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Cancer research

Metabolism and DNA binding of the environmental colon carcinogen 6-nitrochrysene in rats.


PMID 8616850

Abstract

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 mumol/rat (346 microCi/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 mumol/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.

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