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Reaction-kinetic parameters of glycidamide as determinants of mutagenic potency

Lookup NU author(s): Dr Virginia Silvari, Professor Bernard Golding

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Abstract

Values for reaction-kinetic parameters of electrophiles can be used to predict mutagenic potency. One approach employs the Swain-Scott relationship for comparative kinetic studies of electrophilic agents reacting with nucleophiles. In this way glycidamide (GA), the putatively mutagenic/carcinogenic metabolite of acrylamide, was assessed by determining the rates of reaction with different nucleophiles. The rate constants (kNu) were determined using the "supernucleophile" cob(I)alamin [Cbl(I)] as an analytical tool. The Swain-Scott parameters for GA were compared with those of ethylene oxide (EO). The substrate constants, s values, for GA and for EO were found to be 1.0 and 0.93, respectively. The reaction rates at low values of nucleophilic strength (n = 1-3), corresponding to oxygens in DNA, were determined to be 2-3.5 times higher for GA compared to EO. GA was also more reactive than EO towards other nucleophiles (n = 0-6.4). The mutagenic potency of GA was determined in Chinese hamster ovary cells (hprt mutations in CHO-AA8 cells per dose unit with gamma-radiation as reference standard). The potency of GA was estimated to be about three mutations per 105 cells and mMh corresponding to about 400 rad-equ./mMh. A preliminary comparison of the mutagenic potency (per mMh and as rad-equivalents) of GA and EO shows an approximately seven times higher potency for GA. A higher mutagenic potency of GA compared to EO is compatible with expectation from reaction-kinetic data of the two compounds. The data confirmed that GA is not a strong mutagen, which is in line with what is expected for simple oxiranes. The present study shows the value of cob(I)alamin for the determination of reaction-kinetic parameters and their use for prediction of mutagenic potency. © 2004 Elsevier B.V. All rights reserved.


Publication metadata

Author(s): Silvari V, Haglund J, Jenssen D, Golding BT, Ehrenberg L, Tornqvist M

Publication type: Article

Publication status: Published

Journal: Mutation Research - Genetic Toxicology and Environmental Mutagenesis

Year: 2005

Volume: 580

Issue: 1-2

Pages: 91-101

ISSN (print): 1383-5718

ISSN (electronic):

Publisher: Elsevier BV

URL: http://dx.doi.org/10.1016/j.mrgentox.2004.11.004

DOI: 10.1016/j.mrgentox.2004.11.004

PubMed id: 15668111


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