Metabolism of nitrofluoranthenes by rat lung subcellular fractions.

The nitrofluoranthene (NF) family of compounds includes the potent pulmonary carcinogen 3,9-dinitrofluoranthene (3,9-DNF) and the weak carcinogen 3-nitrofluoranthene (3-NF). Although the specific molecular mechanisms involved in this difference in sensitivity for the induction of lung tumors in rats by 3,9-DNF and 3-NF have not been defined, these compounds most likely induce carcinogenesis by metabolic activation to electrophilic metabolites that bind DNA. The purpose of these investigations was to determine the activation pathways in the rat lung for the metabolism of the di-(3,9-DNF) and mono-nitroisomers (3-NF, 8-NF, 2-NF) of NFs. The metabolic rates of NFs were compared for lung subcellular fractions of pristine rats as well as rats previously treated with 3-methylcholanthrene (3-MC) or phenobarbital at levels that would induce cytochrome P450 enzymes. One major metabolite, the amino derivative, was detected by high pressure liquid chromatography following anaerobic incubation of rat lung cytosol with 3-NF, 8-NF, 2-NF or 3,9-DNF. 3,9-DNF was metabolized to its amino derivative, aminonitrofluoranthene, at a higher rate than 3-NF, 8-NF or 2-NF. Pretreatment of the rats with 3-MC or phenobarbital did not affect the metabolic rates of cytosolic reduction. Both 3-NF and 3,9-DNF were metabolized anaerobically to their amino derivatives by microsomal reductas(s). 3,9-DNF was metabolized twice as fast as 3-NF. The formation of the aminonitrofluoranthene metabolite was increased approximately 2 times with microsomes from 3-MC-induced rats, but was unaffected by microsomes from phenobarbital-treated rats. This suggests that the cytochrome P450 isozymes and reductase, which are induced by 3-MC, may be involved in the metabolism of 3-NF and 3,9-DNF. The metabolic products of 3-NF, formed aerobically, consisted of one major and three minor compounds. The major metabolite, tentatively identified as 3-NF-8-ol, was increased approximately 6 times using microsomes from 3-MC-induced rats. In contrast, 3,9-DNF metabolism was not detected aerobically with lung microsomes. Thus, ring hydroxylation was inhibited in the metabolism of 3,9-DNF, and the major pathway was nitroreduction. This higher rate of anaerobic metabolism of 3,9-DNF over 3-NF and the expected high reactivity of the putative N-acetoxy derivative formed from 3,9-DNF may be responsible for the differential potency for lung cancer induction by these two carcinogens.