From dioxin toxicity to putative physiologic functions of the human Ah receptor in homeostasis of stem/progenitor cells

Abstract

Despite decades of intensive research physiologic Ah receptor (AHR) functions are not yet elucidated. Challenges include marked species differences and dependence of AHR function on the cell type and cellular context. Hints to physiologic functions may be derived (i) from feedback loops between endogenous ligands and substrates of major target enzymes such as CYP1A1 and UGT1A1, and (ii) from dioxin toxicity in human individuals. For example, dioxin-mediated chloracne is probably due to dysregulated homeostasis of sebocyte stem/progenitor cells. Dioxin-mediated inflammatory responses may be due to complex dysregulation of hematopoiesis. Comparison of AHR functions with those of PXR and its target enzyme CYP3A4 may be helpful to emphasize AHR functions in specialized cells: PXR is known to be mainly involved in regulation of systemic metabolism of endo- and xenobiotics. However, AHR may be mostly controlling local homeostasis of signals in specialized cells such as stem/progenitor cells. Accumulating evidence suggests that knowledge about physiologic AHR functions may stimulate drug development.

Keywords: 2,3,7,8-Tetrachlorodibenzo-p-dioxin=TCDD (PubChem CID 15625; 3,3′-Diindolylmethane, DIM (PubChem CID 3071); 6-Formylindolo[3,2-b]carbazole=FICZ (PubChem CID 1863); Ah receptor; Chloracne; Feedback loops; PXR; Stem/progenitor cells; StemRegenin 1 (PubChem CID 46199207); Tranilast (PubChem CID 5282230); VAF347 (PubChem CID 10172275).