The organic anion transporter 1 (OAT1) also known as solute carrier family 22 member 6 (SLC22A6) is a protein

Protein

Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

 that in humans is encoded by the SLC22A6 gene

Gene

A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...

. It is a member of the organic anion transporter (OAT) family of proteins. OAT1 is a transmembrane protein

Transmembrane protein

A transmembrane protein is a protein that goes from one side of a membrane through to the other side of the membrane. Many TPs function as gateways or "loading docks" to deny or permit the transport of specific substances across the biological membrane, to get into the cell, or out of the cell as...

 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

Organic anion

Organic anions are chemically heterogeneous substances possessing a carbon backbone and a net negative charge. Organic anions are conjugate bases of organic acids. The following table lists some of the organic anions and their conjugate acids which are substrates of the organic acid transporter ...

 transport. Along with OAT3

SLC22A8

Solute carrier family 22 member 8 is a protein that in humans is encoded by the SLC22A8 gene.-Further reading:...

, OAT1 mediates the uptake of a wide range of relatively small and hydrophilic organic anions from plasma

Blood plasma

Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...

 into the cytoplasm

Cytoplasm

The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...

 of the proximal tubular cells of the kidneys. From there, these substrates are transported into the lumen

Lumen (anatomy)

A lumen in biology is the inside space of a tubular structure, such as an artery or intestine...

 of the nephrons of the kidneys for excretion

Excretion

Excretion is the process by which waste products of metabolism and other non-useful materials are eliminated from an organism. This is primarily carried out by the lungs, kidneys and skin. This is in contrast with secretion, where the substance may have specific tasks after leaving the cell...

. OAT1 homologs have been identified in rats

RATS

RATS may refer to:* RATS , Regression Analysis of Time Series, a statistical package* Rough Auditing Tool for Security, a computer program...

, mice

MICE

-Fiction:*Mice , alien species in The Hitchhiker's Guide to the Galaxy*The Mice -Acronyms:* "Meetings, Incentives, Conferencing, Exhibitions", facilities terminology for events...

, rabbits, pigs

PIGS

PIGS is a four letter acronym that can stand for:* PIGS , Phosphatidylinositol glycan anchor biosynthesis, class S, a human gene* PIGS , the economies of Portugal, Italy , Greece and Spain...

, flounders, and nematodes

Caenorhabditis elegans

Caenorhabditis elegans is a free-living, transparent nematode , about 1 mm in length, which lives in temperate soil environments. Research into the molecular and developmental biology of C. elegans was begun in 1974 by Sydney Brenner and it has since been used extensively as a model...

.

Function

OAT1 functions as organic anion

Organic anion

Organic anions are chemically heterogeneous substances possessing a carbon backbone and a net negative charge. Organic anions are conjugate bases of organic acids. The following table lists some of the organic anions and their conjugate acids which are substrates of the organic acid transporter ...

 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

Endogenous

Endogenous substances are those that originate from within an organism, tissue, or cell. Endogenous retroviruses are caused by ancient infections of germ cells in humans, mammals and other vertebrates...

 dicarboxylic acid

Dicarboxylic acid

Dicarboxylic acids are organic compounds that contain two carboxylic acid functional groups. In molecular formulae for dicarboxylic acids, these groups are often written as HOOC-R-COOH, where R may be an alkyl, alkenyl, alkynyl, or aryl group...

 (such as glutarate, ketoglutarate, etc) is simultaneously transported out of the cell. 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

SLC13A3

Solute carrier family 13 member 3 also called sodium-dependent dicarboxylate transporter is a protein that in humans is encoded by the SLC13A3 gene.-Further reading:...

. 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.

The renal organic anion transporters OAT1, OAT3

SLC22A8

Solute carrier family 22 member 8 is a protein that in humans is encoded by the SLC22A8 gene.-Further reading:...

, OATP4C1

OATP4C1

Organic anion transporter polypeptide 4C1 or OATP4C1 is a human protein. It is also known as "solute carrier organic anion transporter family member 4A1". OATP4C1 is coded for by the gene SLCO4C1, which is located on chromosome 5q21...

, MDR1, MRP2

ABCC2

Multidrug resistance-associated protein 2 also called canalicular multispecific organic anion transporter 1 or ATP-binding cassette sub-family C member 2 is a protein that in humans is encoded by the ABCC2 gene....

, 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.

Substrates

Known substrates of OAT1 include para-aminohippurate (PAH), dicarboxylates

Dicarboxylic acid

Dicarboxylic acids are organic compounds that contain two carboxylic acid functional groups. In molecular formulae for dicarboxylic acids, these groups are often written as HOOC-R-COOH, where R may be an alkyl, alkenyl, alkynyl, or aryl group...

, prostaglandin

Prostaglandin

A prostaglandin is any member of a group of lipid compounds that are derived enzymatically from fatty acids and have important functions in the animal body. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring....

s, cyclic nucleotides, urate, folate, diuretics, ACE inhibitors, antiviral

Antiviral drug

Antiviral drugs are a class of medication used specifically for treating viral infections. Like antibiotics for bacteria, specific antivirals are used for specific viruses...

 agents, beta-lactam antibiotic

Beta-lactam antibiotic

β-Lactam antibiotics are a broad class of antibiotics, consisting of all antibiotic agents that contains a β-lactam nucleus in its molecular structure. This includes penicillin derivatives , cephalosporins , monobactams, and carbapenems...

s, antineoplastics, mycotoxins, sulfate conjugates

Sulfate conjugates

Sulfate conjugates are a heterogeneous class of polar, anionic metabolites that result from the conjugation of endogenous and exogenous compounds....

, glucuronide

Glucuronide

A glucuronide, also known as glucuronoside, is any substance produced by linking glucuronic acid to another substance via a glycosidic bond...

 conjugates, cystein conjugates, ochratoxin A

Ochratoxin A

Ochratoxin A, a toxin produced by Aspergillus ochraceus, Aspergillus carbonarius and Penicillium verrucosum, is one of the most abundant food-contaminating mycotoxins in the world. Human exposure occurs mainly through consumption of improperly stored food products, particularly contaminated grain...

, NSAIDs, and uremic toxins

Uremic toxins

Numerous uremic toxins are accumulating in chronic renal failure patients treated with standard dialysis. These toxins show various cytotoxic activities in the serum, have different molecular weights and some of them are bound to other proteins, primarily to albumin...

.

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

Zidovudine

Zidovudine or azidothymidine is a nucleoside analog reverse-transcriptase inhibitor , a type of antiretroviral drug used for the treatment of HIV/AIDS. It is an analog of thymidine....

 (AZT), didanosine

Didanosine

Didanosine is sold under the trade names Videx and Videx EC. It is a reverse transcriptase inhibitor, effective against HIV and used in combination with other antiretroviral drug therapy as part of highly active antiretroviral therapy .-History:The related pro-drug of didanosine,...

 (ddI), zalcitabine (ddC), lamivudine

Lamivudine

Lamivudine is a potent nucleoside analog reverse transcriptase inhibitor .It is marketed by GlaxoSmithKline with the brand names Zeffix, Heptovir, Epivir, and Epivir-HBV.Lamivudine has been used for treatment of chronic hepatitis B at a lower dose than for treatment of HIV...

 (3TC), stavudine

Stavudine

Stavudine is a nucleoside analog reverse transcriptase inhibitor active against HIV.-History:...

 (d4T), trifluridine

Trifluridine

Trifluridine is an anti-herpesvirus antiviral drug, used primarily on the eye. It was sold under the trade name, Viroptic, by Glaxo Wellcome, now merged into GlaxoSmithKline...

, cidofovir

Cidofovir

Cidofovir is an injectable antiviral medication for the treatment of cytomegalovirus retinitis in patients with AIDS. It suppresses CMV replication by selective inhibition of viral DNA polymerase and therefore prevention of viral replication and transcription...

, adefovir

Adefovir

Adefovir dipivoxil, previously called bis-POM PMEA, with trade names Preveon and Hepsera, is an orally-administered nucleotide analog reverse transcriptase inhibitor .-Uses:...

, and tenofovir (TDF) are substrates of the OAT1 transporter. This may result in the build up of these drugs in the proximal tubule

Proximal tubule

The proximal tubule is the portion of the duct system of the nephron of the kidney which leads from Bowman's capsule to the loop of Henle.-Structure and appearance:...

 cells. At high concentrations, these drugs inhibit DNA replication

DNA replication

DNA replication is a biological process that occurs in all living organisms and copies their DNA; it is the basis for biological inheritance. The process starts with one double-stranded DNA molecule and produces two identical copies of the molecule...

. This, in turn, may impair the function of these cells and may be the cause of antiviral induced Fanconi syndrome

Fanconi syndrome

Falconi syndrome is a disease of the proximal renal tubules of the kidney in which glucose, amino acids, uric acid, phosphate and bicarbonate are passed into the urine, instead of being reabsorbed. Fanconi syndrome affects the proximal tubule, which is the first part of the tubule to process fluid...

. The use of stavudine, didenosine, abacavir, adefovir, cidofovir 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.

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

Dysmorphic feature

Dysmorphic feature is a medical term referring to a difference of body structure that is suggestive of a congenital disorder, genetic syndrome, or birth defect. A dysmorphic feature can be a minor and isolated birth defect...

. In vitro

In vitro

In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...

the antiviral drugs didanosine and zidovudine are more potent inhibitors of mitochondrial DNA synthesis than tenofovir (ddI > AZT > TDF). 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

Herpesviridae

The Herpesviridae are a large family of DNA viruses that cause diseases in animals, including humans. The members of this family are also known as herpesviruses. The family name is derived from the Greek word herpein , referring to the latent, recurring infections typical of this group of viruses...

.

Stavudine, zidovudine and indinavir

Indinavir

Indinavir is a protease inhibitor used as a component of highly active antiretroviral therapy to treat HIV infection and AIDS.-History:...

 (IDV) cause a decrease in mitochondrial respiration

Cellular respiration

Cellular respiration is the set of the metabolic reactions and processes that take place in the cells of organisms to convert biochemical energy from nutrients into adenosine triphosphate , and then release waste products. The reactions involved in respiration are catabolic reactions that involve...

 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

Phosphorylation

Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....

 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

Protease inhibitor (pharmacology)

Protease inhibitors are a class of drugs used to treat or prevent infection by viruses, including HIV and Hepatitis C. PIs prevent viral replication by inhibiting the activity of proteases, e.g.HIV-1 protease, enzymes used by the viruses to cleave nascent proteins for final assembly of new...

 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. Since stavudine and zidovudine are OAT1 substrates, they may have similar affects on proximal renal tubule cells as they do on fat cells.
Lamivudine has reverse chirality

Chirality (chemistry)

A chiral molecule is a type of molecule that lacks an internal plane of symmetry and thus has a non-superimposable mirror image. The feature that is most often the cause of chirality in molecules is the presence of an asymmetric carbon atom....

 compared to didanosine, stavudine, zidovudine, and natural nucleosides. Mitochondrial DNA polymerase

DNA polymerase

A DNA polymerase is an enzyme that helps catalyze in the polymerization of deoxyribonucleotides into a DNA strand. DNA polymerases are best known for their feedback role in DNA replication, in which the polymerase "reads" an intact DNA strand as a template and uses it to synthesize the new strand....

 may not recognize it as a substrate. Lamivudine is not toxic to mitochondria in vivo

In vivo

In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...

. Individuals who had been taking didanosine combined with stavudine exhibited improved mitochondrial function when they switched to lamivudine combined with tenofovir.

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

Further reading