New Insight Regarding the Relationship Between Enantioselective Toxicity Difference and Enantiomeric Toxicity Interaction from Chiral Ionic Liquids

Abstract

Chirality is an important property of molecules. The study of biological activity and toxicity of chiral molecules has important theoretical and practical significance for toxicology, pharmacology, and environmental science. The toxicological significance of chiral ionic liquids (ILs) has not been well revealed. In the present study, the enantiomeric joint toxicities of four pairs of chiral ILs 1-alkyl-3-methylimidazolium lactate to Allivibrio fischeri were systematically investigated by using a comprehensive approach including the co-toxicity coefficient (CTC) integrated with confidence interval (CI) method (CTCICI), concentration-response curve (CRC), and isobole analysis. The direct equipartition ray (EquRay) design was used to design five binary mixtures of enantiomers according to molar ratios of 1:5, 2:4, 3:3, 4:2, and 5:1. The toxicities of chiral ILs and their mixtures were determined using the microplate toxicity analysis (MTA) method. Concentration addition (CA) and independent action (IA) were used as the additive reference models to construct the predicted CRC and isobole of mixtures. On the whole, there was an enantioselective toxicity difference between [BMIM]D-Lac and [BMIM]L-Lac, and [HMIM]D-Lac and [HMIM]L-Lac, while no enantioselective toxicity difference was observed for [EMIM]D-Lac and [EMIM]L-Lac, and [OMIM]D-Lac and [OMIM]L-Lac. Thereinto, the enantiomer mixtures of [BMIM]D-Lac and [BMIM]L-Lac, and [HMIM]D-Lac and [HMIM]L-Lac presented antagonistic action, and the enantiomer mixtures of [EMIM]D-Lac and [EMIM]L-Lac, and [OMIM]D-Lac and [OMIM]L-Lac overall presented additive action. Moreover, the greatest antagonistic toxicity interaction occurred at the equimolar ratio of enantiomers. Based on these results, we proposed two hypotheses, (1) chiral molecules with enantioselective toxicity difference tended to produce toxicity interactions, (2) the highest or lowest toxicity was usually at the equimolar ratio and its adjacent ratio for the enantiomer mixture. These hypotheses will need to be further validated by other enantiomer mixtures.

Novel Segmented Concentration Addition Method to Predict Mixture Hormesis of Chlortetracycline Hydrochloride and Oxytetracycline Hydrochloride to Aliivibrio fischeri

“…On the other hand, the occurrence numbers of antagonism in 9 judgment events for each mixture were 9, 6, 4, and 0 for M5, M4, M3, and M1 respectively. The molar ratios of CTCC:OTCC in these four mixtures were 5:8, 1:1, 8:5, and 12:1 respectively, which proved well the equimolar ratio hypothesis proposed recently [29]. Although this hypothesis was initially developed based on binary enantiomer mixtures, it was suggested that this hypothesis may have a degree of universality for binary antagonistic mixtures, and several examples fitting the hypothesis were also observed in reference [33].…”

“…Isobole was an effective tool for evaluating toxic interactions of binary mixtures within the S-CRC framework, such as the antagonism of chiral ILs enantiomer to Aliivibrio fischeri [29], synergistic antibacterial effect of ribavirin and disulfiram [47], and the estrogenic activity of UV filter mixtures to fish [48]. Only a few examples using isobole to evaluate mixture hormesis such as parthenin and tetraneurin-A on Lactuca sativa [33], it was worth noting that this study contained a non-equivalent isobole i.e., EC m isobole.…”

“…It can also be seen from the computational process based on the common basic elements including EC x,mix , P i and EC x,i . The advantage of isobole was very obvious, which was easy to use, intuitive and convenient [29]. The disadvantage of isobole was also very obvious, which cannot be used for the mixtures with more than three components, even if the isobole can be extended to the equivalent-surface for three-component mixtures [49].…”

“…Previous studies indicated that there was biphasic U or inverted-U relationship between the binary mixture toxicity and the concentration proportion of components [29,49]. We studied the relationship between component molarity proportions and the toxicity of mixtures presenting J-CRC shown in Figure 4, the left and right boundary points corresponded to the single component (CCTC or OTCC) toxicity.…”

“…Since the IA model would lose its probabilistic meaning when negative values (often referred to as a stimulatory response) were included [27], IA was once considered unfit to predict mixture J-CRC. At present, it is generally accepted that CA and IA merely as the working concept, which should not be added additional preconditions [28,29]. In particular, the application domain of IA should be used not only in S-CRC but also in J-CRC.…”