Hormetic & Idiosyncratic Dose Responses

Hormesis is an unusual dose response seen when a lower dose of a drug elicits an outcome whereas the higher dose does not. Idiosyncratic dose response deals with how/why one person gives a unique/allergic response compared to the vast majority of others that don't. The figure below shows increase in concentration on the X-axis (in linear or log scales) and relative activity on the Y-axis. Since the classical enzyme or receptor binding to ligands give a Michaelis-Menten or Hill type profile, we can theoretically get a unidirectionally increasing or decreasing outcomes with respect to increasing concentrations (the curved profiles in A). Simple collision based reactions could also give the linear profiles in A (first order dependence) or C (zero order dependence). Allosteric influences could the profiles shown in B and the bell-shaped curve is seen due to optimal effect of outcome due to miscellaneous physiological considerations. Maverick dose responses of the type D is rather unexplained/inexplicable in the classical purview.

Since murburn concept invokes upon catalytic outcomes and products mediated by diffusible reactive species and radicals, the unusual dose responses observed in physiology can be explained with a reductionist perspective too. Radicals have a small/discrete window of concentration and time frame wherein they are stabilized. Higher concentrations of the effector may give higher radicals which can collapse by reacting among themselves, which would lead to loss of biological activity mediated by the effector. Further, in individual cases, since the outcome is based more in probability (and less in topological determinism), unique type of stabilization/localization can result. These could in turn, amplify certain physiological responses. A scenario for an enzyme with bi-substrate redox reaction is shown below, wherein the first active site substrate gives two types of activations, leading to multiple product formation possibilities, each of which could be stabilized and favored in specific concentration regimes. In the murburn purview of redox metabolism, one-electron intermediates' formation is considered as an essential or unavoidable aspect, which leads to complex interactive networks in milieu. The classical purview disregards these outcomes or considers them as aberrations/artifacts.