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Metabolic Activation of 6-Nitrochrysene in Explants of Human Bronchus and in Isolated Rat Hepatocytes¹

Divisions of Biochemical and Genetic Toxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079 [K. B. D., D. A. C., R. P. W., F. F. K.]; Department of Pathology, Medical College of Ohio, Toledo, Ohio 43699 [N. S., S. M., G. D. S.]; and Division of Chemical Carcinogenesis, American Health Foundation, Valhalla, New York 10595 [K. E-B., S. S. H.]

It has previously been shown that 6-nitrochrysene can be activated to electrophilic species capable of reacting with DNA through metabolic pathways that form N-hydroxy-6-aminochrysene or trans-1,2-dihydroxy-1,2-dihydro-6-aminochrysene as critical intermediates. Since the lung is a known target tissue for the carcinogenic action of polycyclic nitroaromatic hydrocarbons, we investigated the metabolism and DNA binding of [³H]6-nitrochrysene in 11 specimens of human bronchus. Analysis of medium from [³H]6-nitrochrysene-treated explants indicated the presence of trans-9,10-dihydroxy-9,10-dihydro-6-nitrochrysene (0.04–330 pmol/mg epithelial DNA), trans-1,2-dihydroxy-1,2-dihydro-6-nitrochrysene (12–1700 pmol/mg epithelial DNA), 6-aminochrysene (1.6–2200 pmol/mg epithelial DNA), and trans-1,2-dihydroxy-1,2dihydro-6-aminochrysene (3.6–610 pmol/mg epithelial DNA). Both the levels and the relative proportions of these metabolites varied widely in explants from different individuals.

The amount of DNA recovered and the level of DNA modification were sufficient for adduct analysis in eight of the 11 cases for which metabolite data were obtained. Five additional bronchial specimens for which metabolite data were not obtained were also analyzed for carcinogen-DNA adducts. The levels of binding varied from 0.06 to 30.5 pmol [³]6-nitrochrysene bound/mg DNA (two adducts per 10⁸ nucleotides-10 adducts per 10⁶ nucleotides). HPLC analyses of enzymatic hydrolysates of the explant DNA indicated that 11 of 13 cases contained adducts with retention times identical to those of adducts derived from trans-1,2-dihydroxy-1,2-dihydro-6-aminochrysene or N-hydroxy-6-aminochrysene. The adduct derived from trans-1,2-dihydroxy-1,2-dihydro-6-aminochrysene was the major adduct detected in eight of 13 cases.

The reasons for the variation in metabolism and adduct formation observed in [³H]6-nitrochrysene-treated explants of bronchus from different donors are not known but may reflect differences in the activities of enzymes responsible for the metabolism of this compound. The influence of induction of drug metabolizing enzymes on the activation pathway of 6-nitrochyrsene in an intact cell system was tested using rat hepatocytes. 6-Nitrochrysene was incubated with freshly isolated hepatocytes from rats that were either untreated or pretreated with phenobarbital, 3-methylcholanthrene or Aroclor 1254. Although the levels of adducts were similar in all cases, the pattern of DNA adducts formed in these hepatocytes was dependent on the nature of the pretreatment of the rats. As previously reported, hepatocytes from untreated rats contained adducts derived from N-hydroxy-6-aminochrysene. The same adducts were formed in hepatocytes from rats pretreated with phenobarbital. On the other hand, adducts derived from trans-1,2-dihydroxy-1,2-dihydro-6-aminochrysene were the predominant adducts formed in hepatocytes from rats pretreated with Arcolor 1254 or 3-methylcholanthrene.

¹ This work was supported in part by NCI Grants CA28950 (G. D. S.) and CA35519 (K. E-B.).

² To whom requests for reprints should be addressed.

Received 12/12/88. Revised 3/ 1/89. Accepted 3/ 7/89.

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