Metabolism of 2,4-dinitro[14C]toluene by freshly isolated Fischer-344 rat primary hepatocytes.
Fischer-344 rat hepatocytes display a capacity for both oxidation and reduction of 2,4-dinitrotoluene (2,4-DNT), a potent hepatocarcinogen. The major metabolite detected by high-pressure liquid chromatography was 2,4-dinitrobenzyl alcohol (2,4-DNBalc), which accounted for 75-80% of the total metabolites formed. The apparent KM and Vmax for 2,4-DNBalc formation was 58.0 microM and 25.5 nmoles/10(6) cells/30 min, respectively. Formation of 2,4-DNBalc was enhanced by treatment of rats with Aroclor 1254 (6-fold), phenobarbital (3.5-fold), and 3-methylcholanthrene (3.5-fold). In vitro additions of either SKF 525-A or 7,8-benzoflavone inhibited the formation of 2,4-DNBalc. Hepatocytes incubated under decreased oxygen concentrations (15%, 10%, 5% O2 in N2) displayed higher levels of reductive metabolism at 2,4-DNT (up to 5-fold) than when incubated in air. Concomitant decreases in oxidative metabolism of 2,4-DNT were observed in these experiments. Hepatocyte metabolism of 2-amino-4-nitrotoluene and 4-amino-2-nitrotoluene, two major products of rat cecal metabolism of 2,4-DNT, to 2-(N-acetyl)amino-4-nitrotoluene and 4-(N-acetyl)amino-2-nitrololuene, respectively, was observed. The results of this investigation suggest that hepatic reductive metabolism of 2,4-DNT probably plays a minor role in the overall metabolic scheme of 2,4-DNT.
D000818:Animals; D001592:Benzyl Alcohols / Q000378:metabolism; D002273:Carcinogens / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004136:Dinitrobenzenes / Q000378:metabolism*; D066298:In Vitro Techniques; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009578:Nitrobenzenes / Q000378:metabolism*; D010084:Oxidation-Reduction; D010100:Oxygen / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D014052:Toluidines / Q000378:metabolism
D001592:Benzyl Alcohols; D002273:Carcinogens; D004136:Dinitrobenzenes; D009578:Nitrobenzenes; D014052:Toluidines; C029333:4-amino-2-nitrotoluene; C029332:2,4-dinitrobenzyl alcohol; C016403:2,4-dinitrotoluene; D010100:Oxygen