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The human Ah receptor: hints from dioxin toxicities to deregulated target genes and physiological functions

  • Karl Walter Bock

    Karl Walter Bock worked from 1965–68 at the Institute of Biochemistry, University of Freiburg, with Helmut Holzer and Hans Grunicke, and from 1968–70 at the Rockefeller University in New York with Philip Siekevitz and George Palade. From 1970–77 he was with Herbert Remmer at the Institute of Toxicology, University of Tübingen. From 1977–87 he was professor at the Centre of Pharmacology and Toxicology, University of Göttingen, and from 1987–2000 director of the Institute of Toxicology at the University of Tübingen. In 2012 he received the Oswald Schmiedeberg Medal by the German Society of Pharmacology and Toxicology.

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Published/Copyright: January 31, 2013

Abstract

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.


Corresponding author: Karl Walter Bock, Institute of Experimental and Clinical Pharmacology and Toxicology, Department of Toxicology, University of Tübingen, Wilhelmstrasse 56, D-72074 Tübingen, Germany

About the author

Karl Walter Bock

Karl Walter Bock worked from 1965–68 at the Institute of Biochemistry, University of Freiburg, with Helmut Holzer and Hans Grunicke, and from 1968–70 at the Rockefeller University in New York with Philip Siekevitz and George Palade. From 1970–77 he was with Herbert Remmer at the Institute of Toxicology, University of Tübingen. From 1977–87 he was professor at the Centre of Pharmacology and Toxicology, University of Göttingen, and from 1987–2000 director of the Institute of Toxicology at the University of Tübingen. In 2012 he received the Oswald Schmiedeberg Medal by the German Society of Pharmacology and Toxicology.

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Received: 2012-11-27
Accepted: 2013-1-25
Published Online: 2013-01-31
Published in Print: 2013-06-01

©2013 by Walter de Gruyter Berlin Boston

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