The human Ah receptor: hints from dioxin toxicities to deregulated target genes and physiological functions.
Marked species differences of dioxin toxicity prompted the review of three well-studied human dioxin toxicities (chloracne, inflammation and cancer) and deregulated Ah receptor (AhR) target genes to obtain hints as to the physiological functions of this receptor. Dioxin here stands for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Microarray analysis of dermal cysts from a dioxin-poisoned patient revealed, in addition to induced CYP1A1, increased expression of gremlin, an antagonist of bone morphogenetic proteins. Dioxin-mediated skin and intestinal inflammation is associated with deregulated T cell differentiation. In the supernatant of CD4+ T cells obtained from the dioxin-poisoned patient, increased interleukin-22 was detected, a cytokine that may be controlled in part by AhR-regulated Notch. Cancer is one of the long-term consequences of chronic inflammation. In line with dioxin-sensitive lymphoid tissue, enhanced death of lymphoid cancer was observed in the dioxin-exposed Seveso population 25 years after poisoning. Accumulating evidence suggests that endogenous AhR ligands, notably the tryptophan photoproduct 6-formylindolo[3,2-b]carbazole, in contrast to TCDD, is rapidly metabolized by AhR-induced CYP1A1. The feedback loop between 6-formylindolo[3,2-b]carbazole, AhR and CYP1A1 guarantees transient activation that, in contrast to sustained activation by TCDD, may be essential for a putative role of the AhR in stem/progenitor cell homeostasis.
Institute of Experimental and Clinical Pharmacology and Toxicology, Department of Toxicology, University of Tübingen, Wilhelmstrasse 56, D-72074 Tübingen, Germany. bock@uni-tuebingen.de
Karl Walter
KW
Bock
D004194:Disease / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon