Metabolism of 1,8-dinitropyrene by rabbit lung.
Dinitropyrenes are mutagenic and carcinogenic environmental pollutants commonly found in diesel exhaust and airborne particulates. In the present study, the ability of rabbit lung to metabolize 1,8-dinitro[4,5,9,10-3H]pyrene by both oxygen-dependent and oxygen-independent pathways has been investigated. Using lung 9000 g supernatant, the biotransformation of 1,8-dinitropyrene to stable metabolites was more extensive in the absence of oxygen. A major proportion of the metabolites was ether-extractable. Five metabolite peaks (A-E) were detected by HPLC in the absence of oxygen. Formation of metabolites A, C, D and E was decreased under aerobic conditions. Metabolites B and C co-chromatographed with the reference standards 1,8-diaminopyrene and 1-acetyl-amino-8-nitropyrene, respectively. The formation of metabolites A and C was dependent on the presence of acetyl coenzyme A. Binding of radiolabel to calf thymus DNA occurred under both anaerobic and aerobic conditions, although there was significantly higher binding in the presence of oxygen. Omission of acetyl coenzyme A significantly increased DNA binding. In experiments where calf thymus DNA was omitted from the incubation medium, covalent binding of radiolabel to acid-precipitable lung S9 macromolecules was detected only under aerobic conditions (11.1 +/- 4.3 pmol/mg protein). The results indicate that rabbit lung can metabolize 1,8-dinitropyrene by both reductive and oxidative pathways. Reductive metabolism is the major pathway for formation of stable metabolites while alkylation of cellular macromolecules occurs primarily via oxidation. There was no correlation between acetyl coenzyme A-dependent acetylation and activation of 1,8-dinitropyrene to reactive species which bind to DNA.
Tee
L B
LB
Department of Pharmacology, University of Western Australia, Nedlands.
Minchin
R F
RF
Ilett
K F
KF
D000105:Acetyl Coenzyme A / Q000378:metabolism; D000332:Aerobiosis; D000693:Anaerobiosis; D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D007700:Kinetics; D008168:Lung / Q000378:metabolism*; D008297:Male; D008861:Microsomes / Q000378:metabolism*; D011721:Pyrenes / Q000378:metabolism*; D011817:Rabbits
D002273:Carcinogens; D011721:Pyrenes; D000105:Acetyl Coenzyme A; D004247:DNA; C037413:1,3-dinitropyrene