Genotoxicity of methyl acrylate and ethyl acrylate and its relationship with glutathione.

Methyl acrylate (MA) and ethyl acrylate (EA) had previously tested positive for mutagenicity in vitro, but in vivo studies were negative. One of the metabolism pathways of alkyl acrylates is conjugation with glutathione. The glutathione availability is restricted in standard in vitro test systems so that they do not reflect the in vivo metabolism in this respect. We investigated whether the addition of glutathione to the in vitro L5178Y/TK+/- mouse lymphoma mutagenicity test prevents alkyl acrylate's mutagenicity in vitro. We also investigated whether the quantitative relationships support the notion that the GSH supplemented in vitro systems reflect the true in vivo activity. Indeed, glutathione concentrations as low as 1 mM completely negate the mutagenicity of MA and EA in the L5178Y/TK+/- mouse lymphoma mutagenicity test up to the highest concentrations of the two acrylates tested, 35 µg/ml, a higher concentration than that previously found to be mutagenic in this test (14 µg MA/ml and 20 µg EA/ml). 1 mM Glutathione reduced the residual MA and EA at the end of the exposure period in the mutagenicity tests by 96-97%, but in vivo up to 100 mg/kg body weight MA and EA left the glutathione levels in the mouse liver and forestomach completely intact. It is concluded that the in-situ levels of glutathione, 7.55 ± 0.57 and 2.84 ± 0.22 µmol/g mouse liver and forestomach, respectively, can efficiently protect against MA and EA-induced mutagenicity up to the high concentration of 100 mg MA and EA/kg body weight and that the negative in vivo mutagenicity tests on MA and EA reflect the true in vivo situation.

Measuring CAMD technique performance: a virtual screening case study in the design of validation experiments.

The dynamic nature and comparatively young age of computational chemistry is such that novel algorithms continue to be developed at a rapid pace. Such efforts are often wrought at the expense of extensive experimental validations of said techniques, preventing a deeper understanding of their potential utility and limitations. Here we address this issue for ligand-based virtual screening descriptors through design of validation experiments that better reflect the aims of real world application. Applying the newly defined chemotype enrichment approach, a variety of two- and three-dimensional (2D/3D) similarity descriptors have been compared extensively across data sets from four diverse target types. The inhibitors within said data sets contain molecules exhibiting a wide array of substructure functionality, size and flexibility, permitting descriptor comparison in myriad settings. Relative descriptor performance under these conditions is examined, including results obtained using more typical virtual screening validation experiments. Guidelines for optimal application of said descriptors are also discussed in the context of the results obtained, as is the potential utility of fingerprint filtering.

Kinetics of Crystallization in n-Hexadecane and Cocoa Butter Oil-in-Water Emulsions Accounting for Droplet Collision-Mediated Nucleation.

Droplet collision is shown to be important in the propagation of nucleation through supercooled oil-in-water emulsions by the use of a novel membrane technique. On the other hand, nucleation mediated by Tween 20 micelles is shown to be of relatively much less importance in both n-hexadecane and cocoa butter oil-in-water emulsions. The droplet collision phenomenon probably occurs via a surfactant bridge between the colliding droplets. When this process is taken into account we show that the Turnbull model for crystal nucleation kinetics explains very well nucleation in cocoa butter oil-in-water emulsions by seed crystals. On the basis of this model we characterized the seed crystals in cocoa butter via isothermal crystallization studies at 14.2, 15.0, 15.5, and 15.8 degrees C. We suggest that there are few seed crystals whose size exceeds 0.28 µm at 80 degrees C. In our cocoa butter samples there were between 10(16) and 10(17) seed crystals m(-3) whose average size we inferred to be less than 0.09 µm. A value of 0.133 mJ m(-2) is obtained for the Gibbs free energy of the nucleating surface in our West African cocoa butter samples. There is evidence that the alpha-polymorph of POS comprises the nucleating layer in the seed crystal. There is no evidence that surfactant influences the primary nucleation of oil crystals. However, the surfactant has a big effect on the kinetics of the secondary nucleation process, mediated by droplet collision. Copyright 2000 Academic Press.