Role of the constitutive androstane receptor in xenobiotic-induced thyroid hormone metabolism.

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.

journal_name

Endocrinology

journal_title

Endocrinology

authors

Qatanani M,Zhang J,Moore DD

doi

10.1210/en.2004-1350

subject

Has Abstract

pub_date

2005-03-01 00:00:00

pages

995-1002

issue

3

eissn

0013-7227

issn

1945-7170

pii

en.2004-1350

journal_volume

146

pub_type

杂志文章