Polyspecific organic cation transporters: their functions and interactions with drugs

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Abstract

The body is equipped with broad-specificity transporters for the uptake, elimination and distribution of drugs, environmental toxins and metabolic waste products. The organic cation transporters [OCT1–OCT3 (also known as SLC22A1–SLC22A3)], which are expressed in the small intestine, liver, kidney, heart, placenta, lung and brain, facilitate the diffusion of structurally diverse organic cations including monoamine neurotransmitters and many drugs. These transporters contain substrate-binding pockets with partially overlapping binding domains for substrates and inhibitors. Recent studies in knockout mice show that OCT1 in the liver is involved in the hepatic uptake of cationic drugs and, therefore, affects their net hepatobiliary excretion. In addition, OCT1 and OCT2 in renal proximal tubules participate in the secretion of cationic drugs from the kidney. The recent identification of polymorphisms in human OCTs enables the identification of patients who have an increased risk of adverse drug reactions. Transport studies with expressed OCTs will help to optimize pharmacokinetic properties during the development of new drugs.

Section snippets

Cloning of OCTs

In 1994, the first member of the SLC22 family, OCT1, was cloned from rats 6, 8. Later, two additional subtypes, OCT2 and OCT3, and OCT homologs from humans and other species were identified 5, 6. Like most members of the SLC22 family, the predicted membrane topology of OCT1, OCT2 and OCT3 has 12 α-helical transmembrane domains (TMDs), a large glycosylated extracellular loop between TMDs 1 and 2, and a large intracellular loop that contains phosphorylation sites between TMDs 6 and 7 (Figure 1b).

Substrate specificity

The substrate and inhibitor specificities of OCT1, OCT2 and OCT3 overlap extensively, but there are distinct differences in affinity and maximal transport rates between OCT subtypes and species 6, 10. For example, in humans, the affinity of OCT1 and OCT2 for tetraethylammonium (TEA) is one order of magnitude higher than that of OCT3 6, 11, 12. The concentrations of corticosterone required for half-maximal inhibition of human OCT1, OCT2 and OCT3 are ∼10 μM, 30 μM and 0.1 μM, respectively,

Localization and function

In humans, OCT1 is expressed mainly in the liver [6], but also in the heart, skeletal muscle, kidney, placenta and small intestine [6]. In rodents, OCT1 is expressed strongly in the liver, kidney and small intestine 6, 8, and less abundantly in the colon, skin, spleen, choroid plexus and neurons 16, 17, 18, 19. In rodents, OCT1 has been localized to the sinusoidal membrane of hepatocytes and to basolateral membranes of renal proximal tubules and enterocytes 18, 20, 21, 22.

OCT1 mediates the

Transport mechanism and substrate-binding sites

Electrical measurements have been performed following expression of rat OCT1, OCT2, OCT3 and human OCT2 in intact oocytes of Xenopus laevis and inside-out oriented giant patches [6]. The OCTs are facilitative diffusion systems that transport cations in both directions and operate independently of H+ and Na+ gradients [6]. The driving force that determines the direction of translocation is provided jointly by the concentration gradient of the transported substrate and by the membrane potential.

Physiological functions and regulation

The OCTs have physiological functions that await more detailed investigations. In addition to the absorption in the small intestine and to hepatic, small intestinal and renal excretion of drugs and xenobiotics, OCTs are involved in the reabsorption and excretion of endogenous compounds such as choline, dopamine and guanidine. In the CNS and PNS, OCTs are thought to reduce the interstitial concentrations of monoamine neurotransmitters, acetylcholine, agmatine and choline 6, 15, 18, 24, 40. In

Knockout mice

Given the overlapping tissue distributions of polyspecific OCT subtypes and oligospecific organic cation transporters such as Na+-driven monoamine neurotransmitter transporters and transporters for choline, acetylcholine and thiamine [6], it is difficult to identify the crucial functions of the OCTs in vivo. For this purpose, Oct-knockout mice have been generated 49, 50, 51. Furthermore, mice in which the high-affinity Na+−5-HT cotransporter SERT has been knocked out have been used to

Genetic variations

Polymorphic genetic variations have been reported in human OCTs 53, 54, 55. Numerous single-nucleotide polymorphisms (SNPs) have been detected in the gene encoding OCT1, with population-dependent frequencies 53, 55. Although SNPs localize to the promoter region, 17 SNPs result in single amino acid substitutions. Among these, reduced transport activities have been observed for mutations in the large extracellular loop between TMDs 1 and 2, the large intracellular loop between TMDs 6 and 7, the

Clinical aspects

Because OCTs are crucial in the biodistribution of cationic drugs, mutations in OCTs or in proteins that regulate their expression can change the tissue concentrations of drugs. Comedication with drugs that are substrates and others that inhibit OCTs could have severe side-effects. For example, the hepatic excretion of drugs that are translocated by OCT1 could be impeded by comedication with either prazosin, which inhibits OCT1 at low concentration, or with phenoxybenzamine, low concentrations

Concluding remarks

Polyspecific OCTs of the SLC22 family contain large substrate-binding pockets that interact with structurally different substrates and inhibitors. The three OCT subtypes are crucial for hepatic and renal excretion of cationic drugs, and are thought to modulate their distribution in the brain and heart. Loss-of-function mutations in human OCTs can interfere with renal and biliary excretion of drugs. The established expression systems and knockout animals provide tools to identify their role in

Acknowledgments

Supported by research grant of the Deutsche Forschungsgemeinschaft (SFB 487 project A4).

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