Differential binding to the Ah receptor and CYP1A1 induction in support of drug development

Abstract

Although the perception of dioxins is predominantly negative, they have also been shown to exert beneficial effects in animal models, such as immunostimulation, reduced cancer rates and prolongation of life at sufficiently low (hormetic) doses. Furthermore, some effects at supra-hormetic doses can be considered desirable under certain conditions. Lowering of body weight or increased insulin sensitivity could contribute to the quest for treating obesity or diabetes mellitus type II. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) binds readily to the aryl hydrocarbon receptor (AhR), and, thereby exerts many of its effects. The binding of potential drug candidates to the AhR, however, is often considered detrimental. The expected subsequent induction of CYP1A1 activity is still associated with the metabolic activation of potential carcinogens despite naturally occurring AhR agonists in food. Therefore, a separation of AhR interaction and downstream effects could lead to the exploitation of the beneficial effects of dioxins. A competitive displacement assay was applied to quantitate the binding affinity of the TCDD analog 2,3,7,8-tetrachlorophenothiazine (TCPT) to the AhR. It has been reported previously that the ability of TCPT to induce CYP1A1 activity is 370-times lower than that of TCDD. This binding assay, however, revealed that the Ki of TCPT is 0.85 nM, as compared to a Kd of 0.37 nM for TCDD, i.e. the affinity of TCPT to the AhR is less than three times lower than that of TCDD. Therefore, the high affinity of TCPT to the AhR combined with its much lower potency regarding CYP1A1 induction are promising properties for drug development.