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Metabolism and DNA Binding of 2-Nitropyrene in the Rat

Pramod Upadhyaya, Ajit K. Roy, Peter P. Fu and Karam El-Bayoumy
Pramod Upadhyaya
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Ajit K. Roy
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Peter P. Fu
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Karam El-Bayoumy
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DOI:  Published March 1992
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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(U-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 mCi/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 follows: 1.3, 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, N-(deoxyguanosin-8-yl)-2-aminopyrene and N-(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.

Footnotes

  • ↵1 This study was supported by National Cancer Institute Grant CA-35519.

  • ↵3 To whom requests for reprints should be addressed, at American Health Foundation, 1 Dana Road, Valhalla, NY 10595.

  • Received July 22, 1991.
  • Accepted December 17, 1991.
  • ©1992 American Association for Cancer Research.
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March 1992
Volume 52, Issue 5
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Metabolism and DNA Binding of 2-Nitropyrene in the Rat
Pramod Upadhyaya, Ajit K. Roy, Peter P. Fu and Karam El-Bayoumy
Cancer Res March 1 1992 (52) (5) 1176-1181;

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Metabolism and DNA Binding of 2-Nitropyrene in the Rat
Pramod Upadhyaya, Ajit K. Roy, Peter P. Fu and Karam El-Bayoumy
Cancer Res March 1 1992 (52) (5) 1176-1181;
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