Quantitative structure-activity relationships for the mutagenicity of propylene oxides with Salmonella

Abstract

A quantitative structure-activity relationship approach was used to investigate the mutagenicity of a series of seventeen-monosubstituted propylene oxides in Salmonella typhimurium strains TA100 and TA1535. Mutagenicity in strain TA100, using a liquid suspension assay, was found to correlate with chemical reactivity, as measured by the rates of reaction with two model bionucleophiles, nicotinamide and 4-(4-nitrobenzyl)pyridine. However, since the reactivity of three of the epoxides did not correlate to their Taft sigma * values, as a measure of the electronic effects of substituent groups, neither was their mutagenicity predicted by this substituent constant. The relative mutagenicity for the propylene oxides was different in the liquid suspension assay than that determined by the standard plate incorporation assay and also differed between the two bacterial strains. The assay differences were attributed to epoxide stability. The differences between strains was observed to be due to the response of the error-prone repair system, found only in TA100, to the stronger alkylating agents.

Modeling of Toxicity-Relevant Electrophilic Reactivity for Guanine with Epoxides: Estimating the Hard and Soft Acids and Bases (HSAB) Parameter as a Predictor

“…However, the activation energies are lower for the epoxides with electron-withdrawing groups than for other species (e.g., VCE, NMVO, and several halide epoxides) because the electron-withdrawing group increases the electrophilicity of the carbon atom to which it is attached, and as a result, it facilitates the nucleophilic attack. This agrees with experiments showing that both VCE and NMVO possess strong electrophilic, mutagenic, and carcinogenic activities , and that the presence of electron-withdrawing substituents increases the reactivity and mutagenicity of epoxides. − Vinyl halides, which draw considerable attention due to their high-volume industrial use and the environmental health concerns of their carcinogenicity, form halide epoxides with P450 oxidation. There is an increase in mutagenicity and carcinogenicity with the number of halogen substituents in a molecule; as shown in Table , this observation applies for the stronger reactivity between halide epoxides and the guanine N7 site that contain an increasing number of halogen substituents.…”

Hydrolysis of genotoxic methyl‐substituted oxiranes: Experimental kinetic and semiempirical studies

“…Electron‐withdrawing groups in substitued propylene oxides increase the rate of hydrolysis [15]. However, the correlation of the hydrolysis rates with Taft constants is weak (correlation coefficient, r = 0.69, on the basis of published data [15]).…”

“…Electron‐withdrawing groups in substitued propylene oxides increase the rate of hydrolysis [15]. However, the correlation of the hydrolysis rates with Taft constants is weak (correlation coefficient, r = 0.69, on the basis of published data [15]). It was considered of interest to systematically investigate the influence of the number and positioning of substituents in an oxirane ring on the rate of hydrolysis and to model the reactivity of epoxides.…”

“…The acid‐catalyzed reaction may be of importance in view of the existence of subcellular regions with particularly high proton activities [14]. The mutagenicity of epoxides correlates with the rate of alkylation, and in some cases, there is linear correlation between the rates of nucleophilic substitution and hydrolysis [15,16]. On the other hand, hydrolysis is an important process of epoxide detoxification.…”

Metabolism and Pharmacokinetics of Allitinib in Cancer Patients: The Roles of Cytochrome P450s and Epoxide Hydrolase in its Biotransformation

“…Epoxides can react with cellular macromolecules, such as DNA and protein, to exert mutagenic and genotoxic effects. Alternatively, epoxides can be metabolized to GSH conjugates by GST or to dihydrodiol metabolites by epoxide hydrolase with reduced toxicity (Ehrenberg and Hussain, 1981;Hooberman et al, 1993;Faller et al, 2001;Lee et al, 2005;GonzalezPerez et al, 2012). The incubation of allitinib with HLM supplemented with NADPH and GSH confirmed that the pharmacologically active metabolite M10 was the major metabolite, but the GSH conjugate of epoxide M23 was not observed.…”