Influence of structural and functional modifications of selected genotoxic carcinogens on metabolism and mutagenicity – a review

Kulkarni, Sunil; Moir, Deborah; Zhu, Jiping

doi:10.1080/10629360701430090

Cited by 9 publications

(14 citation statements)

References 207 publications

(216 reference statements)

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“…When it comes to reactions of ArNH + with dG in double-stranded DNA, the required initial orientation of the reactants prior to reaction could result from intercalation of metabolically activated forms of ArNH 2 . Precovalent intercalation is proposed to be a distinct step in the mutagenic pathways of several classes of mutagens and carcinogens, including ArNH 2 . ,− It has been noted that the increase of the size of the aromatic system in ArNO 2 beyond a certain limit leads to a drop of compound mutagenicity, and this effect was ascribed to exceeding the size limit imposed by the intercalation site in DNA . If the DNA intercalation is an essential step in the mutagenic pathway of ArNH 2 , disruption of the geometric fit to the intercalation site of DNA could be used in drug discovery programs to remove genotoxocity of aromatic amines to be used as building block in drugs.…”

Section: Resultsmentioning

confidence: 99%

“…The mutagenic potency of ArNH 2 is determined by many factors because of the involvement of several enzymes and chemical steps. ,,,, High reactivity and specificity of ArNH + toward dG is only one of them; other important factors that are known to increase the mutagenic potency include higher rates of N-hydroxylation and bioconjugation, − a higher rate of heterolysis of the N–O bonds in the ultimate mutagenic forms, and slower rates of detoxification. ,, The maximum rate of formation of DNA adducts will be made by compounds, which exhibit the highest rates in all promutagenic steps and minimal rates of detoxification. However, the large number of DNA adducts caused by mutagenic metabolites of ArNH 2 do not necessarily result in the large number of DNA mutations .…”

Section: Introductionmentioning

confidence: 99%

“…The mutagenicity of ArNH 2 is conventionally associated with a high resonance stabilization of ArNH + . − Thus, classical works of Ford et al and Borosky − showed correlations between Ames mutagenic potency of different classes of ArNH 2 and the stability of ArNH + . However, data on ArNH 2 with pyridine-like nitrogens have been difficult to reconcile with the nitrenium stabilization concept as they destabilize ArNH + and simultaneously dramatically increase the mutagenic potency of ArNH 2 . ,, Thus, when pyridine-like aromatic fragments are included, the overall correlation of mutagenic potency with stabilization of ArNH + either had to be split into separate subsets with and without these fragments − or were found to be overall less significant than the link to the electron affinity of the parent ArNH 2 . ,− Additionally, it has been shown that for various classes of ArNH 2 , including analogues of aniline, 2-aminofluorene, 4-aminobiphenyl, and aminoimidazoazaarenes (AIA), the mutagenic potency significantly increases with the addition of electron-withdrawing functions that destabilize ArNH + . ,,,, Promutagenic effects of electron-withdrawing groups are captured in many quantinative structure–activity relationship (QSAR) studies as the importance of lowering the lowest unoccupied molecular orbital (LUMO) of ArNH 2 for increasing mutagenic potency. ,,,,, On the other hand, when the mutagenic potency was not taken into consideration but the Ames mutagenicity of ArNH 2 was binary flagged as Ames positive (Ames+) or Ames negative (Ames−), stabilization of ArNH + again turned out to be the most important single descriptor of Ames mutagenicity . Thus, both stabilization and destabilization of ArNH + can be promutagenic, with the promutagenic effects of electron-withdrawing groups being detected only when the value of mutagenic potency is taken into consideration. ,,,,, …”

Section: Introductionmentioning

confidence: 99%

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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: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…Moreover, the large amount of CYP2E1 is located in the endoplasmic reticulum (Hamberger, Kellert, Schauer, Dekant, & Mally, ). During this process, furan ring is opened; Z‐2‐butene‐1,4dialdehyde (BDA), an α,ß‐unsaturated di‐aldehyde (Kulkarni, Moir, & Zhu, ) and CO 2 are formed. Indeed, BDA is a microsomal metabolite of furan (Bolger et al, ).…”

Section: Introductionmentioning

confidence: 99%

Industrial furan and its biological effects on the body systems

et al. 2018

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Furan as a product of thermal processing is found in many foods and beverages. In vitro and in vivo genotoxicity was positive for furan, also when metabolic preconditions for the formation of Z‐2‐butene‐1,4dialdehyde (BDA), the reactive compound, was met. However, in major studies, high doses represented the genotoxic effect. Moreover, data on toxicity in different cells and organs are inconsistent. For preparing remarkable risk assessments in human, providing bioassay data is necessary. We aimed to review available evidences about furan and BDA. A vast number of studies have been published on toxicity of furan in vitro and in vivo. Thus, we present a comprehensive review on the current status of furan in inducing toxic effects in different body systems, and possible mechanisms involved in the negative effects of this compound. In this article, furan mitigation procedures in foods have been taken into account. Practical applications From industrial point, furan is repeatedly used as an intermediate chemical in the process of producing some compounds such as resins, lacquers, pesticides and drugs. Furthermore, it is common as a side‐product of high‐energy radiation and thermal processes in food production. The current study focused on the effects of furan on the body organs. Furthermore, furan mitigation procedures in foods have been addressed in the current study. Nearly all previous studies on the industrial furan demonstrated that it has adverse health effects on the organs of the body. In order to prove specific results, further studies regarding furan risk assessment is of great importance.

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“…4) provides anchimeric assistance to the syn-quasi diaxial isomer (structure a) to enable it to react with water and other nucleophiles more rapidly than the anti-isomers, thereby reducing the presence of ring opened cationic species which are essential for forming strong covalent bonds with the DNA bases. 42 Hence, the second stable structure with the anti-quasi-diequatorial conformation with (R,S)-diol (S,R)-epoxide absolute configuration (structure b) is used to construct the diol epoxide derivatives of all the PAHs used in the study and is also reported to be the most mutagenic isomer. 6,7…”

Section: Resultsmentioning

confidence: 99%

Theoretical studies on the carcinogenic activity of diol epoxide derivatives of PAH: proton affinity and aromaticity as decisive descriptors

Vijayalakshmi

Suresh

2008

Org. Biomol. Chem.

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A comparative study between bay-region and nonbay-region diol epoxide (DE) derivatives of seventeen carcinogenic polycyclic aromatic hydrocarbons (PAHs) was carried out using the B3LYP/6-31G(d,p) level of density functional theory to understand the factors responsible for the increased carcinogenic activity of bay-region derivatives. Molecular electrostatic potential analysis as well as proton affinity calculations showed that the epoxide sites of bay-region derivatives are much more reactive than the corresponding nonbay-region analogs. The charge delocalization mode in the carbocation intermediates resulting from the protonation reactions was followed through LUMO analysis. The relative aromaticity in the different rings in the arenium ions was gauged by NICS(1)(zz) computations. Both these calculations revealed that the protonated DEs (DEH(+)) are stabilized by higher aromaticity in the bay-region derivatives than the nonbay-region derivatives. Hence, a bay-region DEH(+) can be retained in the reacting medium for a longer time than compared with the DEH(+) formed from a nonbay-region DEs. Thus the high carcinogenic activity of bay-region DEs is attributed to the high reactivity of the epoxide system for protonation and the high thermodynamic stability of the resulting cation. Multiple regression analysis also confirms the above results wherein proton affinity and aromaticity significantly explain the variations in the carcinogenic activity of the molecules under study.

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Influence of structural and functional modifications of selected genotoxic carcinogens on metabolism and mutagenicity – a review

Cited by 9 publications

References 207 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

Industrial furan and its biological effects on the body systems

Theoretical studies on the carcinogenic activity of diol epoxide derivatives of PAH: proton affinity and aromaticity as decisive descriptors

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