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

Tomoki Takeda, Yukiko Komiya, Takayuki Koga, Takumi Ishida, Yuji Ishii, Yasushi Kikuta, Nakaya Michio, Hitoshi Kurose, Takehiko Yokomizo, Takao Shimizu, Uchi Hiroshi, Masutaka Furue, Hideyuki Yamada

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

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-di-oxin (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.

Original languageEnglish
Pages (from-to)10586-10599
Number of pages14
JournalJournal of Biological Chemistry
Volume292
Issue number25
DOIs
Publication statusPublished - Jan 1 2017

Fingerprint

Aryl Hydrocarbon Receptors
Dioxins
Leukotriene B4
Neutrophil Infiltration
Biosynthesis
Infiltration
Liver
Rats
Chemical activation
Leukotriene B4 Receptors
Leukotriene A4
Arachidonate 5-Lipoxygenase
Leukotriene C4
Neutrophil Activation
Metabolomics
Metabolome
Poisons
Enzymes
Metabolites
Bile Acids and Salts

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Dioxin-induced increase in leukotriene B4 biosynthesis through the aryl hydrocarbon receptor and its relevance to hepatotoxicity owing to neutrophil infiltration. / Takeda, Tomoki; Komiya, Yukiko; Koga, Takayuki; Ishida, Takumi; Ishii, Yuji; Kikuta, Yasushi; Michio, Nakaya; Kurose, Hitoshi; Yokomizo, Takehiko; Shimizu, Takao; Hiroshi, Uchi; Furue, Masutaka; Yamada, Hideyuki.

In: Journal of Biological Chemistry, Vol. 292, No. 25, 01.01.2017, p. 10586-10599.

Research output: Contribution to journalArticle

Takeda, Tomoki ; Komiya, Yukiko ; Koga, Takayuki ; Ishida, Takumi ; Ishii, Yuji ; Kikuta, Yasushi ; Michio, Nakaya ; Kurose, Hitoshi ; Yokomizo, Takehiko ; Shimizu, Takao ; Hiroshi, Uchi ; Furue, Masutaka ; Yamada, Hideyuki. / Dioxin-induced increase in leukotriene B4 biosynthesis through the aryl hydrocarbon receptor and its relevance to hepatotoxicity owing to neutrophil infiltration. In: Journal of Biological Chemistry. 2017 ; Vol. 292, No. 25. pp. 10586-10599.
@article{91dc12c489df438c990f1f8ca1ca569e,
title = "Dioxin-induced increase in leukotriene B4 biosynthesis through the aryl hydrocarbon receptor and its relevance to hepatotoxicity owing to neutrophil infiltration",
abstract = "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-di-oxin (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.",
author = "Tomoki Takeda and Yukiko Komiya and Takayuki Koga and Takumi Ishida and Yuji Ishii and Yasushi Kikuta and Nakaya Michio and Hitoshi Kurose and Takehiko Yokomizo and Takao Shimizu and Uchi Hiroshi and Masutaka Furue and Hideyuki Yamada",
year = "2017",
month = "1",
day = "1",
doi = "10.1074/jbc.M116.764332",
language = "English",
volume = "292",
pages = "10586--10599",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "25",

}

TY - JOUR

T1 - Dioxin-induced increase in leukotriene B4 biosynthesis through the aryl hydrocarbon receptor and its relevance to hepatotoxicity owing to neutrophil infiltration

AU - Takeda, Tomoki

AU - Komiya, Yukiko

AU - Koga, Takayuki

AU - Ishida, Takumi

AU - Ishii, Yuji

AU - Kikuta, Yasushi

AU - Michio, Nakaya

AU - Kurose, Hitoshi

AU - Yokomizo, Takehiko

AU - Shimizu, Takao

AU - Hiroshi, Uchi

AU - Furue, Masutaka

AU - Yamada, Hideyuki

PY - 2017/1/1

Y1 - 2017/1/1

N2 - 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-di-oxin (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.

AB - 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-di-oxin (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.

UR - http://www.scopus.com/inward/record.url?scp=85021625710&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85021625710&partnerID=8YFLogxK

U2 - 10.1074/jbc.M116.764332

DO - 10.1074/jbc.M116.764332

M3 - Article

C2 - 28487374

AN - SCOPUS:85021625710

VL - 292

SP - 10586

EP - 10599

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 25

ER -