Metabolism of k-region derivatives of 1-nitropyrene by rat liver in vitro

The metabolism of K-region derivatives of 1-nitropyrene was studied in order to provide insight into factors that may contribute to their mutagenic activities and to obtain information on unknown metabolites of 1-nitropyrene. Using 9000 g supernatant from livers of Aroclor-treated rats, 1-nitropyrene-4,5-diol, a mutagenic metabolite of 1-nitropyrene, was metabolized to 1-aminopyrene-4,5-diol, a mixture of 1-nitropyrene-4,5,9,10-tetraols, 1-amino-4,5-pyrenedione and 1-nitro-4,5-pyrenedione. 1-Nitro-5H-phenanthro[4,5-bcd]pyran-5-one, a highly mutagenic lactone, was not detected. The metabolism of 1-nitro-4,5-pyrenedione yielded only 1-amino-4,5-pyrenedione; the lactone was not observed. No metabolites were detected when the lactone was incubated under conditions identical to those employed for 1-nitro-4,5-diol and 1-nitro-4,5-pyrenedione. Upon re-examination of the metabolism of 1-nitropyrene, we were able to detect 1-nitropyrene-4,5,9,10-tetraol, 1-amino-4,5-pyrenedione and 1-nitro-4,5-pyrenedione as minor metabolites in addition to the major metabolites reported previously. The results of this study, combined with the mutagenicity data for the K-region derivatives of 1-nitropyrene, suggest that nitroreduction of 1-nitropyrene-4,5-diol and 1-nitro-4,5-pyrenedione to the corresponding hydroxylamines is an important pathway for their metabolic activation in Salmonella typhimurium and possibly in mammalian systems.