| Metabolic and genotoxic interactions of 2-aminofluorene and 2,4-diaminotoluene. | |
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MedLine Citation:
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PMID: 9096289 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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We have reported previously that the rodent carcinogen 2,4-diaminotoluene (2,4-DAT) is not activated as a mutagen to the standard Ames S. typhimurium tester strains when oxidized by prostaglandin H synthase (PHS). 2,4-DAT does, however, enhance the bacterial mutagenicity of the potent mutagen 2-aminofluorene (2-AF) when both compounds are incubated with the PHS activating system. Enhancement of activation of 2-AF would provide a plausible mechanism for the observed co-mutagenicity of 2,4-DAT. Co-incubation with 100 microM 2,4-DAT, however, inhibited the total metabolism of 25 microM 2-AF by 60% in both the PHS/H2O2 system and PHS/arachidonic acid system. The inhibition included a 75% decrease in the formation of water-soluble and protein-bound metabolites and about a 35% decrease in production of the peroxidative metabolites 2-nitrofluorene (NF) and 2-aminodifluorenylamine (ADFA). Azofluorene (AzF) production was the most sensitive to the effects of 2,4-DAT, exhibiting an 80% decrease in both PHS-catalyzed systems. No new 2-AF derived products were observed in the presence of 2,4-DAT. This pronounced inhibition of 2-AF metabolism by 2,4-DAT also was observed in incubations of the aromatic amines with PHS in the presence of S. typhimurium strain TA98. Bacterial N-acetylation of 2-AF did not appear to be an important reaction in any of these incubations. 2,4-DAT not only inhibited 2-AF metabolism by PHS, but also decreased the level of 2-AF covalent binding to the bacterial DNA by as much as 81%. This stands in sharp contrast to the enhancement of the mutagenicity of 2-AF elicited by 2,4-DAT in these same incubations. This clear dissociation between the extent of peroxidative activation, and resultant covalent modification of bacterial DNA, by 2-AF and the subsequent mutagenic response indicates that a metabolic interaction is not involved in the co-mutagenicity of 2,4-DAT. |
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Authors:
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Y H Pan; G A Reed |
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Publication Detail:
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Type: Journal Article; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Toxicology letters Volume: 91 ISSN: 0378-4274 ISO Abbreviation: Toxicol. Lett. Publication Date: 1997 Mar |
Date Detail:
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Created Date: 1997-04-28 Completed Date: 1997-04-28 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 7709027 Medline TA: Toxicol Lett Country: NETHERLANDS |
Other Details:
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Languages: eng Pagination: 73-82 Citation Subset: IM |
Affiliation:
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Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City 66160-7417, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Arachidonic Acid / chemistry, metabolism Carcinogens / toxicity* Chromatography, High Pressure Liquid DNA, Bacterial / drug effects Fluorenes / metabolism, toxicity* Male Mutagenicity Tests Mutagens / toxicity* Oxidation-Reduction Phenylenediamines / toxicity* Prostaglandin-Endoperoxide Synthases / chemistry, metabolism Salmonella typhimurium / cytology, genetics, metabolism Sheep |
| Grant Support | |
ID/Acronym/Agency:
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ES-07079/ES/NIEHS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Carcinogens; 0/DNA, Bacterial; 0/Fluorenes; 0/Mutagens; 0/Phenylenediamines; 153-78-6/2-aminofluorene; 506-32-1/Arachidonic Acid; 95-80-7/2,4-diaminotoluene; EC 1.14.99.1/Prostaglandin-Endoperoxide Synthases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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