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 carcinogenicities, particularly of 2, 7-dinitrofluorene (2,7-diNF), for the rat 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 mammary gland. Cytosolic fractions catalyze NADH- and NADPH-dependent reductions of the 2-nitro and 9-oxo to the respective 2-amino and 9-OH compounds at rates 4- and >/=10-fold greater than those with microsomes. Rates of amine formation catalyzed by cytosol from 2, 7-diNF are greater 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 >> 9-oxo-2,7-diNF > 2,7-diNF. Nitroreduction is inhibited by O(2) or allopurinol (20 microM), dicoumarol (100 microM), and rutin (50 microM). 9-Oxoreduction is inhibited by rutin, dicoumarol, and indomethacin (100 microM), but not by O(2) or allopurinol. Pyrazole or menadione does not inhibit nitro or 9-oxoreduction. Xanthine, hypoxanthine, 2-hydroxypyrimidine, and N'-methylnicotinamide support cytosol-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 the nitro and carbonyl reductions of the nitrofluorenes may determine their reactivities with DNA, and thus genotoxicities for the mammary gland.
Ritter
C L
CL
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Decker
R W
RW
Malejka-Giganti
D
D
D000393:Air Pollutants / Q000378:metabolism* / Q000494:pharmacology; D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D001940:Breast / Q000187:drug effects / Q000378:metabolism*; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D001728:Dicumarol / Q000494:pharmacology; D005260:Female; D005449:Fluorenes / Q000378:metabolism* / Q000494:pharmacology; D019271:Hypoxanthine / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D010084:Oxidation-Reduction; D010100:Oxygen / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012431:Rutin / Q000494:pharmacology; D014812:Vitamin K / Q000494:pharmacology; D019820:Xanthine / Q000494:pharmacology
D000393:Air Pollutants; D005449:Fluorenes; D011720:Pyrazoles; D011743:Pyrimidines; D014812:Vitamin K; C019499:2-nitrofluorene; D019820:Xanthine; D009536:Niacinamide; D019271:Hypoxanthine; C031280:pyrazole; C085049:2,7-dinitrofluorene; C041345:2-hydroxypyrimidine; D012431:Rutin; D000493:Allopurinol; D001728:Dicumarol; D010100:Oxygen; C024058:N(1)-methylnicotinamide; D007213:Indomethacin