Structural Identification
and Kinetic Analysis of
the in Vitro Products Formed by Reaction of Bisphenol
A‑3,4-quinone with N‑Acetylcysteine
and Glutathione
Version 2 2018-01-16, 20:17
Version 1 2018-01-14, 18:13
Posted on 2018-01-16 - 20:17
Bisphenol
A (BPA) has received considerable attention as an endocrine
disrupting chemical and a possible substrate for genotoxic metabolites.
BPA metabolism leads to formation of electrophilic o-quinones cable of binding to DNA and other endogenous nucleophiles.
We have structurally identified the products resulting from the reaction
of bisphenol A-3,4-quinone (BPAQ) with N-acetylcysteine
(NAC) and glutathione (GSH). The major and minor isomers are both
the result of 1,6-conjugate addition and are produced almost instantly
in high yield. Reactions using 1.3 equiv of GSH showed the presence
of a bis-glutathionyl adduct which was not observed using higher GSH
concentration relative to BPAQ. NAC reactions with BPAQ showed no
bis-N-acetylcysteinyl adducts. Stopped-flow kinetic
analysis reveals the 1,6-conjugate additions to be reversible with
a forward free energy of activation of 9.2 and 7.8 kcal/mol for the
NAC and GSH reactions, respectively. The bimolecular forward rate
constant at 19.4 °C was approximately three time faster for GSH
compared to NAC, 1547 vs 496 M–1 s–1. The free energy of activation for the reverse reactions were similar,
11.7 and 11.2 kcal/mol for NAC and GSH, respectively. We plan to use
this model system to further explore the mechanism of adduct formation
between sulfur nucleophiles and o-quinones and the
resulting chemical properties of both NAC and GSH adducts.
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Stack, Douglas E.; Conrad, John A.; Mahmud, Bejan (2018). Structural Identification
and Kinetic Analysis of
the in Vitro Products Formed by Reaction of Bisphenol
A‑3,4-quinone with N‑Acetylcysteine
and Glutathione. ACS Publications. Collection. https://doi.org/10.1021/acs.chemrestox.7b00239
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AUTHORS (3)
DS
Douglas E. Stack
JC
John A. Conrad
BM
Bejan Mahmud
KEYWORDS
Kinetic AnalysisBPA metabolismVitro ProductsNAC reactionsadduct formationGSH reactionschemical propertiesStructural IdentificationGSH concentrationquinones cablegenotoxic metabolitesBPAQbis-glutathionyl adductDNA1.3 equivGSH adductsacetylcysteinyl adductssulfur nucleophilesmodel systemGlutathione Bisphenol