CARs and Drugs: A Risky Combination
http://www.100md.com
内分泌学杂志 2005年第3期
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@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.
FIG. 1. Deiodinative and nondeiodinative pathways of thyroid hormone metabolism. T4 is activated by monodeiodination of the phenolic thyronine ring by D1 or D2 to form T3. Deiodination of the tyrosyl ring by D1 or D3 inactivates T4 and T3. This inactivation pathway is markedly favored by sulfation of the phenolic hydroxyl. Glucuronidated T4 and T3 (T4G and T3G) are excreted into the bile but may be partially reabsorbed after deglucuronidation in the intestine.
Monodeiodination of the tyrosyl ring either of T3 by the bifunctional D1 (or a third deiodinase, D3) markedly reduces its affinity for the receptor, thus terminating T3 action (Fig. 1). 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.
References
Swales K, Negishi M 2004 CAR, driving into the future. Mol Endocrinol 18:1589–1598
Surks MI, Sievert R 1995 Drugs and thyroid function. N Engl J Med 333:1688–1694
Alexander EK, Marqusee E, Lawrence J, Jarolim P, Fischer GA, Larsen PR 2004 Timing and magnitude of increases in levothyroxine requirements during pregnancy in women with hypothyroidism. N Engl J Med 351:241–249
Qatanani M, Zhang J, Moore DD 2005 Role of the constitutive androstane receptor in xenobiotic-induced thyroid hormone metabolism. Endocrinology 146:995–1002
Visser TJ, Kaptein E, van Raaij JA, Joe CT, Ebner T, Burchell B 1993 Multiple UDP-glucuronyltransferases for the glucuronidation of thyroid hormone with preference for 3,3',5'-triiodothyronine (reverse T3). FEBS Lett 315:65–68
Kaptein E, van Haasteren GA, Linkels E, de Greef WJ, Visser TJ 1997 Characterization of iodothyronine sulfotransferase activity in rat liver. Endocrinology 138:5136–5143
Visser TJ, Kaptein E, Glatt H, Bartsch I, Hagen M, Coughtrie MW 1998 Characterization of thyroid hormone sulfotransferases. Chem Biol Interact 109:279–291
Waxman DJ 1999 P450 gene induction by structurally diverse xenochemicals: central role of nuclear receptors CAR, PXR, and PPAR. Arch Biochem Biophys 369:11–23
Wang H, LeCluyse EL 2003 Role of orphan nuclear receptors in the regulation of drug-metabolising enzymes. Clin Pharmacokinet 42:1331–1357
Wei P, Zhang J, Egan-Hafley M, Liang S, Moore DD 2000 The nuclear receptor CAR mediates specific xenobiotic induction of drug metabolism. Nature 407:920–923
Bianco AC, Salvatore D, Gereben B, Berry MJ, Larsen PR 2002 Biochemistry, cellular and molecular biology and physiological roles of the iodothyronine selenodeiodinases. Endocr Rev 23:38–89
Kester MH, Kaptein E, Roest TJ, van Dijk CH, Tibboel D, Meinl W, Glatt H, Coughtrie MW, Visser TJ 2003 Characterization of rat iodothyronine sulfotransferases. Am J Physiol Endocrinol Metab 285:E592–E598
Li X, Clemens DL, Anderson RJ 2000 Sulfation of iodothyronines by human sulfotransferase 1C1 (SULT1C1). Biochem Pharmacol 60:1713–1716
Li X, Anderson RJ 1999 Sulfation of iodothyronines by recombinant human liver steroid sulfotransferases. Biochem Biophys Res Commun 263:632–639
Klaassen CD, Boles JW 1997 Sulfation and sulfotransferases 5: the importance of 3'-phosphoadenosine 5'-phosphosulfate (PAPS) in the regulation of sulfation. FASEB J 11:404–418
Mol JA, Visser TJ 1985 Rapid and selective inner ring deiodination of thyroxine sulfate by rat liver deiodinase. Endocrinology 117:8–12
Visser TJ, Kaptein E, Terpstra OT, Krenning EP 1988 Deiodination of thyroid hormone by human liver. J Clin Endocrinol Metab 67:17–24
Visser TJ 1990 Importance of deiodination and conjugation in the hepatic metabolism of thyroid hormone. In: Greer MA, ed. The thyroid gland. New York: Raven Press, Ltd.; 255–282
Findlay KA, Kaptein E, Visser TJ, Burchell B 2000 Characterization of the uridine diphosphate-glucuronosyltransferase-catalyzing thyroid hormone glucuronidation in man. J Clin Endocrinol Metab 85:2879–2883
Hood A, Klaassen CD 2000 Differential effects of microsomal enzyme inducers on in vitro thyroxine (T(4)) and triiodothyronine (T(3)) glucuronidation. Toxicol Sci 55:78–84
Maglich JM, Watson J, McMillen PJ, Goodwin B, Willson TM, Moore JT 2004 The nuclear receptor CAR is a regulator of thyroid hormone metabolism during caloric restriction. J Biol Chem 279:19832–19838
McClain RM, Posch RC, Bosakowski T, Armstrong JM 1988 Studies on the mode of action for thyroid gland tumor promotion in rats by phenobarbital. Toxicol Appl Pharmacol 94:254–265
Suzuki H, Willingham MC, Cheng SY 2002 Mice with a mutation in the thyroid hormone receptor beta gene spontaneously develop thyroid carcinoma: a mouse model of thyroid carcinogenesis. Thyroid 12:963–969
Curran PG, DeGroot LJ 1991 The effect of hepatic enzyme-inducing drugs on thyroid hormones and the thyroid gland. Endocr Rev 12:135–150
Hegedus L, Hansen JM, Luhdorf K, Perrild H, Feldt-Rasmussen U, Kampmann JP 1985 Increased frequency of goitre in epileptic patients on long-term phenytoin or carbamazipine treatment. Clin Endocrinol 23:423–429
Moore LB, Parks DJ, Jones SA, Bledsoe RK, Consler TG, Stimmel JB, Goodwin B, Liddle C, Blanchard SG, Willson TM, Collins JL, Kliewer SA 2000 Orphan nuclear receptors constitutive androstane receptor and pregnane X receptor share xenobiotic and steroid ligands. J Biol Chem 275:15122–15127
Maglich JM, Stoltz CM, Goodwin B, Hawkins-Brown D, Moore JT, Kliewer SA 2002 Nuclear pregnane X receptor and constitutive androstane receptor regulate overlapping but distinct sets of genes involved in xenobiotic detoxification. Mol Pharmacol 62:638–646
Xie W, Barwick JL, Simon CM, Pierce AM, Safe S, Blumberg B, Guzelian PS, Evans RM 2000 Reciprocal activation of xenobiotic response genes by nuclear receptors SXR/PXR and CAR. Genes Dev 14:3014–3023
Wang H, Faucette S, Moore R, Sueyoshi T, Negishi M, LeCluyse E 2004 Human constitutive androstane receptor mediates induction of CYP2B6 gene expression by phenytoin. J Biol Chem 279:29295–29301(Ann Marie Zavacki and P. )
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@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.
FIG. 1. Deiodinative and nondeiodinative pathways of thyroid hormone metabolism. T4 is activated by monodeiodination of the phenolic thyronine ring by D1 or D2 to form T3. Deiodination of the tyrosyl ring by D1 or D3 inactivates T4 and T3. This inactivation pathway is markedly favored by sulfation of the phenolic hydroxyl. Glucuronidated T4 and T3 (T4G and T3G) are excreted into the bile but may be partially reabsorbed after deglucuronidation in the intestine.
Monodeiodination of the tyrosyl ring either of T3 by the bifunctional D1 (or a third deiodinase, D3) markedly reduces its affinity for the receptor, thus terminating T3 action (Fig. 1). 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.
References
Swales K, Negishi M 2004 CAR, driving into the future. Mol Endocrinol 18:1589–1598
Surks MI, Sievert R 1995 Drugs and thyroid function. N Engl J Med 333:1688–1694
Alexander EK, Marqusee E, Lawrence J, Jarolim P, Fischer GA, Larsen PR 2004 Timing and magnitude of increases in levothyroxine requirements during pregnancy in women with hypothyroidism. N Engl J Med 351:241–249
Qatanani M, Zhang J, Moore DD 2005 Role of the constitutive androstane receptor in xenobiotic-induced thyroid hormone metabolism. Endocrinology 146:995–1002
Visser TJ, Kaptein E, van Raaij JA, Joe CT, Ebner T, Burchell B 1993 Multiple UDP-glucuronyltransferases for the glucuronidation of thyroid hormone with preference for 3,3',5'-triiodothyronine (reverse T3). FEBS Lett 315:65–68
Kaptein E, van Haasteren GA, Linkels E, de Greef WJ, Visser TJ 1997 Characterization of iodothyronine sulfotransferase activity in rat liver. Endocrinology 138:5136–5143
Visser TJ, Kaptein E, Glatt H, Bartsch I, Hagen M, Coughtrie MW 1998 Characterization of thyroid hormone sulfotransferases. Chem Biol Interact 109:279–291
Waxman DJ 1999 P450 gene induction by structurally diverse xenochemicals: central role of nuclear receptors CAR, PXR, and PPAR. Arch Biochem Biophys 369:11–23
Wang H, LeCluyse EL 2003 Role of orphan nuclear receptors in the regulation of drug-metabolising enzymes. Clin Pharmacokinet 42:1331–1357
Wei P, Zhang J, Egan-Hafley M, Liang S, Moore DD 2000 The nuclear receptor CAR mediates specific xenobiotic induction of drug metabolism. Nature 407:920–923
Bianco AC, Salvatore D, Gereben B, Berry MJ, Larsen PR 2002 Biochemistry, cellular and molecular biology and physiological roles of the iodothyronine selenodeiodinases. Endocr Rev 23:38–89
Kester MH, Kaptein E, Roest TJ, van Dijk CH, Tibboel D, Meinl W, Glatt H, Coughtrie MW, Visser TJ 2003 Characterization of rat iodothyronine sulfotransferases. Am J Physiol Endocrinol Metab 285:E592–E598
Li X, Clemens DL, Anderson RJ 2000 Sulfation of iodothyronines by human sulfotransferase 1C1 (SULT1C1). Biochem Pharmacol 60:1713–1716
Li X, Anderson RJ 1999 Sulfation of iodothyronines by recombinant human liver steroid sulfotransferases. Biochem Biophys Res Commun 263:632–639
Klaassen CD, Boles JW 1997 Sulfation and sulfotransferases 5: the importance of 3'-phosphoadenosine 5'-phosphosulfate (PAPS) in the regulation of sulfation. FASEB J 11:404–418
Mol JA, Visser TJ 1985 Rapid and selective inner ring deiodination of thyroxine sulfate by rat liver deiodinase. Endocrinology 117:8–12
Visser TJ, Kaptein E, Terpstra OT, Krenning EP 1988 Deiodination of thyroid hormone by human liver. J Clin Endocrinol Metab 67:17–24
Visser TJ 1990 Importance of deiodination and conjugation in the hepatic metabolism of thyroid hormone. In: Greer MA, ed. The thyroid gland. New York: Raven Press, Ltd.; 255–282
Findlay KA, Kaptein E, Visser TJ, Burchell B 2000 Characterization of the uridine diphosphate-glucuronosyltransferase-catalyzing thyroid hormone glucuronidation in man. J Clin Endocrinol Metab 85:2879–2883
Hood A, Klaassen CD 2000 Differential effects of microsomal enzyme inducers on in vitro thyroxine (T(4)) and triiodothyronine (T(3)) glucuronidation. Toxicol Sci 55:78–84
Maglich JM, Watson J, McMillen PJ, Goodwin B, Willson TM, Moore JT 2004 The nuclear receptor CAR is a regulator of thyroid hormone metabolism during caloric restriction. J Biol Chem 279:19832–19838
McClain RM, Posch RC, Bosakowski T, Armstrong JM 1988 Studies on the mode of action for thyroid gland tumor promotion in rats by phenobarbital. Toxicol Appl Pharmacol 94:254–265
Suzuki H, Willingham MC, Cheng SY 2002 Mice with a mutation in the thyroid hormone receptor beta gene spontaneously develop thyroid carcinoma: a mouse model of thyroid carcinogenesis. Thyroid 12:963–969
Curran PG, DeGroot LJ 1991 The effect of hepatic enzyme-inducing drugs on thyroid hormones and the thyroid gland. Endocr Rev 12:135–150
Hegedus L, Hansen JM, Luhdorf K, Perrild H, Feldt-Rasmussen U, Kampmann JP 1985 Increased frequency of goitre in epileptic patients on long-term phenytoin or carbamazipine treatment. Clin Endocrinol 23:423–429
Moore LB, Parks DJ, Jones SA, Bledsoe RK, Consler TG, Stimmel JB, Goodwin B, Liddle C, Blanchard SG, Willson TM, Collins JL, Kliewer SA 2000 Orphan nuclear receptors constitutive androstane receptor and pregnane X receptor share xenobiotic and steroid ligands. J Biol Chem 275:15122–15127
Maglich JM, Stoltz CM, Goodwin B, Hawkins-Brown D, Moore JT, Kliewer SA 2002 Nuclear pregnane X receptor and constitutive androstane receptor regulate overlapping but distinct sets of genes involved in xenobiotic detoxification. Mol Pharmacol 62:638–646
Xie W, Barwick JL, Simon CM, Pierce AM, Safe S, Blumberg B, Guzelian PS, Evans RM 2000 Reciprocal activation of xenobiotic response genes by nuclear receptors SXR/PXR and CAR. Genes Dev 14:3014–3023
Wang H, Faucette S, Moore R, Sueyoshi T, Negishi M, LeCluyse E 2004 Human constitutive androstane receptor mediates induction of CYP2B6 gene expression by phenytoin. J Biol Chem 279:29295–29301(Ann Marie Zavacki and P. )