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Formation of Bulky DNA Adducts by Non-Enzymatic Production of 1,2-Naphthoquinone-Epoxide from 1,2-Naphthoquinone under Physiological Conditions
journal contribution
posted on 2019-08-20, 17:35 authored by Takuya Matsui, Naohito Yamada, Hideyuki Kuno, Robert A. KanalyQuinones may be formed
metabolically or abiotically from environmental
pollutants and polycyclic aromatic hydrocarbons (PAHs); many are recognized
as toxicological intermediates that cause a variety of deleterious
cellular effects including mutagenicity. The PAH-o-quinone, 1,2-naphthoquinone (1,2-NQ), may exert its genotoxic effects
through interactions with cellular nucleophiles such as DNA, however,
the mechanisms of 1,2-NQ adduct formation are still under investigation.
With the aim to further understand these mechanisms, the chemical
structures of adducts formed from the reaction of 2′-deoxyguanosine
(dG) with 1,2-NQ under physiological conditions were investigated
by liquid chromatography electrospray ionization tandem mass spectrometry
and 1H NMR analyses. Results showed that 1,2-NQ underwent
non-enzymatic oxidation to form a 1,2-NQ-epoxide which in turn formed
at least four bulky adducts with dG, and these adducts were more likely
to be formed under physiological conditions. A mechanism was proposed
whereby hydration of 1,2-NQ to form unstable naphthohydroquinones
and 2-hydroxy-1,4-naphthoquinone resulted in formation of hydrogen
peroxide that oxidized 1,2-NQ. These results suggest that the genotoxicity
of 1,2-NQ may not only be caused through oxidative DNA damage and
adduct formation through Michael addition but also through non-enzymatic
oxidative transformation of 1,2-NQ itself to form an intermediate
PAH-epoxide which covalently binds to DNA.
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Keywords
hydrogen peroxidePAHchromatography electrospray ionization tandem mass spectrometry1 H NMR analysesadduct formationNon-Enzymatic ProductionPhysiological Conditions QuinonesBulky DNA AdductsMichael additionchemical structuresNQtoxicological intermediatesmechanismoxidative DNA damageoxidative transformationgenotoxic effects
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