Genotoxic properties of acrylonitrile

Lambotte-Vandepaer, M.; Bogaert, M. Duverger-van

doi:10.1016/0165-1110(84)90014-9

Cited by 15 publications

(2 citation statements)

References 36 publications

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“…After intake the major route of AN metabolism involves direct conjugation via Michael addition to glutathione . However, in the presence of oxygen and NADPH a portion of AN is converted to cyanoethylene oxide (CEO) via the epoxidation by cytochrome P450 2E1. − CEO is a mutagenic and suspectedly a carcinogenic compound.…”

Section: Introductionmentioning

confidence: 99%

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

Gladovic

Španinger

Bren

2018

Chem. Res. Toxicol.

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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.

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Section: Introductionmentioning

confidence: 99%

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

Gladovic

Španinger

Bren

2018

Chem. Res. Toxicol.

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“…La mayoría de las investigaciones se hicieron en la década de los 80. 137,138 El interés por el tema ha aumentado mucho en los últimos años, debido a la alta producción y variedad de usos del acrilonitrilo. 139 El acrilonitrilo puede dar lugar a sustitución de pares de bases y mutaciones en los marcos de lectura en distintas cadenas de Salmonella typhimurium pero, como prerrequisito para la inducción de mutagenia, deben estar presentes sistemas de enzimas microsomiales (S9).…”

Section: Mutagenia Y Carcinogeniaunclassified