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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL
Pharmacogenetics Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina
Received for publication
August 21, 2006
Accepted
October 17, 2006.
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Abstract |
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; Maglich et al., 2004; Qatanani et al., 2005). Thyroid hormone has a well established role in liver regeneration and energy usage and regulates genes involved in gluconeogenesis and fatty acid oxidation (Giralt et al., 1991; Park et al., 1997; Jansen et al., 2000; Boelaert and Franklyn, 2005). Recently it was reported that mice after partial hepatectomy (PH) or mice treated with the PB-like inducer TCPOBOP (a potent CAR activator) regulate the same subset of immediate early genes in their respective livers involved in suppression of apoptosis and alteration of signal transduction (Locker et al., 2003). Based on the similarity between TCPOBOP response and liver regeneration, we performed microarray analysis to examine whether CAR regulates gene expression in the liver after PH using wild-type and CAR knockout (KO) mice. From these arrays, we identified the thyroid hormone-metabolizing enzyme Dio1 as a CAR-regulated gene in the liver after PH. Whereas CAR has been suggested to regulate thyroid hormone, there have been no reports concerning the potential for CAR regulation of the biosynthesis of thyroid hormones. Therefore, we examined whether CAR regulates the synthesis of thyroid hormone in the liver after PH.
PB elicits pleiotropic effects on liver functions, including drug metabolism, energy metabolism, and cell growth by regulating hepatic gene expression (Honkakoski and Negishi, 1998). Of the genes identified on these arrays as regulated by PB, roughly half are regulated by CAR in the liver of PB-treated mice, including various cytochromes P450 (P450s), phosphoenolpyruvate carboxykinase, and carnitine palmitoyl transferase 1 (CPT-1) (Ueda et al., 2002). CAR is a member of the NR1I subfamily of nuclear hormone receptors (Laudet et al., 1999) and was originally found to regulate the CYP2B family of drug-metabolizing enzymes (Honkakoski et al., 1998; Sueyoshi et al., 1999). The CAR KO mouse has confirmed that CAR is the primary regulator of this subfamily of P450s in the presence of CAR activators such as PB or PB-like inducers like TCPOBOP (Wei et al., 2000; Ueda et al., 2002). In addition to P450s, CAR is also known to regulate organic anion transporters, such as organic anion transporting polypeptide 2 and multidrug resistance gene 3 (MDR3), which aid in the removal of bile salts, bilirubin, and hormones, including thyroid hormone, from the blood (Friesema et al., 1999; Guo et al., 2003; Saini et al., 2004; Wong et al., 2005). Recent reports also suggest that CAR is involved in gluconeogenesis through the regulation of genes such as phosphoenolpyruvate carboxykinase (Kodama et al., 2004). Studies have also linked CAR to tumor development in the liver after chronic PB exposure, suggesting a role for the receptor in the promotion of hepatocyte proliferation (Bouzahzah et al., 1998; Yamamoto et al., 2004; Huang et al., 2005).
The deiodinases are the enzymes that convert thyroxine (3–5-3'-5'-tetraiodothyronine, T4) into the various forms of thyroid hormone. Three isoenzymes are known: type 1 deiodinase (D1, gene name Dio1), type 2 (D2, Dio2), and type 3 (D3, Dio3) (Kohrle, 2000). D1 and D2 are responsible for the conversion of T4 into 3–3'-5-triiodothyronine (T3) by outer ring deiodination where the 5' iodine is removed. D1 and D3 catalyze the conversion of T4 into the lesser active 3–3'-5'-triiodothyronine (reverse T3, rT3) through inner ring deiodination, which removes the 5 position iodine. Clearance of thyroid hormone is accomplished through processes including sulfation and glucuronidation for excretion through the bile or urine (Visser, 1994; Visser et al., 1998). Thus, a balance between synthesis and clearance can control the level of thyroid hormone in the serum.
We observed that PH elicits a large increase in the level of rT3 in the serum but no significant change in the levels of total or free T3. A significant down-regulation of D1 activity correlates with the increase of rT3 after PH. Treatment with PB after PH did not affect the level of total T4 but significantly increased the expression and activity of D1 and returned the serum content of rT3 to nearly normal levels in wild-type but not in CAR KO mice. We present experimental results consistent with the hypothesis that CAR and PB activate the Dio1 gene to alter rT3 level in the regenerating liver, modulating the effect of thyroid hormone regulating its target genes.
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Materials and Methods |
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Animal Surgery and Treatments. Female wild-type and CAR KO mice on the C3H/HeNCrIBR genetic background (age 6–10 weeks) were used for these studies. All of the animal handling was performed in accordance with institution ethical guidelines with regard to humane care and treatment. Animals were fed standard mouse chow and allowed free access to food and water. Animals were maintained in a temperature-controlled environment with 12-h light and dark cycles. Mice were anesthetized by vapor inhalation of isoflurane (AErrane, Baxter Pharmaceutical Products, Deerfield, IL) and then underwent PH according to the Higgins and Anderson method (Higgins and Anderson, 1931). Mice were allowed to recover from anesthesia for 24 h, injected i.p. with 100 mg/kg PB or phosphate-buffered saline, and euthanized 12 h postinjection. This experimental design was used for subsequent PH/PB studies to reproduce the microarray data and for consistency. Serum and liver tissue were harvested and analyzed. The same region of the liver was isolated from the sham-treated mice compared with PH mice. For rT3 experiments, female wild-type and CAR KO mice (age 6–10 weeks) were treated with 100 µg/kg rT3 or phosphate-buffered saline via single i.p. injection. After 36 h, mice were euthanized, and serum and liver tissue were isolated and analyzed. The treatment time of 36 h for rT3 injection experiments was chosen to reflect the time frame of the PH/PB studies in which mice underwent surgery and were allowed to recover for 24 h, injected with PB, and euthanized 12 h later (36 h total).
RNA Preparation, Reverse Transcription, and Real-Time Polymerase Chain Reaction. Total RNA was isolated from a small portion (100 mg) of tissue using TRIzol reagent (Invitrogen, Carlsbad, CA) according to manufacturer protocol. RNA was quantitated, and 2 µg was used for reverse transcription-polymerase chain reaction (PCR). Reverse transcription was performed using the High Capacity cDNA Archive Kit (Applied Biosystems, Foster City, CA) according to the manufacturer protocol. Real-time PCR was performed using TaqMan PCR Master Mix (Applied Biosystems) with TaqMan primer-probe sets. TaqMan primer-probe sets for D1 (assay ID: Mm00839358_m1), tyrosine aminotransferase (TAT) (assay ID: Mm00455392_m1), basic transcription element-binding protein (BTEB) (assay ID: Mm00495172_m1), Cpt-1 (custom, forward: 5'-CCCTGGGCATGATTGCAA-3'; reverse: 5'-AAGAGGACGCCACTCACGAT-3'; probe: 5'-6FAM-ACCCTAGACACCACTGGCCGCATGTTAMRA-3'), and Spot14 (assay ID: Mm01273967_m1) were analyzed as multiplex PCR using glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as endogenous control (Rodent GAPDH Control Reagent Kit; Applied Biosystems). Thermocycling reactions were carried out using the ABI Prism 7900 Sequence Detection System. Data were analyzed using S.D.S. 2.2.1 (Applied Biosystems), and values for target genes were corrected for endogenous control (GAPDH). A previous report suggested that GAPDH is significantly regulated by hepatectomy (Iwasaki et al., 2004); however, when GAPDH levels were presented in graphical format, no significant alterations in response to PB or hepatectomy were observed (data not shown).
Microarray Analysis. RNA to be used in microarray analysis was isolated as described and then further purified using RNEasy Midi Kit (Qiagen, Valencia, CA). Gene expression analysis was conducted using Agilent Mouse Oligo arrays (Agilent Technologies, Palo Alto, CA). Total RNA was amplified using the Agilent Low RNA Input Fluorescent Linear Amplification Kit protocol. Starting with 500 ng of total RNA, Cy3- or Cy5-labeled cRNA was produced according to manufacturer's protocol. For each two-color comparison, 750 ng of each Cy3- and Cy5-labeled cRNA was mixed and fragmented using the Agilent in situ hybridization kit protocol. Hybridizations were performed for 17 h in a rotating hybridization oven using the Agilent 60-mer oligo microarray processing protocol. Slides were washed as indicated in this protocol and then scanned with an Agilent Scanner. Data were obtained using the Agilent Feature Extraction software (version 7.1) using defaults for all of the parameters. Hybridizations, scanning, and data analysis were performed by the National Institute of Environmental Health Sciences Microarray Group (http://dir.niehs.nih.gov/microarray/).
Serum Biochemistry. To isolate serum, blood was collected and allowed to coagulate at room temperature for 25 min. Serum was isolated by centrifugation in Microtainer Serum Separation Tubes (Becton Dickson, Franklin Lakes, NJ) according to manufacturer's protocol and analyzed via radioimmunoassay and enzyme-linked immunosorbent assay (ELISA). Serum analysis was performed by Dr. Ralph Wilson at the National Institute of Environmental Health Sciences. Levels of total T4, total T3 (Diagnostic Products Corp., Los Angeles, CA), thyroid-stimulating hormone (TSH) (Amersham Life Science, Buckinghamshire, England), and rT3 (Animal Laboratory Products Company, Windham, NH) were determined using radioimmunoassay according to the manufacturer protocol. In brief, samples or calibrator samples were added to tubes coated with total T4 or total T3 antibody. Labeled (125I) total T4 or total T3 (1 ml) was added to each tube and gently vortexed. Samples were incubated at 37°C (total T4, 1 h; total T3, 2 h). Liquid was removed from each tube, and tubes were counted for 1 min in a gamma counter (Cobra Quantum Gamma Counter, PerkinElmer Life and Analytical Sciences, Boston, MA). Amounts of total T4 or total T3 were calculated by determining the percentage bound to the antibody in each tube (net counts/net max binding counts) compared with standard curve samples. The rT3 assay was performed in a similar manner with a few variations. The rT3 antibody was added to each tube, and samples with antibody were incubated for 20 h at room temperature. Antibody bound to antigen was precipitated out of solution using secondary antibody conjugated to polyethylene glycol resin and centrifugation. The supernatant was removed, and the radioactivity in the tube was counted. Levels of free T3 were determined by colorimetric ELISA assay according to the manufacturer protocol (Animal Laboratory Products Company). In brief, 50 µl of serum was mixed with 100 µl of conjugated hormone competitor. Samples were incubated for 1 h at room temperature and then washed three times with distilled water. Samples were visualized by colorimetric assay by addition of hydrogen peroxide/tetramethylbenzidine and incubated for 20 min at room temperature in the dark. Visualization was stopped by addition of 3N HCl and mixed thoroughly. Absorbance was measured at 450 nm within 30 min of adding HCl. Measurements for all of the assays were performed in triplicate. To measure TSH, standard curve samples were diluted according to manufacturer instructions. Equal amounts of unknown sample and antiserum (100 µl) were pipetted into tubes along with 100 µl of tracer. Tubes were vortexed, capped tightly, and allowed to incubate at room temperature for 24 h. After incubation, 400 µl of second antibody reagent (from kit) was added to tubes and vortexed to mix. Reactions were incubated at room temperature for another 10 min. Samples were centrifuged for 10 min at 1500g at 4°C. The resulting supernatant was removed, and tubes were inverted to allow excess liquid to drain. Samples were then counted on a gamma counter for 1 min/sample.
Deiodinase Activity Assay. Whole liver microsomes were isolated from mouse tissue (approximately 800 mg) by homogenization in 30 ml of 0.25 M sucrose, 50 mM Tris-HCl (pH 7.5), and 1 mM EDTA. Homogenate was centrifuged at 15,000g for 20 min at 4°C. Supernatant was transferred to a fresh tube and centrifuged again at 100,000g for 90 min at 4°C. Resulting pellet was washed three times with 15 ml of 50 mM Tris-HCl (pH 7.5) and 1 mM EDTA, resuspended in 3 ml of wash buffer, aliquoted, and stored at –80°C until use. Protein concentration was determined by Bradford Assay (BioRad, Hercules, CA). Activity assay was performed by mixing 300 µg of whole liver microsomes with 1 µCi of [125I]T4 (GE Healthcare, Piscataway, NJ) to a final volume of 300 µl in Tris-EDTA buffer and 25 mM DTT and incubating for 1 h at 37°C. Cation exchange columns (SP Sepharose, Amersham Biosciences) were prepared with 2 ml of 50% slurry resin. Column was washed with 10 column volumes of Tris-EDTA buffer. The entire volume of the microsome reaction was applied to the column and allowed to drain by gravity, and the flow-through was collected. Activity was measured on a Cobra Quantum Gamma Counter (PerkinElmer Life and Analytical Sciences). Activity was calculated as picomole of 125I liberated per milligram of microsomal protein per hour.
Statistical Analyses. Statistical analysis was performed as oneway analysis of variance of the values using JMP 5.0.1 (SAS, Cary, NC). Error bars are represented as standard errors. Designations for the level of confidence are noted in the legend for each figure.
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Results |
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Decrease in D1 Activity after PH. The levels of thyroid hormone can be regulated by three types of deiodinases: D1, D2, and D3. We first examined expression of all three in the liver in response to PH and PB using real-time PCR. Consistent with a previous report showing that D2 is not expressed in the liver (Connor et al., 2005), we did not detect D2 mRNA in our experiments (data not shown). D3 expression in the liver was nearly undetectable, which is also in agreement with other reports and was not regulated by CAR or hepatectomy (data not shown). In sharp contrast, D1 mRNA was highly expressed in the liver and was significantly repressed after PH in both the wild-type and CAR KO mice by approximately 80%, suggesting a CAR-independent mechanism of repression (Fig. 2A). Treatment with PB reversed this repression of D1 in only wild-type mice, indicating that this effect is CAR-dependent.
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Role of rT3 in Expression of Thyroid Hormone-Targeted Genes after PH. Although the level of total and free T3 remained unchanged, rT3 was altered by PH and PB treatment. Therefore, we examined whether the alterations of rT3 correlated with the expression of genes that are regulated by thyroid hormone. For this purpose, the expression of two known thyroid hormone-regulated genes, BTEB and TAT, were measured in the liver after PH. As shown in Fig. 3, A and B, BTEB and TAT were both significantly down-regulated in both wild-type and CAR KO mice after PH. BTEB was reduced by 60% in both mouse types, and TAT was reduced by 55% in both mouse types. Similar to D1 activity and correlating with the decrease of rT3, both BTEB and TAT were significantly up-regulated by PB after PH, but only in wild-type mice. These results indicated that the high levels of rT3 are associated with the repression of these genes.
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We tested whether rT3 could repress the expression of T3-regulated genes in liver in vivo. Injection of 100 µg/kg rT3 via i.p. injection resulted in an rT3 level of approximately 75 ng/dl, which is comparable with the approximately 100 ng/dl level seen in both wild-type and CAR KO mice after PH and significantly higher than the rT3 level seen in sham mice. As shown in Fig. 4, A, B, and D, mice treated with a single injection of rT3 exhibited significantly reduced mRNA expression of TAT, BTEB, and CPT-1, all known thyroid hormone-regulated genes. All of these mRNA were down-regulated by at least 40% after treatment with rT3 in both wild-type and CAR KO mice. Interestingly, D1 was not repressed by injection of rT3, even though D1 is regulated by T3 (Fig. 4C). These findings clearly showed that rT3 can regulate the expression of some thyroid hormone target genes, such as Tat, Bteb, and Cpt-1, but not Dio1.
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). It is also well established that thyroid hormone can increase the growth of the liver after PH because injection of T3 into mice after PH increases the rate of liver regeneration (Moro et al., 2004; Alisi et al., 2005). It does not appear that CAR directly regulates the levels of T3, although ability of CAR to regulate the levels of rT3 may be akin to regulation of T3 itself. We treated wild-type and CAR KO mice with a single injection of PB after PH and observed significantly increased liver weight gain only in wild-type mice, suggesting that PB can positively influence the regenerative rate of the liver through activation of CAR (Fig. 5). This result is consistent with a previous report suggesting CAR activation plays a positive role in bile acid-induced liver regeneration (Huang et al., 2006).
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Discussion |
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Reverse T3 has very low hormone activity, and reports have begun to suggest that rT3 may decrease T3 activity by competing with T3 for binding to lipids, transporters, and receptors, affecting the activity of hormone in cells (Benvenga et al., 1993; Mitchell et al., 1999). That rT3 may function as an inhibitor of T3 offers an interesting new regulatory pathway in the thyroid hormone signaling cascade. In support of this hypothesis, injection of rT3 into mice revealed that rT3 is capable of significantly decreasing the expression of multiple T3-regulated genes (Bteb, Tat, and Cpt-1) in the liver.
T4 is converted to rT3 by the activity of D3 (reviewed in Kohrle, 2000). Thus, the extremely low hepatic expression of D3 means that the liver is not the primary site of rT3 production. Rather, rT3 production is primarily carried out in extrahepatic tissues where D3 is highly expressed. In our studies, we observed that the liver is sensitive to circulating rT3 because the injection of exogenous rT3 can repress T3-targeted genes. To counter the repressive activity of rT3, the liver uses D1 to convert rT3 to T2 for excretion. In regenerating liver, down-regulation of D1 may decrease conversion of rT3 to T2, disrupting this rT3 clearance mechanism, allowing rT3 to accumulate in the circulation and resulting in inhibition of hepatic thyroid hormone responsive gene expression. PB treatment increases the D1 activity in the CAR-dependent manner, reopening the clearance of rT3 by converting it to T2 and decreasing rT3 level. This hypothesis is supported by the fact that the level of D1 activity is inversely related to the level of rT3 as shown in the recently described Dio1 KO mouse. This mouse exhibited a very similar phenotype as observed in our work: abrogated D1 activity and an increased level of rT3 in the circulation (Schneider et al., 2006). In our study, the CAR-dependent increase in D1 activity was higher than that of D1 mRNA in the PB-treated PH livers when corrected to wild-type sham vehicle-treated control values. This difference of induction is intriguing and raises the question that post-transcriptional regulation such as translational regulation, protein stabilization and degradation, and enzyme activation may also be involved in the PB induction of D1 enzyme. These post-transcriptional events would also be regulated by CAR (because these PB effects are absent in the CAR KO mouse) and present interesting subjects for future investigations.
Both wild-type and CAR KO mice exhibit elevated rT3 and down-regulated D1 after PH, meaning that these effects do not involve CAR. Interestingly, rT3 is unable to inhibit expression of D1, even though D1 is known to be regulated by T3 (Toyoda et al., 1992). This suggests that the increase in rT3 seen after PH is not responsible for the decrease in D1 expression. It is unknown at this point what signaling pathways evoke this D1 repression, although recent reports suggest that cytokines such as interleukin 6 may be involved in the repression of D1 in the liver during nonthyroidal illness, a condition in which rT3 is also elevated (Yu and Koenig, 2006). It is entirely possible that such a signal is at work after PH. The lack of inhibition of D1 by rT3 also suggests that rT3 does not affect all of the T3-regulated genes in the same manner, and more work is needed to determine how this occurs.
Thus, in the PH model system, the decrease in D1 activity brought about by PH may adversely affect the conversion of rT3 into T2, allowing rT3 to accumulate. D1 is also responsible for the conversion of T4 into T3, but a PH-induced decrease in hepatic D1 did not significantly affect T3 levels, suggesting that the conversion of T4 into T3 is rather unaffected and that extrahepatic tissues are able to compensate for the lost T3 production in the liver through the activity of D2. This situation is also in agreement with the Dio1 KO mouse, which also showed no significant difference in T3 level between wild-type and KO mice (Schneider et al., 2006).
Total T4 levels were slightly decreased after PH, regardless of CAR status. This effect is possibly linked to the increase in rT3. One function of rT3 is to facilitate the removal of excess T4. Increased rT3 after PH indicates that removal of rT3 is not functioning properly, thus prompting the decreased production of T4 by the thyroid gland. Qatanani et al. (2005) suggested that a decrease of T4 level in response to PB results in a hypothyroid state leading to an increase of TSH secretion by the pituitary gland. In our studies, however, no alteration in the level of TSH was observed after PH or PB treatment. In addition, PB treatment alone or after PH did not affect the level of total T4, which is inconsistent with previous reports (Maglich et al., 2004; Qatanani et al., 2005). Such a difference may be because the mice used in our studies were bred on the C3H background and not on the C57BL/6 background used in other studies. There are many known differences between these two mouse strains, especially concerning the promotion of hepatocyte proliferation and tumor formation (Diwan et al., 1986). The difference in response to PB with regard to thyroid hormone may be yet another facet of this strain difference.
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Footnotes |
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: PB, phenobarbital; CAR, constitutive active/androstane receptor; PH, partial hepatectomy; TCPOBOP, 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene; KO, knockout; P450, cytochrome P450; CPT-1, carnitine palmitoyl transferase 1; T4, tetraiodothyronine; D1, type 1 deiodinase; D2, type 2 deiodinase; D3, type 3 deiodinase; T3, triiodothyronine; rT3, reverse triiodothyronine; PCR, polymerase chain reaction; TAT, tyrosine aminotransferase; BTEB, basic transcription element binding protein; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; ELISA, enzyme-linked immunosorbent assay; TSH, thyroid-stimulating hormone.
Address correspondence to: Dr. Masahiko Negishi, Pharmacogenetics Section, Laboratory of Reproductive and Developmental Toxicology, MD: E4-07, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709. E-mail: negishi{at}niehs.nih.gov
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References |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
Alisi A, Demori I, Spagnuolo S, Pierantozzi E, Fugassa E, and Leoni S (2005) Thyroid status affects rat liver regeneration after partial hepatectomy by regulating cell cycle and apoptosis. Cell Physiol Biochem 15: 69–76.[CrossRef][Medline]
Benvenga S, Cahnmann HJ, and Robbins J (1993) Characterization of thyroid hormone binding to apolipoprotein-E: localization of the binding site in the exon 3-coded domain. Endocrinology 133: 1300–1305.
Boelaert K and Franklyn JA (2005) Thyroid hormone in health and disease. J Endocrinol 187: 1–15.
Bouzahzah B, Pavier D, and Barbason H (1998) The role of corticoids, adrenalectomy, phenobarbital and pentobarbital in the promotion of DEN-hepatocarcinogenesis. In Vivo 12: 411–419.[Medline]
Connor EE, Laiakis EC, Fernandes VM, Williams JL, and Capuco AV (2005) Molecular cloning, expression and radiation hybrid mapping of the bovine deiodinase type II (DIO2) and deiodinase type III (DIO3) genes. Anim Genet 36: 240–243.[CrossRef][Medline]
Diwan BA, Rice JM, Ohshima M, and Ward JM (1986) Interstrain differences in susceptibility to liver carcinogenesis initiated by N-nitrosodiethylamine and its promotion by phenobarbital in C57BL/6NCr, C3H/HeNCrMTV- and DBA/2NCr mice. Carcinogenesis 7: 215–220.
Friesema EC, Docter R, Moerings EP, Stieger B, Hagenbuch B, Meier PJ, Krenning EP, Hennemann G, and Visser TJ (1999) Identification of thyroid hormone transporters. Biochem Biophys Res Commun 254: 497–501.[CrossRef][Medline]
Giralt M, Park EA, Gurney AL, Liu JS, Hakimi P, and Hanson RW (1991) Identification of a thyroid hormone response element in the phosphoenolpyruvate carboxykinase (GTP) gene. Evidence for synergistic interaction between thyroid hormone and cAMP cis-regulatory elements. J Biol Chem 266: 21991–21996.
Guo GL, Lambert G, Negishi M, Ward JM, Brewer HB Jr, Kliewer SA, Gonzalez FJ, and Sinal CJ (2003) Complementary roles of farnesoid X receptor, pregnane X receptor, and constitutive androstane receptor in protection against bile acid toxicity. J Biol Chem 278: 45062–45071.
Higgins G and Anderson R (1931) Experimental pathology of the liver: restoration of the liver following partial hepatectomy. Arch Pathol 12: 186–202.
Honkakoski P and Negishi M (1998) Regulatory DNA elements of phenobarbital-responsive cytochrome P450 CYP2B genes. J Biochem Mol Toxicol 12: 3–9.[CrossRef][Medline]
Honkakoski P, Zelko I, Sueyoshi T, and Negishi M (1998) The nuclear orphan receptor CAR-retinoid X receptor heterodimer activates the phenobarbital-responsive enhancer module of the CYP2B gene. Mol Cell Biol 18: 5652–5658.
Huang W, Ma K, Zhang J, Qatanani M, Cuvillier J, Liu J, Dong B, Huang X, and Moore DD (2006) Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration. Science (Wash DC) 312: 233–236.
Huang W, Zhang J, Washington M, Liu J, Parant JM, Lozano G, and Moore DD (2005) Xenobiotic stress induces hepatomegaly and liver tumors via the nuclear receptor constitutive androstane receptor. Mol Endocrinol 19: 1646–1653.
Iwasaki T, Nakahama K, Nagano M, Fujioka A, Ohyanagi H, and Shigeyoshi Y (2004) A partial hepatectomy results in altered expression of clock-related and cyclic glyceraldehyde 3-phosphate dehydrogenase (GAPDH) genes. Life Sci 74: 3093–3102.[CrossRef][Medline]
Jansen MS, Cook GA, Song S, and Park EA (2000) Thyroid hormone regulates carnitine palmitoyltransferase Ialpha gene expression through elements in the promoter and first intron. J Biol Chem 275: 34989–34997.
Kodama S, Koike C, Negishi M, and Yamamoto Y (2004) Nuclear receptors CAR and PXR cross talk with FOXO1 to regulate genes that encode drug-metabolizing and gluconeogenic enzymes. Mol Cell Biol 24: 7931–7940.
Kohrle J (2000) The deiodinase family: selenoenzymes regulating thyroid hormone availability and action. Cell Mol Life Sci 57: 1853–1863.[CrossRef][Medline]
Laudet V, Auwerx J, Gustafsson J, and Wahli W (1999) A unified nomenclature system for the nuclear receptor superfamily. Cell 97: 161–163.[CrossRef][Medline]
Locker J, Tian J, Carver R, Concas D, Cossu C, Ledda-Columbano GM, and Columbano A (2003) A common set of immediate-early response genes in liver regeneration and hyperplasia. Hepatology 38: 314–325.[Medline]
Maglich JM, Watson J, McMillen PJ, Goodwin B, Willson TM, and Moore JT (2004) The nuclear receptor CAR is a regulator of thyroid hormone metabolism during caloric restriction. J Biol Chem 279: 19832–19838.
Mitchell AM, Manley SW, Rowan KA, and Mortimer RH (1999) Uptake of reverse T3 in the human choriocarcinoma cell line, JAr. Placenta 20: 65–70.[CrossRef][Medline]
Moro L, Marra E, Capuano F, and Greco M (2004) Thyroid hormone treatment of hypothyroid rats restores the regenerative capacity and the mitochondrial membrane permeability properties of the liver after partial hepatectomy. Endocrinology 145: 5121–5128.
Park EA, Song S, Olive M, and Roesler WJ (1997) CCAAT-enhancer-binding protein alpha (C/EBP alpha) is required for the thyroid hormone but not the retinoic acid induction of phosphoenolpyruvate carboxykinase (PEPCK) gene transcription. Biochem J 322: 343–349.
Qatanani M, Zhang J, and Moore DD (2005) Role of the constitutive androstane receptor in xenobiotic-induced thyroid hormone metabolism. Endocrinology 146: 995–1002.
Saini SP, Sonoda J, Xu L, Toma D, Uppal H, Mu Y, Ren S, Moore DD, Evans RM, and Xie W (2004) A novel constitutive androstane receptor-mediated and CYP3A-independent pathway of bile acid detoxification. Mol Pharmacol 65: 292–300.
Schneider MJ, Fiering SN, Thai B, Wu SY, St Germain E, Parlow AF, St Germain DL, and Galton VA (2006) Targeted disruption of the type 1 selenodeiodinase gene (Dio1) results in marked changes in thyroid hormone economy in mice. Endocrinology 147: 580–589.[CrossRef][Medline]
Sueyoshi T, Kawamoto T, Zelko I, Honkakoski P, and Negishi M (1999) The repressed nuclear receptor CAR responds to phenobarbital in activating the human CYP2B6 gene. J Biol Chem 274: 6043–6046.
Toyoda N, Nishikawa M, Mori Y, Gondou A, Ogawa Y, Yonemoto T, Yoshimura M, Masaki H, and Inada M (1992) Thyrotropin and triiodothyronine regulate iodothyronine 5'-deiodinase messenger ribonucleic acid levels in FRTL-5 rat thyroid cells. Endocrinology 131: 389–394.
Ueda A, Hamadeh HK, Webb HK, Yamamoto Y, Sueyoshi T, Afshari CA, Lehmann JM, and Negishi M (2002) Diverse roles of the nuclear orphan receptor CAR in regulating hepatic genes in response to phenobarbital. Mol Pharmacol 61: 1–6.
Visser TJ (1994) Role of sulfation in thyroid hormone metabolism. Chem Biol Interact 92: 293–303.[CrossRef][Medline]
Visser TJ, Kaptein E, Glatt H, Bartsch I, Hagen M, and Coughtrie MW (1998) Characterization of thyroid hormone sulfotransferases. Chem Biol Interact 109: 279–291.[CrossRef][Medline]
Wei P, Zhang J, Egan-Hafley M, Liang S, and Moore DD (2000) The nuclear receptor CAR mediates specific xenobiotic induction of drug metabolism. Nature (Lond) 407: 920–923.[CrossRef][Medline]
Wong H, Lehman-McKeeman LD, Grubb MF, Grossman SJ, Bhaskaran VM, Solon EG, Shen HS, Gerson RJ, Car BD, Zhao B, et al. (2005) Increased hepatobiliary clearance of unconjugated thyroxine determines DMP 904-induced alterations in thyroid hormone homeostasis in rats. Toxicol Sci 84: 232–242.
Yamamoto Y, Moore R, Goldsworthy TL, Negishi M, and Maronpot RR (2004) The orphan nuclear receptor constitutive active/androstane receptor is essential for liver tumor promotion by phenobarbital in mice. Cancer Res 64: 7197–7200.
Yu J and Koenig RJ (2006) Induction of type 1 iodothyronine deiodinase to prevent the nonthyroidal illness syndrome in mice. Endocrinology 147: 3580–3585.
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  M. H. A. Kester, M. J. M. Toussaint, C. A. Punt, R. Matondo, A. M. Aarnio, V. M. Darras, M. E. Everts, A. de Bruin, and T. J. Visser Large Induction of Type III Deiodinase Expression After Partial Hepatectomy in the Regenerating Mouse and Rat Liver Endocrinology, January 1, 2009; 150(1): 540 - 545. [Abstract] [Full Text] [PDF]
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 D. T. Szabo, V. M. Richardson, D. G. Ross, J. J. Diliberto, P. R. S. Kodavanti, and L. S. Birnbaum Effects of Perinatal PBDE Exposure on Hepatic Phase I, Phase II, Phase III, and Deiodinase 1 Gene Expression Involved in Thyroid Hormone Metabolism in Male Rat Pups Toxicol. Sci., January 1, 2009; 107(1): 27 - 39. [Abstract] [Full Text] [PDF]
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 T. Sueyoshi, R. Moore, J. Sugatani, Y. Matsumura, and M. Negishi PPP1R16A, The Membrane Subunit of Protein Phosphatase 1{beta}, Signals Nuclear Translocation of the Nuclear Receptor Constitutive Active/Androstane Receptor Mol. Pharmacol., April 1, 2008; 73(4): 1113 - 1121. [Abstract] [Full Text] [PDF]
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