Quantitative structure-activity relationships in the mutagenicity and detoxication of aliphatic epoxides.

Abstract

The genotoxicity of aliphatic epoxides is dependent on a balance between those pathways leading to DNA binding and those leading to detoxication to less active species. The objective of this research project was to examine the structural factors that influence the mutagenicity of aliphatic epoxides in terms of both chemical reactivity and detoxication. A quantitative structure-activity relationship approach was used to investigate the mutagenicity in Salmonella typhimurium of a series of propylene oxides. The volatile nature of members of the propylene oxide series led to the use of a modified liquid suspension assay. Mutagenicity in strain TA100 was found to correlate with Taft $\sigma$* values, which measure the electronic effects of substituent groups. Mutagenicity in TA100 was also correlated to chemical reactivity, as measured by the rates of reaction to two model bionucleophiles, nicotinamide and 4-(4-nitrobenzyl)pyridine. Similar correlations could not be made for mutagenicity in strain TA1535. It was postulated that the strain differences were associated with the effects of the stronger alkylating epoxides on the error-prone DNA repair system found in TA100. Steric effects of epoxide substituent groups also may be of importance in explaining the different mutagenic response in the two strains. In the course of this investigation, it was found that relative mutagenicity for the propylene oxides was different in the liquid suspension assay (LSA) than that determined by the standard plate incorporation assay (PIA). These method differences were attributed to epoxide stability. A regression model defining mutagenicity in LSA as a function of that in PIA showed increased correlation when rates of epoxide decay were included in the equation. The detoxication of the propylene oxides was found to correlate to chemical reactivity. The largest loss of mutagenic activity was seen when S9 or cytosolic rat liver fractions were combined with glutathione. The detoxication of another series of aliphatic epoxides, glycidyl phenyl ethers, was also investigated and glutathione conjugation was again found to be a more important route of detoxication than the epoxide hydrolases.