Document Detail


Effects of deuterium labeling on azido amino acid mutagenicity in Salmonella typhimurium.
MedLine Citation:
PMID:  7516484     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The mutagenic effects of azide (N3-) anion in bacterial test systems require the formation of the novel mutagenic metabolite, 3-azido-L-alanine (AZAL). Although the mechanism of AZAL-induced mutagenicity is unknown, subsequent bioactivation of this metabolite appears likely. Earlier studies have shown that other azide-containing amino acids are mutagenic as well. In fact, the mutagenic potency of the synthetic AZAL homologue, L-2-amino-4-azidobutanoic acid (HomoAZAL), was several times that of AZAL. To gain insight into the biochemical processing and mutagenicity of azido amino acids in Salmonella typhimurium, several specifically deuterium-labeled azido amino acids have been prepared and tested for mutagenic potency. In addition, the effect of (aminooxy)acetic acid (AOA) (a potent inhibitor of pyridoxal-dependent processes) on AZAL-induced mutagenesis was examined. The results showed that 2-deuterium substitution of AZAL resulted in a slight increase in mutagenic potency, while AOA treatment resulted in no change in AZAL potency. Taken together these findings did not support the involvement of pyridoxal-dependent processes in AZAL bioactivation. In contrast, deuterium substitution adjacent to the azide group in HomoAZAL and 5-azido-L-norvaline (N3-Norval) resulted in a large decrease in mutagenic potency when compared to the non-deuterium labeled compounds. These observations are consistent with a bioactivation mechanism involving rate-limiting C-H bond cleavage in the formation of the ultimate mutagen. Moreover, this effect of deuterium labeling points to processing of the azide-containing side chain as a key feature in the mutagenic activation mechanism.
Authors:
J B Mangold; Y Du; M R Mischke; J M LaVelle
Related Documents :
4039974 - Inhibition of benzo(a)pyrene and benzo(a)pyrene-trans-7,8-diol metabolism and dna bindi...
12084 - Effect of thiocyanate on nitrite estimation and the cleavage of nitrosamines.
16569034 - A sensitive enzyme-linked immunosorbent assay for detecting carcinogenic aristolochic a...
8624494 - Intrinsic mutagenicity and electrophilicity of 1-sulfooxy-3-methylcholanthrene: implica...
333094 - Intraindividual relationships between serum protein binding of drugs in normal human su...
8842654 - The role of ascorbic acid and xylitol in etomidate-induced adrenocortical suppression i...
Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Mutation research     Volume:  308     ISSN:  0027-5107     ISO Abbreviation:  Mutat. Res.     Publication Date:  1994 Jul 
Date Detail:
Created Date:  1994-07-20     Completed Date:  1994-07-20     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0400763     Medline TA:  Mutat Res     Country:  NETHERLANDS    
Other Details:
Languages:  eng     Pagination:  33-42     Citation Subset:  IM    
Affiliation:
Medicinal Chemistry Program, School of Pharmacy, University of Connecticut, Storrs.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Alanine / analogs & derivatives*,  pharmacology
Azides / pharmacology*
Biotransformation
Deuterium
Isotope Labeling
Mutagenicity Tests
Mutagens
Salmonella typhi / drug effects,  genetics
Grant Support
ID/Acronym/Agency:
ES03666/ES/NIEHS NIH HHS
Chemical
Reg. No./Substance:
0/Azides; 0/Mutagens; 56-41-7/Alanine; 7782-39-0/Deuterium; 88192-18-1/azidoalanine

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  Novel types of mutation identified at the hprt locus of human T-lymphocytes.
Next Document:  Mutagenicity of 5-bromouracil and N6-hydroxyadenine studied by yeast oligonucleotide transformation ...