Formation of Bulky DNA Adducts by Non-Enzymatic Production of 1,2-Naphthoquinone-Epoxide from 1,2-Naphthoquinone under Physiological Conditions

Abstract

Quinones 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 1 H 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.

A Classification Model to Identify Direct-Acting Mutagenic Polycyclic Aromatic Hydrocarbon Transformation Products

“…This is a well-recognized indicator of mutagenicity and is often used as a structural alert for mutagenicity . SHBint3 tends to select molecules with ortho-oxygen groups, which can also be mutagenic. ,,, TDB8r is the 3D topological distance-based autocorrelation, lag 8, weighted by a covalent radius. Lag refers to how close the atoms are together in the molecular structure.…”

“…AATSC4m is the average autocorrelation, lag 4, weighted by atomic mass. This descriptor tends to highlight molecules with oxygen groups close together on a molecule’s perimeter which, like the epoxide group, tends to be a mutagenic substructure. , TDB1i, the 3D topological distance based autocorrelation, lag 1, is the highest for molecules with more oxygens close or on the molecule rings and lower for molecules without oxygens or with them on aliphatic chains. AATSC5c, the average centered Broto–Moreau autocorrelation, lag 5, weighted by charge, indicates oxygen groups five atoms apart, such as para-oxygen groups.…”

“…103,113,114 The ortho-quinone structure has also been shown to be directly mutagenic through this mechanism in the Ames test. 35,41,94,115 Benzo[a]pyrene is the most studied PAH in this category, but it is not the only PAH that exhibits this mechanism of mugatenicity. 39−41 Stable covalent adducts may be formed with either of the purine bases, primarily at the exocyclic nitrogen group.…”

“…These adducts can be either stable adducts, which persist within the DNA strand and interfere with proper replication of the strand, or unstable adducts, which remove the purine from the DNA strand. The bay region diol epoxide group is well established as a structural indicator of covalent adduct mutagenicity. ,, The ortho-quinone structure has also been shown to be directly mutagenic through this mechanism in the Ames test. ,,, Benzo­[a]­pyrene is the most studied PAH in this category, but it is not the only PAH that exhibits this mechanism of mugatenicity. − …”

Disruption of Atrial Rhythmicity by the Air Pollutant 1,2-Naphthoquinone: Role of Beta-Adrenergic and Sensory Receptors

“…Later, the same authors showed that the mediated-covalent interaction between CREB and 1,2-NQ through Cys-286 blocks the DNA binding activity of CREB, resulting in the repression of CREB-regulated genes [79]. Knowing that a variety of environmental pollutants, including 1,2-NQ (or its metabolites), may cause abnormal DNA methylation, which further disturbs gene expression [80][81][82][83], it is possible that due to the chemical nature of 1,2-NQ (and its metabolite) that displays cytotoxic and genotoxic properties. This could include increasing topoisomerase II-mediated doublestranded DNA scission [84,85] and non-enzymatic oxidative transformation of 1,2-NQ to form an intermediate PAH-epoxide, which covalently binds to DNA [80].…”