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J Biol Chem. 2017 Jun 23;292(25):10586-10599. doi: 10.1074/jbc.M116.764332. Epub 2017 May 9.

Dioxin-induced increase in leukotriene B4 biosynthesis through the aryl hydrocarbon receptor and its relevance to hepatotoxicity owing to neutrophil infiltration.

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From the Laboratory of Molecular Life Sciences and
From the Laboratory of Molecular Life Sciences and.
the Department of Applied Biological Science, Fukuyama University, Hiroshima 729-0292, Japan.
the Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
the Department of Biochemistry, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
the Department of Lipid Signaling, Research Institute National Center for Global Health and Medicine, Tokyo 162-8655, Japan.
the Department of Lipidomics, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan, and.
the Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
the Research and Clinical Center for Yusho and Dioxin, Kyushu University Hospital, Fukuoka 812-8582, Japan.


Dioxin and related chemicals alter the expression of a number of genes by activating the aryl hydrocarbon receptors (AHR) to produce a variety of disorders including hepatotoxicity. However, it remains largely unknown how these changes in gene expression are linked to toxicity. To address this issue, we initially examined the effect of 2,3,7,8-tetrachrolodibenzo-p-dioxin (TCDD), a most toxic dioxin, on the hepatic and serum metabolome in male pubertal rats and found that TCDD causes many changes in the level of fatty acids, bile acids, amino acids, and their metabolites. Among these findings was the discovery that TCDD increases the content of leukotriene B4 (LTB4), an inducer of inflammation due to the activation of leukocytes, in the liver of rats and mice. Further analyses suggested that an increase in LTB4 comes from a dual mechanism consisting of an induction of arachidonate lipoxygenase-5, a rate-limiting enzyme in LTB4 synthesis, and the down-regulation of LTC4 synthase, an enzyme that converts LTA4 to LTC4. The above changes required AHR activation, because the same was not observed in AHR knock-out rats. In agreement with LTB4 accumulation, TCDD caused the marked infiltration of neutrophils into the liver. However, deleting LTB4 receptors (BLT1) blocked this effect. A TCDD-produced increase in the mRNA expression of inflammatory markers, including tumor-necrosis factor and hepatic damage, was also suppressed in BLT1-null mice. The above observations focusing on metabolomic changes provide novel evidence that TCDD accumulates LTB4 in the liver by an AHR-dependent induction of LTB4 biosynthesis to cause hepatotoxicity through neutrophil activation.


aryl hydrocarbon receptor (AHR); dioxin; leukotriene; liver injury; metabolomics

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