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Submitted on October 14, 2004
Accepted on November 19, 2004
Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030
* To whom correspondence should be addressed. E-mail: moore{at}bcm.tmc.edu.
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 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 hormones levels. Here we show that CAR is required for PB mediated disruption of thyroid hormones 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 (TCPOBOP) resulted in universal induction of thyroid hormones 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.
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