Reaction kinetic studies for comparison of mutagenic potency between butadiene monoxide and glycidamide. (25th May 2018)

• Record Type: Journal Article
• Authors: Motwani, Hitesh V.; Eriksson, Lars; Göpfert, Lisa; Larsen, Kristian
• Is Part Of: Chemico-biological interactions. Volume 288(2018)
• Page Start: 57
• Page End: 64
• Publication Date: 2018-05-25
• Subjects: DNA adducts -- Epoxides -- Reaction kinetics -- Mutagenic potency; Biochemistry -- Periodicals; Toxicological chemistry -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biochimie -- Périodiques; Toxicologie biochimique -- Périodiques; 572
• DOI: 10.1016/j.cbi.2018.03.017
• Languages: English
• ISSNs: 0009-2797

Abstract

Abstract: DNA adducts can be formed from covalent binding of electrophilic reactive compounds to the nucleophilic N - and O -atoms of the biomolecule. The O -sites on DNA, with nucleophilic strength ( n ) of ca. 2, is recognized as a critical site for mutagenicity. Characterization of the reactivity of electrophilic compounds at the O -sites can be used to predict their mutagenic potency in relative terms. In the present study, reaction kinetic experiments were performed for butadiene monoxide (BM) in accordance with the Swain-Scott relation using model nucleophiles representing N - and O -sites on DNA, and earlier for glycidamide (GA) using a similar approach. The epoxide from the kinetic experiments was trapped by cob(I)alamin, resulting in formation of an alkylcobalamin which was analyzed by liquid chromatography tandem mass spectrometry. The Swain-Scott relationship was used to determine selectivity constant ( s ) of BM and GA as 0.86 and 1.0, respectively. The rate constant for the reaction at n of 2 was extrapolated to 0.023 and 0.038 M −1 h −1 for BM and GA, respectively, implying a higher mutagenic potency per dose unit of GA compared to BM. The reaction kinetic parameters associated with mutagenic potency were also estimated by a density functional theory approach, which were in accordance to the experimental determined values. These types of reaction kinetic measures could be useful in development of a chemical reactivity based prediction tool that could aid in reduction of animal experiments in cancer risk assessment procedures for relative mutagenicity. Graphical abstract: Highlights: Reaction kinetic parameters as determinants of mutagenic potency are estimated. Cob(I)alamin is used for trapping of epoxides from kinetic experiments. Experimental kinetic studies and related DFT calculations are in accordance. Mutagenic potency of glycidamide is predicted to be higher than butadiene monoxide. Described chemical reactivity approach has a potential to reduce animal experiments.