WordNet

simple and healthful and close to nature; "an organic lifestyle"
a fertilizer that is derived from animal or vegetable matter (同)organic fertilizer, organic fertiliser
being or relating to or derived from or having properties characteristic of living organisms; "organic life"; "organic growth"; "organic remains found in rock"
involving or affecting physiology or bodily organs; "an organic disease"
of or relating to foodstuff grown or raised without synthetic fertilizers or pesticides or hormones; "organic eggs"; "organic vegetables"; "organic chicken"
relating or belonging to the class of chemical compounds having a carbon basis; "hydrocarbons are organic compounds"
move something or somebody around; usually over long distances
an exchange of molecules (and their kinetic energy and momentum) across the boundary between adjacent layers of a fluid or across cell membranes
move while supporting, either in a vehicle or in ones hands or on ones body; "You must carry your camping gear"; "carry the suitcases to the car"; "This train is carrying nuclear waste"; "These pipes carry waste water into the river" (同)carry
transport commercially (同)send, ship
wind instrument whose sound is produced by means of pipes arranged in sets supplied with air from a bellows and controlled from a large complex musical keyboard (同)pipe_organ
a fully differentiated structural and functional unit in an animal that is specialized for some particular function
a government agency or instrument devoted to the performance of some specific function; "The Census Bureau is an organ of the Commerce Department"
a periodical that is published by a special interest group; "the organ of the communist party"
a long truck for carrying motor vehicles (同)car transporter
a crane for moving material with dispatch as in loading and unloading ships
a negatively charged ion

PrepTutorEJDIC

有機体の,生物の,生物から生じた / (動植物の)器官の / 有機肥料を用いる(を用いて育った)・有機的な,組織的な,系統的な・有機質の
(ある場所からある場所へ)…‘を'『輸送する』,運搬する《+名+from+名+to+名》 / 《文》《受動態で》(…で)…‘を'夢中にする,有頂天にする《+名+with+名》 / 〈罪人〉‘を'流刑にする / 〈U〉輸送,運送,輸送(交通)機関(transportation) / 〈C〉(軍隊や軍需品を運ぶ)輸送船,輸送機
『オルガン』,パイプオルガン(pipe organ),リードオルガン(reed organ),電子オルガン(electronic organ),手回しオルガン(barrel organ) / (動植物の)『器官』 / (政党・会社などの)機関誌,機関紙 / 《しばしば複数形で》(行動・実施などの)組織,機関
自動車運搬用大型トラック
陰イオン

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/05/21 21:24:51」(JST)

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Figure 1
Schematic representation of transmembrane proteins:
1. a membrane protein with one transmembrane domain
2. a membrane protein with three transmembrane domains
3. OAT1 is believed to have twelve transmembrane domains. ^[1]

The membrane is represented in light brown.

The organic anion transporter 1 (OAT1) also known as solute carrier family 22 member 6 (SLC22A6) is a protein that in humans is encoded by the SLC22A6 gene.^[2]^[3]^[4] It is a member of the organic anion transporter (OAT) family of proteins. OAT1 is a transmembrane protein that is expressed in the brain, the placenta, the eyes, smooth muscles, and the basolateral membrane of proximal tubular cells of the kidneys. It plays a central role in renal organic anion transport. Along with OAT3, OAT1 mediates the uptake of a wide range of relatively small and hydrophilic organic anions from plasma into the cytoplasm of the proximal tubular cells of the kidneys. From there, these substrates are transported into the lumen of the nephrons of the kidneys for excretion. OAT1 homologs have been identified in rats, mice, rabbits, pigs, flounders, and nematodes.^[5]

Function

OAT1 functions as organic anion exchanger. When the uptake of one molecule of an organic anion is transported into a cell by an OAT1 exchanger, one molecule of an endogenous dicarboxylic acid (such as glutarate, ketoglutarate, etc.) is simultaneously transported out of the cell.^[5] As a result of the constant removal of endogenous dicarboxylic acid, OAT1-positive cells are at risk of depleting their supply of dicarboxylates. Once the supply of dicarboxylates is depleted, the OAT1 transporter can no longer function.

To prevent the loss of endogenous dicarboxylates, OAT1-positive cells also express a sodium-dicarboxylate cotransporter called NaDC3. NaDC3 transports dicarboxylates back into the OAT1-positive cell. Sodium is required to drive this process. In the absence of a sodium gradient across the cell membrane, the NaDC3 cotransporter ceases to function, intra-cellular dicarboxylates are depleted, and the OAT1 transporter also grinds to a halt.^[6]

The renal organic anion transporters OAT1, OAT3, OATP4C1, MDR1, MRP2, MRP4 and URAT1 are expressed in the S2 segment of the proximal convoluted tubules of the kidneys. OAT1, OAT3, and OATP4C1 transport small organic anions from the plasma into the S2 cells. MDR1, MRP2, MRP4 and URAT1 then transports these organic anions from the cytoplasm of the S2 cells into the lumen of the proximal convoluted tubules. These organic anions are then excreted in the urine.^[5]

Substrates

Known substrates of OAT1 include para-aminohippurate (PAH), dicarboxylates, prostaglandins, cyclic nucleotides, urate, folate, diuretics, ACE inhibitors, antiviral agents, beta-lactam antibiotics, antineoplastics, mycotoxins, sulfate conjugates, glucuronide conjugates, cysteine conjugates, ochratoxin A, NSAIDs, and uremic toxins.^[5]

Antiviral induced Fanconi syndrome

Nucleoside analogs are a class of antiviral drugs that work by inhibiting viral nucleic acid synthesis. The nucleoside analogs acyclovir (ACV), zidovudine (AZT), didanosine (ddI), zalcitabine (ddC), lamivudine (3TC), stavudine (d4T), trifluridine,^[7] cidofovir, adefovir, ^[8] and tenofovir (TDF) ^[9] are substrates of the OAT1 transporter. This may result in the build up of these drugs in the proximal tubule cells. At high concentrations, these drugs inhibit DNA replication. This, in turn, may impair the function of these cells and may be the cause of antiviral induced Fanconi syndrome. The use of stavudine,^[10] didenosine, abacavir, adefovir,^[11] cidofovir ^[12] and tenofovir has been associated with Fanconi syndrome. Clinical features of tenofovir-induced Fanconi syndrome include glycosuria in the setting of normal serum glucose levels, phosphate wasting with hypophosphatemia, proteinuria (usually mild), acidosis, and hypokalemia, with or without acute renal failure.^[13]

Mitochondrial inhibition

Since nucleoside analogs can build up in OAT1-positive cells and can inhibit mitochondrial replication, these drugs may lead to the depletion of mitochondria inside renal proximal tubules. Renal biopsies have demonstrated the depletion of tubule cell mitochondria among individuals receiving antiviral therapy with tenofovir. The remaining mitochondria were enlarged and dysmorphic. ^[14] In vitro the antiviral drugs didanosine and zidovudine are more potent inhibitors of mitochondrial DNA synthesis than tenofovir (ddI > AZT > TDF).^[15] In its non-phosphorylated form, the drug acyclovir does not significantly inhibit mitochondrial DNA synthesis, unless the cell happens to be infected with a herpes virus.^{[citation needed]}

Stavudine, zidovudine and indinavir (IDV) cause a decrease in mitochondrial respiration and an increase in mitochondrial mass in fat cells. Stavudine also causes severe mitochondrial DNA depletion. Combining zidovudine with stavudine does not increase the mitochondrial toxicity compared to stavudine alone. Both of these drugs must be phosphorylated by host enzymes before they become active. Zidovudine inhibits the phosphorylation of stavudine. This might reduce the toxicity of the combination. Using indinavir in combination with the other two drugs did not increase the toxicity of the combination. Indinavir is a protease inhibitor and works by a different mechanism than the other antiviral drugs. (d4T+AZT+IDV = d4T+AZT = d4T+IDV > AZT+IDV = AZT = IDV). All three of these drugs inhibit the expression of respiratory chain subunits (cytochrome c oxidase [CytOx]2 and CytOx4) in white fat cells but not brown fat cells. ^[16] Since stavudine and zidovudine are OAT1 substrates, they may have similar effects on proximal renal tubule cells as they do on fat cells.

Lamivudine has reverse chirality compared to didanosine, stavudine, zidovudine, and natural nucleosides. Mitochondrial DNA polymerase may not recognize it as a substrate. Lamivudine is not toxic to mitochondria in vivo. ^[17] Individuals who had been taking didanosine combined with stavudine exhibited improved mitochondrial function when they switched to lamivudine combined with tenofovir.^[17]^[18]

Mitochondrial toxicity of OAT1 substrates:

in vitro:
- d4T+AZT = d4T > AZT
- ddI > AZT > TDF > ACV
in vivo
- d4T > AZT
- ddI > AZT > TDF
- d4T + ddI > 3TC + TDF

References

^ Sekine T, Cha SH, Endou H (July 2000). "The multispecific organic anion transporter (OAT) family" (PDF). Pflugers Arch. 440 (3): 337–50. doi:10.1007/s004240000297. PMID 10954321.
^ Reid G, Wolff NA, Dautzenberg FM, Burckhardt G (Jan 1999). "Cloning of a human renal p-aminohippurate transporter, hROAT1". Kidney Blood Press Res 21 (2–4): 233–7. doi:10.1159/000025863. PMID 9762842.
^ Lu R, Chan BS, Schuster VL (Mar 1999). "Cloning of the human kidney PAH transporter: narrow substrate specificity and regulation by protein kinase C". Am J Physiol 276 (2 Pt 2): F295–303. PMID 9950961.
^ "Entrez Gene: SLC22A6 solute carrier family 22 (organic anion transporter), member 6".
^ ^a ^b ^c ^d Sekine T, Miyazaki H, Endou H (February 2006). "Molecular physiology of renal organic anion transporters". Am. J. Physiol. Renal Physiol. 290 (2): F251–61. doi:10.1152/ajprenal.00439.2004. PMID 16403838.
^ Stellmer F, Keyser B, Burckhardt BC, et al. (July 2007). "3-Hydroxyglutaric acid is transported via the sodium-dependent dicarboxylate transporter NaDC3". J. Mol. Med. 85 (7): 763–70. doi:10.1007/s00109-007-0174-5. PMID 17356845.
^ Wada S, Tsuda M, Sekine T, Cha SH, Kimura M, Kanai Y, Endou H (September 2000). "Rat multispecific organic anion transporter 1 (rOAT1) transports zidovudine, acyclovir, and other antiviral nucleoside analogs". J. Pharmacol. Exp. Ther. 294 (3): 844–9. PMID 10945832.
^ Ho ES, Lin DC, Mendel DB, Cihlar T (March 2000). "Cytotoxicity of antiviral nucleotides adefovir and cidofovir is induced by the expression of human renal organic anion transporter 1". J. Am. Soc. Nephrol. 11 (3): 383–93. PMID 10703662.
^ Kohler JJ, Hosseini SH, Green E, Russ R, Santoianni R, Lewis w (April 2010). "OAT1 Knock-out Mice Define Its Role in Tenofovir Transport and Renal Proximal Tubular Mitochondrial Toxicity". FASEB J. 24 (1_MeetingAbstracts): Meeting abstracts, 1030.1.
^ Nelson M, Azwa A, Sokwala A, Harania RS, Stebbing J (2008). "Fanconi syndrome and lactic acidosis associated with stavudine and lamivudine therapy.". AIDS 22 (11): 1374–6. doi:10.1097/QAD.0b013e328303be50. PMID 18580619.
^ Ahmad M (2006). "Abacavir-induced reversible Fanconi syndrome with nephrogenic diabetes insipidus in a patient with acquired immunodeficiency syndrome.". J Postgrad Med 52 (4): 296–7. PMID 17102551.
^ Vittecoq D, Dumitrescu L, Beaufils H, Deray G (August 1997). "Fanconi syndrome associated with cidofovir therapy". Antimicrob. Agents Chemother. 41 (8): 1846. PMC 164022. PMID 9257778.
^ Atta MG, Fine DM (March 2009). "Editorial comment: tenofovir nephrotoxicity--the disconnect between clinical trials and real-world practice". AIDS Read 19 (3): 118–9. PMID 19334329.
^ Herlitz LC, Mohan S, Stokes MB, Radhakrishnan J, D'Agati VD, Markowitz GS (September 2010). "Tenofovir nephrotoxicity: acute tubular necrosis with distinctive clinical, pathological, and mitochondrial abnormalities". Kidney Int 78 (11): 1171–1177. doi:10.1038/ki.2010.318. PMID 20811330.
^ Vidal F, Domingo JC, Guallar J, et al. (November 2006). "In vitro cytotoxicity and mitochondrial toxicity of tenofovir alone and in combination with other antiretrovirals in human renal proximal tubule cells". Antimicrob. Agents Chemother. 50 (11): 3824–32. doi:10.1128/AAC.00437-06. PMC 1635212. PMID 16940060.
^ Viengchareun S, Caron M, Auclair M, et al. (2007). "Mitochondrial toxicity of indinavir, stavudine and zidovudine involves multiple cellular targets in white and brown adipocytes". Antivir. Ther. (Lond.) 12 (6): 919–29. PMID 17926646.
^ ^a ^b Honkoop P, de Man RA, Scholte HR, Zondervan PE, Van Den Berg JW, Rademakers LH, et al. (1997). "Effect of lamivudine on morphology and function of mitochondria in patients with chronic hepatitis B.". Hepatology 26 (1): 211–5. doi:10.1002/hep.510260128. PMID 9214472.
^ Ananworanich J, Nuesch R, Côté HC, Kerr SJ, Hill A, Jupimai T, et al. (2008). "Changes in metabolic toxicity after switching from stavudine/didanosine to tenofovir/lamivudine--a Staccato trial substudy.". J Antimicrob Chemother 61 (6): 1340–3. doi:10.1093/jac/dkn097. PMID 18339636.

UpToDate Contents

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English Journal

Evaluation of transporter-mediated hepatic uptake in a non-radioactive high-throughput assay: a study of kinetics, species difference and plasma protein effect.

Li L, Nouraldeen A, Wilson AG.SourceDepartments of Drug Metabolism, Pharmacokinetics, Toxicology and Pathology , Lexicon Pharmaceuticals, Inc., The Woodlands, TX , USA.
Xenobiotica; the fate of foreign compounds in biological systems.Xenobiotica.2013 Mar;43(3):253-62. doi: 10.3109/00498254.2012.713146. Epub 2012 Aug 28.
1. In this manuscript we describe a non-radioactive, high-throughput method to evaluate hepatic uptake using cryopreserved hepatocytes. We have validated the uptake of pravastatin with different amounts of hepatocytes and the impact of the oil layer used in separation. The time- and concentration-
PMID 22928802

The Potential of Sutherlandia frutescens for Herb-Drug Interaction.

Fasinu PS, Gutmann H, Schiller H, James AD, Bouic PJ, Rosenkranz B.SourceDivision of Pharmacology, Department of Medicine, University of Stellenbosch, PO Box 19063, Tygerberg, Cape Town, 7505, South Africa. 16669967@sun.ac.za.
Drug metabolism and disposition: the biological fate of chemicals.Drug Metab Dispos.2013 Feb;41(2):488-97. doi: 10.1124/dmd.112.049593. Epub 2012 Dec 3.
In Africa, Sutherlandia frutescens is a popular medicinal herb widely consumed by people living with human immunodeficiency virus/AIDS. Concomitant use with antiretroviral drugs has generated concerns of herb-drug interaction (HDI). This study investigated the inhibitory effects of the crude extract
PMID 23209194

Analysis of the repaglinide concentration increase produced by gemfibrozil and itraconazole based on the inhibition of the hepatic uptake transporter and metabolic enzymes.

Kudo T, Hisaka A, Sugiyama Y, Ito K.SourceMusashino University, Research Institute of Pharmaceutical Sciences, 1-1-20 Shinmachi, Nishitokyo-shi, Tokyo 202-8585, Japan. k-ito@musashino-u.ac.jp.
Drug metabolism and disposition: the biological fate of chemicals.Drug Metab Dispos.2013 Feb;41(2):362-71. doi: 10.1124/dmd.112.049460. Epub 2012 Nov 8.
The plasma concentration of repaglinide is reported to increase greatly when given after repeated oral administration of itraconazole and gemfibrozil. The present study analyzed this interaction based on a physiologically based pharmacokinetic (PBPK) model incorporating inhibition of the hepatic upt
PMID 23139378

Japanese Journal

プロスタグランジンと有機アニオンのトランスポーター(<特集>第66回大会シンポジウム「ビタミン・バイオファクタートランスポーター研究の最前線」)

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Mangiferin Inhibits Renal Urate Reabsorption by Modulating Urate Transporters in Experimental Hyperuricemia

Biological and Pharmaceutical Bulletin 38(10), 1591-1598, 2015
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Mangiferin Inhibits Renal Urate Reabsorption by Modulating Urate Transporters in Experimental Hyperuricemia

Biological and Pharmaceutical Bulletin advpub(0), 2015
NAID 130005090663

Related Pictures

★リンクテーブル★

リンク元	「有機アニオン輸送体1」「有機アニオントランスポーター1」「OAT1」「SLC22A6」
関連記事	「transport」「organic」「anion transporter」「transporter」「ani」

「有機アニオン輸送体1」

solute carrier family 22 (organic anion transporter), member 6
Identifiers
Aliases	SLC22A6, HOAT1, OAT1, PAHT, ROAT1, Organic anion transporter 1
External IDs	MGI: 892001 HomoloGene: 16813 GeneCards: 9356
Gene ontology
Molecular function	• sodium-independent organic anion transmembrane transporter activity; • protein homodimerization activity; • transmembrane transporter activity; • anion:anion antiporter activity; • protein binding; • inorganic anion exchanger activity; • chloride ion binding; • organic anion transmembrane transporter activity;
Cellular component	• integral component of membrane; • membrane; • plasma membrane; • integral component of plasma membrane; • protein complex; • basolateral plasma membrane; • caveola; • extracellular exosome;
Biological process	• sodium-independent organic anion transport; • response to methotrexate; • renal tubular secretion; • anion transport; • anion transmembrane transport; • alpha-ketoglutarate transport; • transmembrane transport; • organic anion transport; • protein homooligomerization;
	Sources:Amigo / QuickGO
RNA expression pattern
	; ;
	More reference expression data
Orthologs
	9356
	18399
	ENSG00000197901
	ENSMUSG00000024650
	Q4U2R8
	Q8VC69
	NM_153279; NM_004790; NM_153276; NM_153277; NM_153278
	NM_008766
	NP_004781.2; NP_695008.1; NP_695009.1; NP_695010.1
	NP_032792.2
	Wikidata
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