Flame retardant BDE-47 effectively activates nuclear receptor CAR in human primary hepatocytes.
Polybrominated diphenyl ether BDE-47 (2,2',4,4'-tetrabromodiphenyl ether) is a thyroid hormone disruptor in mice; hepatic induction of various metabolic enzymes and transporters has been suggested as the mechanism for this disruption. Utilizing Car (-/-) and Pxr (-/-) mice as well as human primary hepatocytes, here we have demonstrated that BDE-47 activated both mouse and human nuclear receptor constitutive activated/androstane receptor (CAR). In mouse livers, CAR, not PXR, was responsible for Cyp2b10 mRNA induction by BDE-47. In human primary hepatocytes, BDE-47 was able to induce translocation of YFP-tagged human CAR from the cytoplasm to the nucleus andCYP2B6 and CYP3A4 mRNAs expressions. BDE-47 activated human CAR in a manner akin to the human CAR ligand CITCO (6-(4-Chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl)oxime) in luciferase-reporter assays using Huh-7 cells. In contrast, mouse CAR was not potently activated by BDE-47 in the same reporter assays. Furthermore, human pregnane X receptor (PXR) was effectively activated by BDE-47 while mouse PXR was weakly activated in luciferase-reporter assays. Our results indicate that BDE-47 induces CYP genes through activation of human CAR in addition to the previously identified pathway through human PXR.
Pharmacogenetics Section, Laboratory of Reproductive and Developmental Toxicology and.
Tatsuya
T
Sueyoshi
Linhao
L
Li
Hongbing
H
Wang
Rick
R
Moore
Prasada Rao S
PR
Kodavanti
Hans-Joachim
HJ
Lehmler
Masahiko
M
Negishi
Linda S
LS
Birnbaum
D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D000090702:Constitutive Androstane Receptor; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D052244:Endocrine Disruptors / Q000633:toxicity*; D005411:Flame Retardants / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects; D017930:Genes, Reporter; D055768:Halogenated Diphenyl Ethers / Q000633:toxicity*; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D000077297:Pregnane X Receptor; D061251:Primary Cell Culture; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism; D014162:Transfection
D000090702:Constitutive Androstane Receptor; D052244:Endocrine Disruptors; D005411:Flame Retardants; D055768:Halogenated Diphenyl Ethers; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; C511295:2,2',4,4'-tetrabromodiphenyl ether; D003577:Cytochrome P-450 Enzyme System
CAR; PBDE; PXR; xenobiotic receptor.