Laboratory of Environmental Biotechnology, Institute of Microbiology of the CAS, v.v.i., Vídeňská 1083, Prague, 142 20, Czech Republic.
Laboratory of Environmental Biotechnology, Institute of Microbiology of the CAS, v.v.i., Vídeňská 1083, Prague, 142 20, Czech Republic; Institute for Environmental Studies, Faculty of Science, Charles University in Prague, Albertov 6, Prague, 128 43, Czech Republic.
Toxicology. 2018 Jun 1;402-403:9-16. doi: 10.1016/j.tox.2018.04.004. Epub 2018 Apr 13.
Receptor ligands in mixtures may produce effects that are greater than the effect predicted from their individual dose-response curves. The historical basis for predicting the mixture effect is based on Loewe's concept and its mathematical formulation. This concept considers compounds with constant relative potencies (parallel dose-response curves) and leads to linear additive isoboles. These lines serve as references for distinguishing additive from nonadditive interactions according to the positions of the experimental data on or outside of the lines. In this paper, we applied a highly relevant two-state model for a description of the receptor-ligand interaction in the construction of the isobologram. In our model we consider partial agonists that have dose-response curve slopes differing from one. With this theoretical basis, we demonstrated that a combination of compounds with different efficacies leads to curved isoboles. This model should overwrite Tallarida's flawed assumption about isobolographic analysis of partial agonists and enhance our understanding of how the partial agonists contribute to the overall mixture effect.
混合物中的受体配体可能产生大于其各自剂量-反应曲线预测的效果。预测混合物效应的历史基础基于 Loewe 的概念及其数学公式。该概念考虑了具有恒定相对效力（平行剂量-反应曲线）的化合物，并导致线性加性等摩尔线。这些线根据实验数据在线上或线外的位置，作为区分加性和非加性相互作用的参考。在本文中，我们应用了一个高度相关的两态模型来描述受体-配体相互作用，以构建等摩尔图。在我们的模型中，我们考虑了具有不同斜率的部分激动剂的剂量-反应曲线。基于这一理论基础，我们证明了具有不同效能的化合物组合会导致曲线等摩尔线。该模型应覆盖 Tallarida 关于部分激动剂等摩尔分析的有缺陷的假设，并增强我们对部分激动剂如何对整体混合物效应做出贡献的理解。
