Reductions of nitro and 9-oxo groups of environmental nitrofluorenes by the rat mammary gland in vitro

Nitrofluorenes and C-9-oxidized nitrofluorenes are widespread environmental genotoxins which may be relevant for breast cancer on the basis of their c arcinogenicities, particularly of 2,7-dinitrofluorene (2,7-diNF), for the r at mammary gland. Since their metabolism to active carcinogens may involve nitroreduction, this study examined the reduction of 2-nitrofluorene (2-NF) and 2,7-diNF and their 9-oxo- and 9-hydroxy (OH) derivatives by the rat ma mmary gland. Cytosolic fractions catalyze NADH- and NADPH-dependent reducti ons of the 2-nitro and 9-oxo to the respective 2-amino and 9-OH compounds a t rates 4- and greater than or equal to 10-fold greater than those with mic rosomes. Rates of amine formation catalyzed by cytosol from 2,7-diNF are gr eater than the rate from 2-NF and increase for C-9-oxidized derivatives: 9- oxo-2-NF > 9-OH-2-NF > 2-NF and 9-OH-2,7-diNF much greater than 9-oxo-2,7-d iNF > 2,7-diNF. Nitroreduction is inhibited by O-2 or allopurinol (20 mu M) , dicoumarol (100 mu M), and rutin (50 mu M). 9-Oxoreduction is inhibited b y rutin, dicoumarol, and indomethacin (100 mu M), but not by O-2 or allopur inol. Pyrazole or menadione does not inhibit nitro or 9-oxoreduction. Xanth ine, hypoxanthine, 2-hydroxypyrimidine, and N'-methylnicotinamide support c ytosol-catalyzed nitro, but not 9-oxo, reduction. The data suggest that the nitroreduction is catalyzed largely by a xanthine oxidase and partially by a diaphorase and 9-oxoreduction by a carbonyl reductase. The extents of th e nitro and carbonyl reductions of the nitrofluorenes may determine their r eactivities with DNA, and thus genotoxicities for the mammary gland.