Identification of Thyroid Hormone Transporters in Humans: Different Molecules Are Involved in a Tissue-Specific Manner*,†

Fujiwara, Koh; Adachi, Hisanobu; Nishio, Takeshi; Unno, Michiaki; Tokui, Taro; Okabe, Mitsunori; Onogawa, Tohru; Suzuki, Takehiro; Asano, Naoki; Tanemoto, Masayuki; Seki, Makoto; Shiiba, Kenichi; Suzuki, Masanori; Kondo, Yoshiaki; Nunoki, Kazuo; Shimosegawa, Tooru; Iinuma, Kazuie; Ito, Sadayoshi; Matsuno, Seiki; Abe, Takaaki

doi:10.1210/endo.142.5.8115

Cited by 139 publications

(47 citation statements)

References 43 publications

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“…The OATPs are involved in transporting organic anions such as steroid conjugates, bile salts, drugs and thyroid hormones into the cells. Some OATPs show preference for the transport of certain substances and are predominantly expressed in a particular tissue, rendering their action more specific (Fujiwara et al , 2001). …”

Section: Thyroid Hormone Receptors and Transporters In Testicular mentioning

confidence: 99%

The role of thyroid hormone in testicular development and function

Wagner¹,

Wajner²,

Maia³

2008

Journal of Endocrinology

236

151

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Thyroid hormone is a critical regulator of growth, development, and metabolism in virtually all tissues, and altered thyroid status affects many organs and systems. Although for many years testis has been regarded as a thyroid hormone unresponsive organ, it is now evident that thyroid hormone plays an important role in testicular development and function. A considerable amount of data show that thyroid hormone influences steroidogenesis as well as spermatogenesis. The involvement of tri-iodothyronine (T 3 ) in the control of Sertoli cell proliferation and functional maturation is widely accepted, as well as its role in postnatal Leydig cell differentiation and steroidogenesis. The presence of thyroid hormone receptors in testicular cells throughout development and in adulthood implies that T 3 may act directly on these cells to bring about its effects. Several recent studies have employed different methodologies and techniques in an attempt to understand the mechanisms underlying thyroid hormone effects on testicular cells. The current review aims at presenting an updated picture of the recent advances made regarding the role of thyroid hormones in male gonadal function.

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Section: Thyroid Hormone Receptors and Transporters In Testicular mentioning

confidence: 99%

The role of thyroid hormone in testicular development and function

Wagner¹,

Wajner²,

Maia³

2008

Journal of Endocrinology

236

151

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“…OATP4C1 and rat Oatp4c1 also have a moderate sequence homology to other OATP family. The overall amino acid sequence identities of human OATP4C1 with other human OATPs were 44.2% for human gonad-specific transporter (GST) (9) and 40.4% for OATP-E (22). Those of rat Oatp4c1 with other rat oatp family were 43.2% for rat oatp-E (22) and 36.4% for GST1 (9).…”

Section: Isolation and Structural Analysis Of Human Oatp4c1 And Rat Omentioning

confidence: 99%

Isolation and characterization of a digoxin transporter and its rat homologue expressed in the kidney

Mikkaichi

Suzuki

Onogawa

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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257

242

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Digoxin, which is one of the most commonly prescribed drugs for the treatment of heart failure, is mainly eliminated from the circulation by the kidney. P-glycoprotein is well characterized as a digoxin pump at the apical membrane of the nephron. However, little is known about the transport mechanism at the basolateral membrane. We have isolated an organic anion transporter (OATP4C1) from human kidney. Human OATP4C1 is the first member of the organic anion transporting polypeptide (OATP) family expressed in human kidney. The isolated cDNA encodes a polypeptide of 724 aa with 12 transmembrane domains. The genomic organization consists of 13 exons located on chromosome 5q21. Its rat counterpart, Oatp4c1, is also isolated from rat kidney. Human OATP4C1 transports cardiac glycosides (digoxin, K m ‫؍‬ 7.8 M and ouabain, K m ‫؍‬ 0.38 M), thyroid hormone (triiodothyronine, Km ‫؍‬ 5.9 M and thyroxine), cAMP, and methotrexate in a sodiumindependent manner. Rat Oatp4c1 also transports digoxin (K m ‫؍‬ 8.0 M) and triiodothyronine (Km ‫؍‬ 1.9 M). Immunohistochemical analysis reveals that rat Oatp4c1 protein is localized at the basolateral membrane of the proximal tubule cell in the kidney. These data suggest that human OATP4C1͞rat Oatp4c1 might be a first step of the transport pathway of digoxin and various compounds into urine in the kidney.

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“…To exert their physiological effects, the ligands of nuclear receptors need to enter their target cells and transport proteins play a role during this process. For instance, the pregnane X receptor (PXR) ligand rifampicin [15,16] and the farnesoid X receptor (FXR) ligand cholic acid [17,18] are transported by OATP1B1 and 1B3; the thyroid hormones triiodothyronine (T 3 ) and L-thyroxine (T 4 ) are transported by OATP1 and OATP4 family members [4,19-23]. Besides being transported directly, interactions of nuclear receptor ligands with transporters could result in unexpected potentially adverse effects.…”

Section: Introductionmentioning

confidence: 99%

Identification, Ki determination and CoMFA analysis of nuclear receptor ligands as competitive inhibitors of OATP1B1-mediated estradiol-17β-glucuronide transport

Gui

Wahlgren

Lushington

et al. 2009

Pharmacological Research

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Evidence shows that drug-drug interactions can occur at the level of drug transporters such as the organic anion transporting polypeptides (OATPs), a group of membrane solute carriers that mediate the sodium-independent transport of a wide range of amphipathic organic compounds. The polyspecific OATP1B1 is exclusively expressed at the basolateral membrane of hepatocytes and mediates uptake of amphipathic organic compounds from blood into hepatocytes. Nuclear receptors are ligand-activated transcription factors that play an important role in xenobiotic disposition and human diseases. Quite a few nuclear receptor ligands interact with transport proteins.A high-resolution three-dimensional structure is critical to understand the polyspecificity of OATP1B1 to predict and prevent adverse drug-drug interactions. Unfortunately there are no crystal structures of OATPs/Oatps available to date. Therefore, in this study we attempted to elucidate the characteristics of the substrate binding site of OATP1B1 based on small molecules interacting with it. First, we identified inhibitors of the OATP1B1 model substrate estradiol-17β-glucuronide from about forty nuclear receptor ligands. Among them, GW1929, paclitaxel and troglitazone were strong inhibitors, while 5α-androstane, 5α-androstane-3β, 17β-diol-17-hexahydrobenzoate and estradiol-3-benzoate were weak inhibitors. Then, we selected 25 compounds and performed inhibition kinetic studies to identify competitive inhibitors and determine their K i values which ranged from submicromolar to submillimolar. Finally, we performed CoMFA analysis on the identified competitive inhibitors. The CoMFA results indicate that the substrate binding site of OATP1B1 consists of a large hydrophobic middle part with basic residues at both ends that could be very important for substrate binding.

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Identification of Thyroid Hormone Transporters in Humans: Different Molecules Are Involved in a Tissue-Specific Manner*,†

Cited by 139 publications

References 43 publications

The role of thyroid hormone in testicular development and function

The role of thyroid hormone in testicular development and function

Isolation and characterization of a digoxin transporter and its rat homologue expressed in the kidney

Identification, Ki determination and CoMFA analysis of nuclear receptor ligands as competitive inhibitors of OATP1B1-mediated estradiol-17β-glucuronide transport

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