The Laboratory of Environmental Biotechnology, Institute of Microbiology of the Czech Academy of Sciences, Vídeňská 1083, Prague, 142 20, Czech Republic.
Toxicol Lett. 2021 Oct 10;350:22-29. doi: 10.1016/j.toxlet.2021.06.016. Epub 2021 Jun 24.
Concentration addition as a classic null model for toxicology and pharmacology is based on Loewe's mathematical formulation and the linearity of the isoboles. Novel mathematical models, however, propose curved isoboles in certain conditions. This article aims to test the hypothesis of the curvature of isoboles in experimental measurements. With the assumption of linear isoboles, a partial agonist acts as an antagonist above its maximal effect level. The isoboles automatically convert to a positive slope. For curved isoboles, a partial agonist acts as an antagonist at higher effect levels than its maximal effect alone. The discrepancies between effect levels were studied with an estrogen receptor binding assay (BMAEREluc/ERα) using a mixture of 17β-estradiol and fulvestrant as a partial agonist. A mixture of 17β-estradiol and fulvestrant acts as a partial agonist and causes the diminishing of the effect level of 17β-estradiol at a significantly higher level than the maximal effect of their partial-agonistic dose-response curve. Measured, elevated effect levels were well predicted by the mathematical model. Nonlinear isoboles may change our understanding and definition of synergism or antagonism and prompt further attention in receptor theory.
浓度加和作为毒理学和药理学的经典零假设模型，是基于 Loewe 的数学公式和等效应线的线性。然而，新的数学模型在某些条件下提出了曲线等效应线。本文旨在检验实验测量中等效应线弯曲的假设。在等效应线线性的假设下，部分激动剂在其最大效应水平之上表现为拮抗剂。等效应线自动变为正斜率。对于曲线等效应线，部分激动剂在比其单独最大效应更高的效应水平上表现为拮抗剂。通过使用 17β-雌二醇和氟维司群混合物作为部分激动剂的雌激素受体结合测定（BMAEREluc/ERα）研究了效应水平的差异。17β-雌二醇和氟维司群的混合物作为部分激动剂，导致 17β-雌二醇的效应水平在比其部分激动剂剂量反应曲线的最大效应显著更高的水平上降低。所测量的升高的效应水平被数学模型很好地预测。非线性等效应线可能会改变我们对协同作用或拮抗作用的理解和定义，并促使受体理论进一步关注。
