TY - JOUR
T1 - Aryl hydrocarbon receptor ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin enhances liver damage in bile duct-ligated mice
AU - Ozeki, Jun
AU - Uno, Shigeyuki
AU - Ogura, Michitaka
AU - Choi, Mihwa
AU - Maeda, Tetsuyo
AU - Sakurai, Kenichi
AU - Matsuo, Sadanori
AU - Amano, Sadao
AU - Nebert, Daniel W.
AU - Makishima, Makoto
N1 - Funding Information:
This work was supported in part by grants from the Ministry of Education, Culture, Sports, Science and Technology, Japan [Grant-in-Aid for Scientific Research on Priority Areas (No. 18077995 )] and, in part, by NIH grants R01 ES014403 and P30 ES06096 .
PY - 2011/2/4
Y1 - 2011/2/4
N2 - The environmental pollutant 2,3,7,8-tetracholorodibenzo- p-dioxin (TCDD) is known to cause a wide variety of toxic effects, including hepatotoxicity, by way of the aryl hydrocarbon receptor (AHR). Although inducible expression of cytochrome P450 (CYP) 1A1 and CYP1A2 is associated with liver injury caused by high-dose TCDD, the specific role of the AHR-CYP1 cascade in hepatotoxicity remains unclear. We investigated the effects of AHR activation under conditions of cholestasis. We administered oral TCDD to mice at a dose that can effectively induce Cyp1 gene expression without overt liver toxicity and then ligated their bile ducts. TCDD pretreatment enhanced bile duct ligation (BDL)-induced increases in liver and plasma bile acids, bilirubin, and aminotransferases. Histology of TCDD-pretreated BDL mice revealed massive hepatic necrosis without any increase in number of apoptotic cells. Whereas induction of AHR-target genes by TCDD was observed similarly in sham-operated as well as in BDL mice, TCDD pretreatment of BDL mice altered the expression of hepatic genes involved in bile acid synthesis and transport. Increased plasma proinflammatory cytokines, tumor necrosis factor and interleukin-1β, in BDL mice were further elevated by TCDD pretreatment. Liver injury by TCDD plus BDL, such as increased plasma bile acids, bilirubin and aminotransferases, liver necrosis, and increased tumor necrosis factor production, was exaggerated in Cyp1a1/. 1a2(-/-) double knockout mice. These findings indicate that TCDD aggravates cholestatic liver damage and that the presence of CYP1A1 and CYP1A2 plays a protective role in liver damage caused by TCDD and BDL.
AB - The environmental pollutant 2,3,7,8-tetracholorodibenzo- p-dioxin (TCDD) is known to cause a wide variety of toxic effects, including hepatotoxicity, by way of the aryl hydrocarbon receptor (AHR). Although inducible expression of cytochrome P450 (CYP) 1A1 and CYP1A2 is associated with liver injury caused by high-dose TCDD, the specific role of the AHR-CYP1 cascade in hepatotoxicity remains unclear. We investigated the effects of AHR activation under conditions of cholestasis. We administered oral TCDD to mice at a dose that can effectively induce Cyp1 gene expression without overt liver toxicity and then ligated their bile ducts. TCDD pretreatment enhanced bile duct ligation (BDL)-induced increases in liver and plasma bile acids, bilirubin, and aminotransferases. Histology of TCDD-pretreated BDL mice revealed massive hepatic necrosis without any increase in number of apoptotic cells. Whereas induction of AHR-target genes by TCDD was observed similarly in sham-operated as well as in BDL mice, TCDD pretreatment of BDL mice altered the expression of hepatic genes involved in bile acid synthesis and transport. Increased plasma proinflammatory cytokines, tumor necrosis factor and interleukin-1β, in BDL mice were further elevated by TCDD pretreatment. Liver injury by TCDD plus BDL, such as increased plasma bile acids, bilirubin and aminotransferases, liver necrosis, and increased tumor necrosis factor production, was exaggerated in Cyp1a1/. 1a2(-/-) double knockout mice. These findings indicate that TCDD aggravates cholestatic liver damage and that the presence of CYP1A1 and CYP1A2 plays a protective role in liver damage caused by TCDD and BDL.
KW - Aryl hydrocarbon receptor
KW - Bile duct ligation
KW - Cholestasis
KW - Hepatotoxicity
KW - TCDD
KW - Tumor necrosis factor
UR - http://www.scopus.com/inward/record.url?scp=78650522347&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=78650522347&partnerID=8YFLogxK
U2 - 10.1016/j.tox.2010.11.003
DO - 10.1016/j.tox.2010.11.003
M3 - Article
C2 - 21095216
AN - SCOPUS:78650522347
SN - 0300-483X
VL - 280
SP - 10
EP - 17
JO - Toxicology
JF - Toxicology
IS - 1-2
ER -