METABOLISM AND DNA-BINDING OF THE ENVIRONMENTAL COLON CARCINOGEN 6-NITROCHRYSENE IN RATS

The environmental contaminant 6-nitrochrysene (6-NC) has been shown to induce adenomas and adenocarcinomas in the colons of rats, The presen t study aimed at providing a better understanding of mechanisms that a re responsible for this effect, Three female CD rats were injected i.p . with [3,4,9,10-H-3]6-NC [9 mu mol/rat (316 mu Ci/rat)], and urine an d feces were collected daily for 3 days, In the first 24 h, radioactiv ity corresponding to 1.3% of the dose was excreted in the urine, where as 23.0% was recovered in the feces, After 3 days, the total excretion s in urine and feces were 2.8% and 34.9% of the dose, respectively, Ra dioactivity measured in various organs 3 days after injection of [3,4, 9,10-H-3]6-NC amounted to 24.8% of the administered dose, Fecal metabo lites were identified, based on comparison of their chromatographic ch aracteristics with those of standards, as trans-1,2-dihydro-1,2-dihydr oxy-6-NC, chrysene-5,6-quinone, and 6-aminochrysene (6-AC); the struct ure of the latter was further confirmed by mass spectrometry and UV sp ectral 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 P-32-postlabeling assay was used to determine the metabolic pathwa ys 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 bioassa y (total, 14.8 mu mol/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-A C were higher than those derived from N-hydroxg-6-AC in all organs exa mined; however, the highest levels of DNA adducts were found in the lu ng and not in the target organ, the colon, Although the role of each a dduct in colon carcinogenesis needs to be determined, the results favo r the ring oxidation and nitroreduction combination pathway as the pri mary contributor to the activation of 6-NC as a colon carcinogen in th e rat.