Document Detail

Metabolic and genotoxic interactions of 2-aminofluorene and 2,4-diaminotoluene.
MedLine Citation:
PMID:  9096289     Owner:  NLM     Status:  MEDLINE    
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.
Y H Pan; G A Reed
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Toxicology letters     Volume:  91     ISSN:  0378-4274     ISO Abbreviation:  Toxicol. Lett.     Publication Date:  1997 Mar 
Date Detail:
Created Date:  1997-04-28     Completed Date:  1997-04-28     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  7709027     Medline TA:  Toxicol Lett     Country:  NETHERLANDS    
Other Details:
Languages:  eng     Pagination:  73-82     Citation Subset:  IM    
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City 66160-7417, USA.
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MeSH Terms
Arachidonic Acid / chemistry,  metabolism
Carcinogens / toxicity*
Chromatography, High Pressure Liquid
DNA, Bacterial / drug effects
Fluorenes / metabolism,  toxicity*
Mutagenicity Tests
Mutagens / toxicity*
Phenylenediamines / toxicity*
Prostaglandin-Endoperoxide Synthases / chemistry,  metabolism
Salmonella typhimurium / cytology,  genetics,  metabolism
Grant Support
Reg. No./Substance:
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 Synthases

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