Role of Free Radical Reactions in the Formation of DNA Damage

Shafirovich, Vladimir; Geacintov, Nicholas E.

doi:10.1002/9783527630110.ch4

Cited by 6 publications

(3 citation statements)

References 106 publications

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“…Notably, benzidine 10 , a well-known mutagen and human carcinogen, and four included derivatives are located to the left of the “area −20”, which is indicative of too stable ArNH + for forming DNA adducts. This result is in line with experimental results that demonstrated that the mechanism of mutagenicity and carcinogenicity of these compounds is different and primarily caused by their ability to generate free radicals and oxidative stress, which cause the oxidative damage of DNA. ,− The standard bacterial Ames mutagenicity tests in strains TA98 and TA100 are just not sensitive to oxidative genotoxicity …”

Section: Resultssupporting

confidence: 85%

Theoretical Studies of Chemical Reactivity of Metabolically Activated Forms of Aromatic Amines toward DNA

Shamovsky

Ripa

Blomberg

et al. 2012

Chem. Res. Toxicol.

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The metabolism of aromatic and heteroaromatic amines (ArNH₂) results in nitrenium ions (ArNH⁺) that modify nucleobases of DNA, primarily deoxyguanosine (dG), by forming dG-C8 adducts. The activated amine nitrogen in ArNH⁺ reacts with the C8 of dG, which gives rise to mutations in DNA. For the most mutagenic ArNH₂, including the majority of known genotoxic carcinogens, the stability of ArNH⁺ is of intermediate magnitude. To understand the origin of this observation as well as the specificity of reactions of ArNH⁺ with guanines in DNA, we investigated the chemical reactivity of the metabolically activated forms of ArNH₂, that is, ArNHOH and ArNHOAc, toward 9-methylguanine by DFT calculations. The chemical reactivity of these forms is determined by the rate constants of two consecutive reactions leading to cationic guanine intermediates. The formation of ArNH⁺ accelerates with resonance stabilization of ArNH⁺, whereas the formed ArNH⁺ reacts with guanine derivatives with the constant diffusion-limited rate until the reaction slows down when ArNH⁺ is about 20 kcal/mol more stable than PhNH⁺. At this point, ArNHOH and ArNHOAc show maximum reactivity. The lowest activation energy of the reaction of ArNH⁺ with 9-methylguanine corresponds to the charge-transfer π-stacked transition state (π-TS) that leads to the direct formation of the C8 intermediate. The predicted activation barriers of this reaction match the observed absolute rate constants for a number of ArNH⁺. We demonstrate that the mutagenic potency of ArNH₂ correlates with the rate of formation and the chemical reactivity of the metabolically activated forms toward the C8 atom of dG. On the basis of geometric consideration of the π-TS complex made of genotoxic compounds with long aromatic systems, we propose that precovalent intercalation in DNA is not an essential step in the genotoxicity pathway of ArNH₂. The mechanism-based reasoning suggests rational design strategies to avoid genotoxicity of ArNH₂ primarily by preventing N-hydroxylation of ArNH₂.

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Section: Resultssupporting

confidence: 85%

Theoretical Studies of Chemical Reactivity of Metabolically Activated Forms of Aromatic Amines toward DNA

Shamovsky

Ripa

Blomberg

et al. 2012

Chem. Res. Toxicol.

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“…Replication of covalent DNA adducts results in frameshift mutations, ,, with persistent mutations in DNA hotspots being able to cause cancer. , Because there are many enzymes, activation steps, and factors involved in mutagenesis and carcinogenesis of ArNH 2 , ,,,,− the resulting structure–mutagenicity relationships are poorly understood. ,,, The C8 position of guanine residues of DNA is known to be the primary target for covalent modifications; , however, particular nitrenium ions may also react with other guanine atoms or other DNA bases, ,,,, which further complicates the structure–mutagenicity relationships. In addition to the formation of pro-mutagenic ArNH 2 –DNA adducts, it has been suggested that interaction of a number of ArNH 2 with P450 enzymes and peroxidases caused formation of reactive oxygen species (ROS) and induced lipid peroxidation, which may also lead to mutations in DNA and cancer (Figure ). − …”

Section: Introductionmentioning

confidence: 99%

Explanation for Main Features of Structure–Genotoxicity Relationships of Aromatic Amines by Theoretical Studies of Their Activation Pathways in CYP1A2

et al. 2011

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Aromatic and heteroaromatic amines (ArNH(2)) represent a class of potential mutagens that after being metabolically activated covalently modify DNA. Activation of ArNH(2) in many cases starts with N-hydroxylation by P450 enzymes, primarily CYP1A2. Poor understanding of structure-mutagenicity relationships of ArNH(2) limits their use in drug discovery programs. Key factors that facilitate activation of ArNH(2) are revealed by exploring their reaction intermediates in CYP1A2 using DFT calculations. On the basis of these calculations and extensive analysis of structure-mutagenicity data, we suggest that mutagenic metabolites are generated by ferric peroxo intermediate, (CYP1A2)Fe(III)-OO(-), in a three-step heterolytic mechanism. First, the distal oxygen of the oxidant abstracts proton from H-bonded ArNH(2). The subsequent proximal protonation of the resulting (CYP1A2)Fe(III)-OOH weakens both the O-O and the O-H bonds of the oxidant. Heterolytic cleavage of the O-O bond leads to N-hydroxylation of ArNH(-) via S(N)2 mechanism, whereas cleavage of the O-H bond results in release of hydroperoxy radical. Thus, our proposed reaction offers a mechanistic explanation for previous observations that metabolism of aromatic amines could cause oxidative stress. The primary drivers for mutagenic potency of ArNH(2) are (i) binding affinity of ArNH(2) in the productive binding mode within the CYP1A2 substrate cavity, (ii) resonance stabilization of the anionic forms of ArNH(2), and (iii) exothermicity of proton-assisted heterolytic cleavage of N-O bonds of hydroxylamines and their bioconjugates. This leads to a strategy for designing mutagenicity free ArNH(2): Structural alterations in ArNH(2), which disrupt geometric compatibility with CYP1A2, hinder proton abstraction, or strongly destabilize the nitrenium ion, in this order of priority, prevent genotoxicity.

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“…Indeed, radicals appear in many organic reactions [11,12], inorganic coordination complexes in which metal ions have unpaired electrons [13][14][15], and modern industrial processes [16], i.e., radical polymerization [17]. Moreover, radicals play the essential role in a whole host of various disease states and their perpetuation [18,19], including cancer and DNA damage [20][21][22], skin aging [23], and cardiovascular [24], neurodegenerative [25,26], and immunological diseases [27], as well as atherosclerosis, diabetes, dyslipidemia [28], etc. However, radicals are also studied to improve the diagnostic and therapeutic capabilities of various medicines, e.g., [29][30][31][32][33][34][35][36][37].…”

Section: Introductionmentioning

confidence: 99%

Substituent Effect in the Cation Radicals of Monosubstituted Benzenes

Dobrowolski

Dudek

Karpińska

et al. 2021

IJMS

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In 30 monosubstituted benzene cation radicals, studied at the ωB97XD/aug-cc-pVTZ level, the phenyl rings usually adopt a compressed form, but a differently compressed form—equivalent to an elongated one—may coexist. The computational and literature ionization potentials are well correlated. The geometrical and magnetic aromaticity, estimated using HOMA and NICS indices, show the systems to be structurally aromatic but magnetically antiaromatic or only weakly aromatic. The partial charge is split between the substituent and ring and varies the most at C(ipso). In the ring, the spin is 70%, concentrated equally at the C(ipso) and C(p) atoms. The sEDA(D) and pEDA(D) descriptors of the substituent effect in cation radicals, respectively, were determined. In cation radicals, the substituent effect on the σ-electron system is like that in the ground state. The effect on the π-electron systems is long-range, and its propagation in the radical quinone-like ring is unlike that in the neutral molecules. The pEDA(D) descriptor correlates well with the partial spin at C(ipso) and C(p) and weakly with the HOMA(D) index. The correlation of the spin at the ring π-electron system and the pEDA(D) descriptor shows that the electron charge supplied to the ring π-electron system and the spin flow oppositely.

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Role of Free Radical Reactions in the Formation of DNA Damage

Cited by 6 publications

References 106 publications

Theoretical Studies of Chemical Reactivity of Metabolically Activated Forms of Aromatic Amines toward DNA

Theoretical Studies of Chemical Reactivity of Metabolically Activated Forms of Aromatic Amines toward DNA

Explanation for Main Features of Structure–Genotoxicity Relationships of Aromatic Amines by Theoretical Studies of Their Activation Pathways in CYP1A2

Substituent Effect in the Cation Radicals of Monosubstituted Benzenes

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