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Metabolism and DNA Binding of the Environmental Colon Carcinogen 6-Nitrochrysene in Rats¹

Division of Cancer Etiology and Prevention, American Health Foundation, Valhalla, New York 10595 [Y-H. C., K. E-B.], and Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079 [K. B. D., B. B.]

The environmental contaminant 6-nitrochrysene (6-NC) has been shown to induce adenomas and adenocarcinomas in the colons of rats. The present study aimed at providing a better understanding of mechanisms that are responsible for this effect. Three female CD rats were injected i.p. with [3,4,9,10-³H]6-NC [9 µmol/rat (346 µCi/rat)], and urine and feces were collected daily for 3 days. In the first 24 h, radioactivity corresponding to 1.3% of the dose was excreted in the urine, whereas 23.0% was recovered in the feces. After 3 days, the total excretions in urine and feces were 2.8% and 34.9% of the dose, respectively. Radioactivity measured in various organs 3 days after injection of [3,4,9,10-³H]6-NC amounted to 24.8% of the administered dose. Fecal metabolites were identified, based on comparison of their chromatographic characteristics with those of standards, as trans-1,2-dihydro-1,2-dihydroxy-6-NC, chrysene-5,6-quinone, and 6-aminochrysene (6-AC); the structure of the latter was further confirmed by mass spectrometry and UV spectral analysis. Metabolites identified in the urine were 6-AC, trans-1,2-dihydro-1,2-dihydroxy-6-NC, and trans-9,10-dihydro-9,10-dihydroxy-6-NC in free forms and also as glucuronide and/or sulfate conjugates. The ³²P-postlabeling assay was used to determine the metabolic pathways that were leading to DNA adduct formation in the target (colon) and nontarget (liver, lung, and mammary tissues) organs of female CD rats injected with 6-NC under conditions identical to those of the bioassay (total, 14.8 µmol/rat; single i.p. injections on days 1, 8, 15, 22, and 29). Twenty-four h after the last carcinogen administration, the levels of the adduct derived from trans-1,2-dihydro-1,2-dihydroxy-6-AC were higher than those derived from N-hydroxy-6-AC in all organs examined; however, the highest levels of DNA adducts were found in the lung and not in the target organ, the colon. Although the role of each adduct in colon carcinogenesis needs to be determined, the results favor the ring oxidation and nitroreduction combination pathway as the primary contributor to the activation of 6-NC as a colon carcinogen in the rat.

¹ This work was supported in part by National Cancer Institute Grant CA 35519. The Research Animal Facility at the American Health Foundation is partially supported by National Cancer Institute Cancer Center Support Grant CA 17613.

² To whom requests for reprints should be addressed, at Division of Cancer Etiology and Prevention, American Health Foundation, 1 Dana Road, Valhalla, New York 10595.

Received 12/12/95. Accepted 3/ 1/96.

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