Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.3.1.107 (DAT)
 1,471 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

2,4-Diaminotoluene (2,4-DAT), a high volume synthetic compound, is moderately carcinogenic to rodents. We report here that 2,4-DAT is a substrate for the peroxidase activity of prostaglandin H synthase (PHS). In contrast to many aromatic amines which are activated as mutagens by PHS, we find that 2,4-DAT is not mutagenic to six S. typhimurium strains with this activation system. The strains tested include YG1006, YG1024, and YG1029, which are far more sensitive to the mutagenicity of aromatic amines and nitroarenes than are the standard tester strains. Although not mutagenic itself, 2,4-DAT does enhance the mutagenicity of 2-aminofluorene (2-AF) in the PHS-catalyzed system in strains TA98, YG1006, and YG1024, with maximal enhancement of 140%, 1831%, and 1216%, respectively. Half-maximal enhancement of 2-AF mutagenicity is observed at 15-20 microM 2,4-DAT for strains YG1006 and YG1024, and about 80 microM for TA98. Studies with compounds structurally related to 2,4-DAT revealed enhancement of 2-AF mutagenicity with 2,5-DAT and o-phenylenediamine (o-PD) but not for other DAT isomers, toluidines, and phenylenediamines. Maximal enhancement of 2-AF mutagenicity observed in TA98 with PHS-catalyzed activation was 110% for o-PD and 60% for 2,5-DAT. This comutagenic effect of 2,4-DAT appears quite specific for 2-AF, as it fails to enhance either the PHS-dependent mutagenicity of the aromatic amines benzidine and 2-naphtylamine, or the direct mutagenicity of N-acetoxy-acetylaminofluorene,2-nitrofluorene,4- nitroquinoline-N-oxide and 1,1,1-trichloropropene-2,3-oxide. Enhancement of 2-AF mutagenicity by 2,4-DAT is also observed with cytochrome P-450-dependent activation, however the half-maximal 2,4-DAT concentration was 400 microM, and the maximal enhancement was only 50%. The ability of 2,4-DAT, under conditions where it is not itself mutagenic, to enhance the genotoxicity of the potent carcinogen 2-AF comprises an intriguing toxicological interaction, and underscores the inherent difficulties in assessing the genotoxic risks posed by mixtures of compounds.
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PMID:Prostaglandin H synthase-dependent genotoxicity of 2,4-diaminotoluene. 157 43

Primary cultures of hepatocytes from adult male F344 rats were used to investigate the activation of the hepatocarcinogen 2,4-diaminotoluene (2,4-DAT) to metabolites which bound covalently to DNA. Covalent binding of 2,4-DAT to DNA was significantly greater than that of a non-carcinogenic isomer, 2,6-DAT. Treatment of male rats with 5,6-benzoflavone (BNF), an inducer of cytochrome P-450c and P-450d, had no effect on the binding of 2,4-DAT to DNA of hepatocytes from these animals. However, treatment of hepatocytes in vitro with metyrapone or piperonyl butoxide, two general inhibitors of P-450 enzymes, inhibited the binding of 2,4-DAT to DNA by approximately 80-85%. Two inhibitors of sulfation, pentachlorophenol and 2,5-dichloro-4-nitrophenol, also inhibited DNA binding in hepatocytes from both BNF-induced (91 and 85% respectively) and control rats (82 and 41% respectively), indicating that sulfation may also be required. 2,4-DAT was a more potent mutagen than 2,5- or 2,6-DAT in the Ames Salmonella mutagenesis assay using hepatic S9 fractions from F344 rats as an activating system. In contrast to DNA binding, activation of 2,4-DAT to mutagens by S9 fractions from BNF-treated rats was greater than that by S9 from control rats. The present study shows that 2,4-DAT is activated by hepatocytes of F344 rats to products which bind covalently to DNA. Both cytochrome P-450 and sulfation appear to be involved in the activation.
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PMID:Covalent binding to DNA and mutagenicity of 2,4-diaminotoluene metabolites produced by isolated hepatocytes and 9000 g supernatant from Fischer 344 rats. 380 8

2,4-Dinitrotoluene (2,4-DNT) is an important industrial nitroaromatic compound. 2,4-Diaminotoluene (2,4-DAT), one of the urinary metabolites of 2,4-DNT, is carcinogenic when fed to rats. The objectives of these studies were to determine whether 2,4-DAT was formed from 2,4-DNT in rat liver and to clarify the nature of enzymes responsible for reduction of 2,4-DNT to 2,4-DAT. Data obtained from thin-layer and high-pressure liquid chromatography indicated that metabolites produced by microsomal preparations were 2-amino-4-nitrotoluene (2A4NT) and its isomer (4A2NT). This microsomal activity is probably mediated by cytochrome P-450 because the reduction is blocked by carbon monoxide and primary amines [aniline, n-octylamine, and 2,4-dichloro-6-phenylphenoxyethylamine (DPEA)]. In contrast, 2,4-DNT was metabolized via 2A4NT and 4A2NT to 2,4-DAT by cytosolic preparations. The greatest part of the reduction activity was due to cytosolic xanthine oxidase because the reduction was blocked by allopurinol. The results of this investigation suggest that reduction of 2,4-DNT to 2,4-DAT by cytosolic xanthine oxidase may play a role in 2,4-DNT hepatocarcinogenicity.
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PMID:Reduction of 2,4-dinitrotoluene by Wistar rat liver microsomal and cytosol fractions. 654 24