight). The levels of binding (pM bound/mg DNA) were as foUows: 13, liver; 1.14, mammary tissue; 0.65, lung; 1.67, kidney; and 1.8, bladder. Upon high-performance liquid chromatographic analysis of the DNA hydrolysate (liver, mammary, and kidney), approximately 2.0% of the radioactivity coeluted with the synthetic markers derived from nitroreduction, AKdeoxyguanosin-8-yl)-2-aminopyrene and ^V-(deoxyadenosin-8-yl)-2-aminopyrene. Thus, simple nitroreduction of 2-NP does not significantly contribute to the total DNA binding of 2-NP metabolites in vivo. The significance of each pathway for the tumorigenic effects of 2-NP remains to be examined.

AB - 2-Nitropyrene (2-NP), a contaminant of ambient air, is a potent bacterial mutagen in the Ames assay and induces leukemia/lymphoma in female Sprague-Dawley rats. To understand the mechanistic basis for its tumorigenic activity, it is essential to elucidate the metabolic pathways of 2-NP in vivo. Such knowledge will also assist in developing analytical methods for monitoring human exposure to nitropolynuclear aromatic hydrocarbons in ambient air. Thus, 2-nitro(£/-4,5,9,10-14C]pyrene was synthesized and administered to male F344 rats by intragastric gavage at a dose of 30 mg (0.4 mO/ mM)/kg body weight. During the first 48 h, 57.5% of the dose was eliminated in the feces and 9.7% was eliminated in the urine. Correspondingly, after 168 h, 58.9 and 10.6% were excreted in feces and urine, respectively. Fecal metabolites (isolated amounts) included 6-hydroxy-2-acetylaminopyrene (19.5%), 6-hydroxy-2-aminopyrene (10.4%), 2-aminopyrene (10.0%), 2-acetylaminopyrene (0.8%), and unmetabolized 2-nitropyrene (10.0%). 6-Hydroxy-2-acetylaminopyrene, 6-hydroxy-2-aminopyrene, and 2-aminopyrene were identified as their acetyl derivatives by comparison of their chromatographic retention times, mass spectra, and UV spectra to those of synthetic standards. Urinary metabolites included 6-hydroxy-2-acetylaminopyrene (2.0%); glucuronide conjugates were tentatively identified (3.2%). The results of this study indicate that nitroreduction and ring oxidation are metabolic pathways in vivo. For DNA binding studies, rats were treated with 2-nitro[4,5,9,10-3H] pyrene [1.6 mg (598 mCi/mM)/kg body weight). The levels of binding (pM bound/mg DNA) were as foUows: 13, liver; 1.14, mammary tissue; 0.65, lung; 1.67, kidney; and 1.8, bladder. Upon high-performance liquid chromatographic analysis of the DNA hydrolysate (liver, mammary, and kidney), approximately 2.0% of the radioactivity coeluted with the synthetic markers derived from nitroreduction, AKdeoxyguanosin-8-yl)-2-aminopyrene and ^V-(deoxyadenosin-8-yl)-2-aminopyrene. Thus, simple nitroreduction of 2-NP does not significantly contribute to the total DNA binding of 2-NP metabolites in vivo. The significance of each pathway for the tumorigenic effects of 2-NP remains to be examined.

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Upadhyaya P, Roy AK, Fu PP, El-Bayoumy K. Metabolism and DNA Binding of 2-Nitropyrene in the Rat. Cancer Research. 1992 Mar;52(5):1176-1181.