Metabolism of 2, 4-Dinitrotoluene, 2, 4-Dinitrobenzyl Alcohol and 2, 4-Dinitrobenzaldehyde by Rat Liver Microsomal and Cytosol Fractions(Environmental)

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The metabolism of 2, 4-dinitrotoluene (2, 4-DNT), 2, 4-dinitrobenzyl alcohol (2, 4-DNB) and 2, 4-dinitrobenzaldehyde (2, 4-DNAl) in rat liver microsomal and cytosol fractions was investigated. The objectives of these studies were to determine whether 2, 4-DNAl, a potent mutagen, is produced in the oxidation of 2, 4-DNB to 2, 4-DNBA and to clarify the nature of the enzymes responsible for the oxidation of 2, 4-DNT to 2, 4-DNB, 2, 4-DNAl and 2, 4-dinitrobenzoic acid (2, 4-DNBA). Data obtained from high-performance liquid chromatography indicated that the major products of 2, 4-DNT, 2, 4-DNB and 2, 4-DNAl in the microsomal and cytosol preparations were 2, 4-DNB, 2, 4-DNAl, and 2, 4-DNBA and 2, 4-DNB, respectively. The results indicate that 2, 4-DNAl is an intermediate in the oxidation of 2, 4-DNB to 2, 4-DNBA. In addition, data obtained by incubating 2, 4-DNT, 2, 4-DNB or 2, 4-DNAl with microsomal or cytosol fraction under air, nitrogen and various concentrations of CO in oxygen, using cofactors nicotinamide adenine dinucleotide phosphate and reduced nicotinamide adenine dinucleotide phosphate [NAD (P) and NAD (P) H] and inhibitors (SKF-525A, dimethyl sulfoxide, chloral hydrate, allopurinol, pyrazole and o-phenanthroline) suggest that : (a) oxidation of 2, 4-DNT to 2, 4-DNB is mediated by microsomal P-450 ; (b) oxidation of 2, 4-DNB to 2, 4-DNAl is mediated mainly by cytochrome P-450 and NAD-dependent alcohol dehydrogenase ; (c) oxidation of 2, 4-DNAl to 2, 4-DNBA and reduction of 2, 4-DNAl to 2, 4-DNB may be mediated by NAD( P)-dependent aldehyde dehydrogenases and NAD (P) H-dependent aldehyde reductases, respectively. These results indicate that 2, 4-DNT is metabolized stepwise to 2, 4-DNB, 2, 4-DNAl and 2, 4-DNBA in the rat liver and suggest that the oxidation of 2, 4-DNB to 2, 4-DNAl is a metabolic activation of 2, 4-DNT and that the microsomal cytochrome P-450 and alcohol dehydrogenase may play an important role in the metabolic activation of 2, 4-DNT.
社団法人日本薬学会の論文
1987-04-25

Metabolism of 2, 4-Dinitrotoluene, 2, 4-Dinitrobenzyl Alcohol and 2, 4-Dinitrobenzaldehyde by Rat Liver Microsomal and Cytosol Fractions(Environmental)

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