Abstract
The induction of hepatic drug metabolizing enzymes alters not only the metabolism of the xenobiotic substances that induce them but also the metabolism of various endogenous hormones. The xenobiotic receptor constitutive androstane receptor (CAR) (NR1I3) mediates the well-studied induction of CYP2B genes and other drug-metabolizing enzymes by phenobarbital (PB), an antiepileptic drug that has been shown to alter thyroid hormone (TH) levels. Here we show that CAR is required for PB-mediated disruption of TH homeostasis and the induction of thyroid follicular cell proliferation. Treatment with PB or the more potent and more effective CAR ligand 1, 4-bis-[2-(3, 5,-dichloropyridyloxy)] benzene resulted in universal induction of thyroid hormone glucuronidation and sulfation pathways in a CAR-dependent manner. This resulted in a decrease in serum T4 concentration and a concomitant increase in serum TSH levels. CAR activation also decreased serum T3 levels in mice in which T3 production was blocked. The increase in serum TSH levels resulted in the stimulation of thyroid-follicular cell proliferation. These results highlight the central role of the xenosensor CAR in drug-hormone interactions.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Anticonvulsants / pharmacology*
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Blotting, Northern
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Cell Proliferation
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Constitutive Androstane Receptor
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Dose-Response Relationship, Drug
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Female
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Humans
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Immunohistochemistry
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Male
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Mice
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Models, Biological
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Mutation
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Phenobarbital / pharmacology*
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Proliferating Cell Nuclear Antigen / metabolism
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Propylthiouracil / pharmacology
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Pyridines / pharmacology
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RNA / metabolism
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RNA, Messenger / metabolism
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Receptors, Cytoplasmic and Nuclear / metabolism*
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Receptors, Cytoplasmic and Nuclear / physiology*
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Reverse Transcriptase Polymerase Chain Reaction
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Thyroid Hormones / metabolism*
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Thyroid Neoplasms / etiology
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Thyroid Neoplasms / metabolism
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Thyroxine / metabolism
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Transcription Factors / metabolism*
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Transcription Factors / physiology*
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Triiodothyronine / metabolism
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Xenobiotics / pharmacology*
Substances
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Anticonvulsants
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Constitutive Androstane Receptor
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NR1I3 protein, human
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Nr1i3 protein, mouse
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Proliferating Cell Nuclear Antigen
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Pyridines
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RNA, Messenger
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Receptors, Cytoplasmic and Nuclear
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Thyroid Hormones
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Transcription Factors
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Xenobiotics
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Triiodothyronine
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RNA
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Propylthiouracil
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1,4-bis(2-(3,5-dichloropyridyloxy))benzene
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Thyroxine
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Phenobarbital