Nucleic Bases Alkylation with Acrylonitrile and Cyanoethylene Oxide: A Computational Study

Abstract

Acrylonitrile (AN) is widely used in the manufacture of resins, plastics, and polymers, where workers are exposed to it during its production, transportation, and application. After intake a portion of AN is converted to cyanoethylene oxide (CEO) by cytochrome P450 2E1. Both AN and CEO represent possible chemical carcinogens leading to DNA damage mainly in the form of the major 7-(2-oxoethyl)deoxyguanosine adduct. A kinetic model for its formation was devised and a corresponding second-order rate constant obtained from the experimental data on the reaction with CEO. A series of ab initio, density functional theory, and semiempirical calculations of activation free energies was then performed on the alkylation of nucleic bases with both CEO and AN. The combination of Hartree-Fock level of theory with the flexible 6-311++G(d,p) basis set and Langevin dipoles implicit solvation model gave the best agreement with the experimental activation barrier. It also predicted relative reactivities of all four nucleobases that are in agreement with the experimentally reported adduct yields. Moreover, this combination predicted higher reactivity of CEO than AN with all four nucleobases corroborating the experimental hypothesis that S2 substitution of CEO rather than direct Michael addition of AN is responsible for the genotoxic properties of AN. In a broader context this paper points to the applicability of quantum chemical methods to the studies of carcinogenesis.

Hop Compounds: Extraction Techniques, Chemical Analyses, Antioxidative, Antimicrobial, and Anticarcinogenic Effects

“…For obtaining and optimizing structures the Gaussian Suite of Programs [169] was used. The analysis was performed with the Molden program [170], which also enables capturing frames to obtain pictures as seen in Figure 4 where the reactant and the transition state of the reaction between xanthohumol (polyphenol found in hops and known antigenotoxic agent) and cyanoethylene oxide—cytochrome P450 2E1 metabolized form of food carcinogen acrylonitrile [171], acquired using the Gaussian 09 suite of programs [172] according to the Hartree–Fock method and 6-31G(d) basis set presented. Xanthohumol was chosen as its antigenotoxic activity was already confirmed through in vivo and in vitro studies and simulation of its reaction with cyanoethylene oxide, a typical and common epoxy-type chemical carcinogen with confirmed carcinogenicity, can uncover xanthohumol’s antigenotoxic mechanism of action.…”

“…Quantum chemical model of ( a ) the reactant state and ( b ) the transition state of the reaction between xanthohumol and cyanoethylene oxide acquired according to the Hartree–Fock method and 6-31G(d) basis set [171]. Carbon atoms are depicted in gray, oxygen atoms in red, nitrogen atoms in blue, and hydrogen atoms in white.…”

Protective Effects of [6]-Gingerol Against Chemical Carcinogens: Mechanistic Insights

“…The Hartree−Fock (HF) level of theory, combined with flexible 6-311++G(d,p) basis set and implicit solvation model, was found to give a very good agreement with the experimental activation free energies for the alkylation reactions between all nine studied ultimate chemical carcinogens and the most reactive DNA base guanine [1,7,12,13,16]. Moreover, an observation has been reported in the scientific literature, that both the B3LYP density functional and the MP2 theory levels, which include a certain degree of dynamical electron correlation, exhibit moderate to significant underestimation of the experimental ∆G ‡ regardless of the applied solvation model [1,7,12,13,16]. Hartree-Fock level of theory also provides a strong argument in favor of the proposed S N 2 reaction mechanism for guanine alkylation by these chemical carcinogens.…”

“…Hartree-Fock level of theory also provides a strong argument in favor of the proposed S N 2 reaction mechanism for guanine alkylation by these chemical carcinogens. Moreover, it represents a good confirmation of the applicability of quantum chemical simulations to alkylation reactions related to carcinogenesis [12,16]. This encouraged us to employ the Hartree-Fock method with three different flexible basis sets to predict the activation barriers of chemical reactions involving the nine ultimate carcinogens and two natural scavengers, namely [6]-gingerol and glutathione, for which kinetic experiments have not been performed yet.…”

Analysis of Biomarkers of DNA Damage and Mutagenicity in Mice Exposed to Acrylonitrile

“…While positive results for the genetic toxicity of ACN have been obtained in an wide array of in vitro assays, significant in vivo clastogenic or mutagenic effects have not been reported in rodents exposed to ACN alone . The lack of such reports has led to the hypothesis that (i) the DNA-reactive metabolite of ACN, or the DNA adducts possibly induced by CEO, are formed in small amounts or are very short-lived or unstable, or (ii) CEO does not reach target tissues in vivo. , Another hypothesis is that ACN interaction with cellular macromolecules via CEO reactivity or induction of reactive oxygen species leads to cellular stress response induction, the formation of difficult-to-repair or persistent lesions, activation of translesion synthesis, and cellular stress resolution that tolerates a damage burden. , On the other hand, studies of mutations arising in vivo at either the gene or chromosomal level are understood to have the most relevance for estimating the oncogenic potential of a chemical carcinogen.…”