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Thyroid Section, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital Boston, Massachusetts 02115
Address all correspondence and requests for reprints to: P. Reed Larsen, Thyroid Section, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, 77 Avenue Louis Pasteur, HIM 641, Boston, Massachusetts 02115. E-mail: plarsen{at}partners.org.
Complex, inducible enzymatic pathways are present in vertebrates to permit the detoxification of potentially harmful endogenous metabolic end products. These pathways facilitate the metabolism of these compounds and also increase their elimination via cellular transport proteins or conjugation to sulfate or glucuronic acid. These same responses often mediate the clearance of foreign chemicals or xenobiotics that include a wide variety of therapeutic drugs. The xenobiotic-mediated activation of such responses, however, can interfere with normal endocrine signaling by increasing the clearance of endogenous hormones, thus causing these xenobiotics to become endocrine disruptors (1). A relevant example is the common experience that hypothyroid patients receiving thyroid hormone replacement therapy require an increase in their dosage if they initiate treatment with anticonvulsants (phenobarbital, phenytoin, or carbamezepine), certain antibiotics (rifampicin), or if estradiol levels increase to high levels such as during pregnancy (2, 3). Similar events occur in normal individuals, but the operation of normal feedback cycles results in a compensatory increase in thyroid hormone synthesis. In this issue, Qatanani et al. (4) address the molecular explanation for these events, showing that, in mice, the constitutive androstane receptor (CAR) (NR1I3) is required for the increased expression of sulfo- and glucuronyl-transferases that accelerate the clearance of thyroid hormones (5, 6, 7) in turn resulting in decreased serum T4 levels (4).
CAR and its closely related family member, pregnane X receptor (PXR) (NR1I2), are two of several nuclear receptor proteins known to play key roles in the metabolism and elimination of xenobiotics (8, 9). These receptors mediate the xenobiotic-induced transcriptional regulation of a number of cytochrome p450 (CYP) family members needed to metabolize foreign substances and induce genes involved in the elimination of these compounds (8, 9). In particular, CAR regulates the induction of many of the CYP2B family of enzymes that are highly inducible by the phenobarbital-like class of xenobiotics (8). Phenobarbital, and a more potent member of this group of inducers, the pesticide contaminant 1,4-bis [2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP), have both been shown to activate murine CAR by facilitating the entry of this transcriptionally active cytosolic protein to the nucleus in a yet-to-be-defined manner in which direct ligand binding is not an absolute requirement (1). CAR knockout (CAR–/–) mice no longer activate the cyp2B10 gene in response to phenobarbital or TCPOBOP, nor do the liver hypertrophic and hyperplastic responses elicited by these compounds occur (10).
Qatanani et al. (4) show that CAR controls the expression of key enzymes that accelerate the clearance of thyroid hormones. How does this happen? T4 is a prohormone that must be specifically monodeiodinated in the phenolic ring to produce the active hormone, T3, that binds with high affinity to its nuclear receptors (Fig. 1
). This reaction is catalyzed by either the type 1 or type 2 iodothyronine deiodinase (D1 or D2) (11). T3 is also secreted directly into the plasma from thyroid cells, which are under hypothalamic-pituitary regulation by T3-mediated feedback regulation of TSH synthesis and secretion. The binding of T3 to its receptors in the pituitary thyrotrophs and the hypothalamic TRH-producing neurons is the critical signal in this pathway. The required T3, however, is derived in roughly equal amounts from the circulation and from D2-catalyzed T4 monodeiodination that occurs in the thyrotrophs and the TRH-producing neurons (11). This can explain the apparent paradox in Fig. 1 in the article by Quatanani et al. (4), which shows that the CAR-dependent reduction in plasma T4 after phenobarbital or TCPOBOP treatment causes an increase in TSH, despite normal plasma T3 levels. In fact, as the authors show in Fig. 2 of that article, TSH-stimulated thyroidal T3 secretion is required to maintain normal serum T3 levels after xenobiotic exposure.
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). Monodeiodination of the tyrosyl ring of T4 by D1 can also produce the inactive metabolite 3,3', 5'T3 (reverse T3). Although CAR activation is not known to alter D1 or D2 activities, the CAR-dependent enzymes catalyzing the sulfation of the phenolic hydroxyl of T4 or T3 (forming T4S or T3S) such as sulfotransferase (SULT)2A1, SULT1C1, SULT1E1, 3'-phosphoadenosine 5'-phosphosulfate (PAPS)S2, and sulfate anion transporter (SAT) 1 (12, 13, 14, 15) have a major influence on whether the hepatic D1 enzyme activates or inactivates T4, or inactivates T3. The maximum velocity (Vmax)/Michaelis Menten constant (Km) ratio for tyrosyl ring deiodination is several hundred fold higher for both T4S and T3S relative to that for the unconjugated hormones. Thus, sulfation would result in an increased production of the inactive compounds, reverse T3 and 3,3'-diiodothyronine (Fig. 1) (16, 17). Hence, this is probably the major pathway by which CAR activation accelerates thyroid hormone clearance in the mouse.
T4 and T3 glucuronides, the water-soluble products of glucuronyl transferase reactions, are secreted into the bile where bacterial glucuronidases in intestinal contents can release the iodothyronines for reabsorption (Fig. 1) (18). Qatanani et al. (4) also show that xenobiotics induce a CAR-dependent up-regulation of the glucuronyl transferases [uridine diphosphate glucoronsyltransferase (UGT) 1A1, UGT2B1, and UGT2B5] known to glucuronidate T3 and T4 (5, 19, 20). Thus, it is also possible there may be rapid transfer of glucuronide-conjugated thyroid hormones into the intestinal lumen contributing to the transient reduction in circulating hormones. A recent publication has shown CAR-dependent activation of several sulfotransferases and the UGT1A1 gene during a 24-h fast in mice, suggesting that CAR could play an indirect role in the acute reduction of serum thyroid hormone in rodents during fasting or food deprivation (21).
It is likely then, as shown in Fig. 7 of the article by Qatanani et al. (4), that CAR activation by chronic xenobiotic administration would accelerate both T4 and T3 inactivation via sulfation and biliary excretion of the glucuronidated iodothyronines. A increase in TSH would compensate for this by accelerating T4 and T3 secretion. The sustained TSH-driven increase in the rate of thyroid follicular cell division can lead to thyroid malignancies in rodents, although not in humans (22, 23, 24, 25). Despite this increased stress upon the thyroid, hypothyroidism should not occur as long as the hypothalamic-pituitary thyroid axis is intact and iodine supplies are sufficient.
For humans, less is known about the specific regulation of the pathways leading to the increased requirements for T4 in patients receiving pharmacological agents such as phenytoin, carbamazepine, rifampin, or even estradiol, although both sulfation and glucuronidation of T3 and T4 do occur (13, 14, 19). There are significant sequence differences between mouse CAR and human CAR, and also a marked divergence in the effectiveness of different compounds to activate these receptors (26). Additionally, there is substantial overlap between CAR- and PXR-target genes in different species; thus, continued investigations are required to sort out the details for each xenobiotic or hormone (27, 28). Still, keeping all this in mind, recent data show that the response to phenytoin in human cells is regulated by CAR and not PXR (29).
There also may be species-specific consequences of the secondary adaptation mechanisms. As mentioned, the chronic elevation in TSH secretion documented in both rodents and humans receiving such compounds causes thyroid malignancies in rodents, whereas only thyroid enlargement has been observed in humans (22, 23, 24, 25). In patients without the capacity for internal compensation, such as those with hypothyroidism, the xenobiotic-induced increase in the rate of hormone metabolism will increase the replacement dosage requirement that can be critically important to fetal development during pregnancy. As more is learned about these specific pathways, it is likely that genetic differences in the responses controlled by CAR, PXR, and other systems will be found to explain differences between patients in both the efficacy and toxicity of the same therapeutic agent.
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Received December 8, 2004.
Accepted for publication December 9, 2004.
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