Molecular Structure of the Caronrier Responsible for Hepatic Uptake of Catecholamines

Gründemann, Dirk; Breidert, Tilo; Spitzenberger, Folker; Schömig, Edgar

doi:10.1016/s1054-3589(08)60761-9

Cited by 6 publications

(7 citation statements)

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“…rOCT1 was previously found to transport the exogenous organic cations tetraethylammonium (Gründemann et al 1994;Breidert et al 1998) and MPP + (Martel et al 1996a;Breidert et al 1998), and to accept biogenic amines (dopamine, noradrenaline and 5-hydroxytryptamine) as substrates (Busch et al 1996;Breidert et al 1997Breidert et al , 1998Gründemann et al 1998b). Recently, the affinities of some biogenic amines for this transporter have been reported (Breidert et al 1998).…”

Section: Discussionmentioning

confidence: 96%

“…Concerning the last point, it was recently shown that rOCT1 accepts the biogenic amines noradrenaline and dopamine as substrates (Busch et al 1996;Breidert et al 1997Breidert et al , 1998Gründemann et al 1998b), being most probably responsible for the transport of catecholamines from blood into cells in the kidney (Ullrich et al 1992) and liver (Martel et al 1996a,b,c).…”

Section: Introductionmentioning

confidence: 99%

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Comparison between uptake2 and rOCT1: effects of catecholamines, metanephrines and corticosterone

Martel¹,

Ribeiro²,

Calhau³

et al. 1999

Naunyn-Schmiedeberg's Arch Pharmacol

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Active and specialized transmembrane transport systems are responsible for the functional inactivation of catecholamines. Uptake2, the classical extraneuronal uptake system, and rOCT1, a recently cloned organic cation transporter, share a number of properties. The present study was undertaken to investigate putative differences between these two transporters that might clarify their relative physiological roles. Uptake of [3H]MPP+ ([3H]1-methyl-4-phenylpyridinium) by Caki-1 cells (to study uptake2) and by primary cultured rat hepatocytes (to study rOCT1) was kinetically and pharmacologically characterized. In both cell types, [3H]MPP+ was avidly taken up and accumulated. All compounds tested (catecholamines, metanephrines and corticosterone) inhibited [3H]MPP+ uptake, albeit with different potencies. In Caki-1 cells, the ranking order of inhibitory potency was: (-)isoprenaline> (-)adrenaline >> (-)noradrenaline > dopamine. Metanephrine and normetanephrine were equipotent. Corticosterone had an IC50 of 102 nM. In cultured hepatocytes, the ranking order of inhibitory potency was: (-)isoprenaline > dopamine > (-)adrenaline >> (-)noradrenaline. Metanephrine was about seven times more potent than normetanephrine. Corticosterone had an IC50 of 72 microM, being about 700-fold less potent in inhibiting rOCT1 than uptake2. The results showed that uptake2 and rOCT1 can be clearly distinguished on a functional basis. On the one hand, uptake2 prefers adrenaline among the endogenous catecholamines, whereas rOCT1 has similar affinity for adrenaline and dopamine. On the other hand, corticosterone and normetanephrine are significantly more potent in inhibiting uptake2 than rOCT1. The results are compatible with a possible physiological role of corticosteroids in the modulation of adrenaline effects in tissues equipped with uptake2, without significant interference with the hepatic and renal excretion of catecholamines.

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Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Comparison between uptake2 and rOCT1: effects of catecholamines, metanephrines and corticosterone

Martel¹,

Ribeiro²,

Calhau³

et al. 1999

Naunyn-Schmiedeberg's Arch Pharmacol

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“…The cloned OCT1, OCT2, and OCT3 transporters were heterologously expressed in Xenopus oocytes (5-7, 10, 13, 14, 20, 22, 29, 32, 35, 52, 76, 79), HEK-293 cells (2,5,11,12,20,22,29), Madin-Darby canine kidney cells (72), HeLa cells (20,80), and HRPE cells (76). Most experiments on substrate specificity have been performed with rat OCT1 as well as with rat and human OCT2.…”

Section: Functional Characterization Of Octsmentioning

confidence: 99%

“…Most experiments on substrate specificity have been performed with rat OCT1 as well as with rat and human OCT2. Although uptake of radiolabeled cimetidine (2,12), quinidine, and quinine (32) could not be demonstrated, choline (7,10), dopamine (2,6,7,12), epinephrine (2, 12), 5-hydroxytryptamine (5-HT; 2, 6, 12), MPP (2,6,7,12,13,29,52,79), NMN (7), norepinephrine (2,12), TEA (2,7,12,13,72,80), and tyramine (2,12) did show an enhanced tracer uptake in oocytes or cells expressing OCT1, proving the broad substrate specificity of this transporter. As expected for an electrogenic transporter, the addition of potential substrates to OCT1-expressing oocytes resulted in an inward current in voltage-clamped oocytes (6, 7).…”

Section: Functional Characterization Of Octsmentioning

confidence: 99%

Structure of renal organic anion and cation transporters

Burckhardt

Wolff

2000

American Journal of Physiology-Renal Physiology

258

241

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Here we review the structural and functional properties of organic anion transporters (OAT1, OAT2, OAT3) and organic cation transporters (OCTN1, OCTN2, OCT1, OCT2, OCT3), some of which are involved in renal proximal tubular organic anion and cation secretion. These transporters share a predicted 12-transmembrane domain (TMD) structure with a large extracellular loop between TMD1 and TMD2, carrying potential N-glycosylation sites. Conserved amino acid motifs revealed a relationship to the sugar transporter family within the major facilitator superfamily. Following heterologous expression, most OATs transported the model anion p-aminohippurate (PAH). OAT1, but not OAT2, exhibited PAH-alpha-ketoglutarate exchange. OCT1-3 transported the model cations tetraethylammonium (TEA), N(1)-methylnicotinamide, and 1-methyl-4-phenylpyridinium. OCTNs exhibited transport of TEA and/or preferably the zwitterionic carnitine. Substrate substitution as well as cis-inhibition experiments demonstrated polyspecificity of the OATs, OCTs, and OCTN1. On the basis of comparison of the structurally closely related OATs and OCTs, it may be possible to delineate the binding sites for organic anions and cations in future experiments.

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“…Organic cation transporter 3 (OCT3), encoded by the solute carrier 22A3 ( SLC22A3 ), is expressed in various organs in humans, including skeletal and smooth muscle, liver, heart, intestine, brain, placenta, salivary glands, and kidneys 1 – 4 . It mediates the transport of 1-methyl-4-phenylpyridium (MPP + ) and several cationic drugs including metformin 5 , 6 . OCT3 is also defined as an extraneuronal monoamine transporter because it is known to play an important role in transporting norepinephrine, epinephrine, and histamine 5 , 7 – 9 .…”

Section: Introductionmentioning

confidence: 99%

OCT3 promoter haplotype is associated with metformin pharmacokinetics in Koreans

Kwon

Chung

Park

et al. 2018

Sci Rep

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Organic cation transporter 3 (OCT3) is expressed in various organs in humans and plays an important role in the transport of organic cations and drugs including metformin. In this study, we identified genetic variations of the OCT3 promoter and functionally characterized each variant by in vitro assays. Next, the association between the functional haplotype of the OCT3 promoter and pharmacokinetics of metformin was evaluated. In our study population, 7 variations and 2 major haplotypes were identified, of which H2 haplotype yielded a significantly higher luciferase activity than did the wild type. Two variants of H2, c.-1603G > A and c.-1547T > G, yielded significantly lower luciferase activities, whereas the luciferase activity of another variant, c.-29G > A, was significantly higher. Two transcription factors, Sp1 and USF1, were involved in the regulation of OCT3 transcription. Analysis of clinical data revealed that 25 subjects, either homozygous or heterozygous for H2, showed increased AUCinf and Cmax by 17.2% and 15.9%, respectively [P = 0.016 and 0.031, GMR (90% CI) = 1.17 (1.06–1.29) and 1.17 (1.04–1.31), respectively], compared to the 20 subjects in the control group. Our study suggests that an OCT3 promoter haplotype affects the pharmacokinetics of metformin in Koreans as well as the OCT3 transcription rate.

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Molecular Structure of the Caronrier Responsible for Hepatic Uptake of Catecholamines

Cited by 6 publications

References 1 publication

Comparison between uptake2 and rOCT1: effects of catecholamines, metanephrines and corticosterone

Comparison between uptake2 and rOCT1: effects of catecholamines, metanephrines and corticosterone

Structure of renal organic anion and cation transporters

OCT3 promoter haplotype is associated with metformin pharmacokinetics in Koreans

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