Renal transport mechanisms for xenobiotics: chemicals and drugs

Ullrich, Karl Julius; Rumrich, Gerhard

doi:10.1007/bf00190334

Cited by 33 publications

(20 citation statements)

References 29 publications

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“…sulfate and glucuronide conjugates. The kidney and the liver play a central role in the elimination of these toxic anionic compounds from the body (1)(2)(3)(4)(5). In the kidney, proximal tubular cells take up organic anions from the blood via multispecific organic anion transport pathway(s) in the basolateral membrane (1)(2)(3).…”

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confidence: 99%

Molecular Cloning and Characterization of Multispecific Organic Anion Transporter 4 Expressed in the Placenta

Ho¹,

Sekine²,

Kusuhara³

et al. 2000

Journal of Biological Chemistry

373

318

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A cDNA encoding a novel multispecific organic anion transporter, OAT4, was isolated from a human kidney cDNA library. The OAT4 cDNA consisted of 2210 base pairs that encoded a 550-amino acid residue protein with 12 putative membrane-spanning domains. The amino acid sequence of OAT4 showed 38 to 44% identity to those of other members of the OAT family. Northern blot analysis revealed that OAT4 mRNA is abundantly expressed in the placenta as well as in the kidney. When expressed in Xenopus oocytes, OAT4 mediated the high affinity transport of estrone sulfate (K m ‫؍‬ 1.01 M) and dehydroepiandrosterone sulfate (K m ‫؍‬ 0.63 M) in a sodium-independent manner. OAT4 also mediated the transport of ochratoxin A. OAT4-mediated transport of estrone sulfate was inhibited by several sulfate conjugates, such as p-nitrophenyl sulfate, ␣-naphthyl sulfate, ␤-estradiol sulfate, and 4-methylumbelliferyl sulfate. By contrast, glucuronide conjugates showed little or no inhibitory effect on the OAT4-mediated transport of estrone sulfate. OAT4 interacted with chemically heterogeneous anionic compounds, such as nonsteroidal antiinflammatory drugs, diuretics, sulfobromophthalein, penicillin G, and bile salts, whereas tetraethylammonium, an organic cation, did not. OAT4 is the first member of the multispecific organic anion transporter family, which is expressed abundantly in the placenta. OAT4 might be responsible for the elimination and detoxification of harmful anionic substances from the fetus.

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confidence: 99%

Molecular Cloning and Characterization of Multispecific Organic Anion Transporter 4 Expressed in the Placenta

Ho¹,

Sekine²,

Kusuhara³

et al. 2000

Journal of Biological Chemistry

373

318

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“…The kidney provides a pivotal route for the elimination and excretion of a wide range of structurally dissimilar compounds (Moller and Sheikh, 1983;Pritchard and Miller, 1993;Ullrich and Rumrich, 1993;Ullrich 1997). Renal excretion of organic compounds involves three steps: glomerular filtration, secretion, and reabsorption.…”

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confidence: 99%

Renal Transport of Organic Compounds Mediated by Mouse Organic Anion Transporter 3 (Moat3): Further Substrate Specificity of Moat3

Kobayashi¹,

Ohshiro²,

Tsuchiya³

et al. 2004

Drug Metab Dispos

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ABSTRACT:Organic anion transporter 3 [Oat3(Slc22a8)] plays an important role in the renal handling of organic compounds. The substrate specificity of rat Oat3 and human Oat3 has been elucidated; information on mouse Oat3 (mOat3) is less defined. The aim of this study was to extend the substrate selectivity of mOat3. When expressed in Xenopus laevis oocytes, mOat3 mediated the uptake of p-aminohippuric acid and estron sulfate (ES). In addition to these substrates, we found that several organic compounds such as prostaglandin E 2 , prostaglandin F 2␣ , allopurinol, 6-mercaptopurine (6-MP), 5-fluorouracil (5-FU), and L-carnitine are substrates of mOat3, compounds identified for the first time. The apparent K m values for the uptake of mOat3 that mediated the transport of 6-MP, 5-FU, and L-carnitine were 4.01 ؎ 0.7 M, 53.9 ؎ 8.9 nM, and 61.9 ؎ 1.1 nM, respectively. Northern blot analysis revealed that gene coding for mOat3 is predominant in the kidney and, to a lesser extent, in the brain and the eye. Our findings thus provide further insights into the role of Oat3 in renal drug transport.

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“…Current extensive molecular studies have identified several families of multispecific organic anion transporters that are involved in the elimination of various organic anions (Moller and Sheikh, 1983;Boyer et al, 1992;Pritchard and Miller, 1993;Ullrich and Rumrich, 1993;Petzinger, 1994;Meier, 1995;Muller and Jansen, 1997;Ullrich, 1997). In the liver and kidney, water-soluble metabolites and organic anions are actively eliminated from the body via transporters across their basolateral and/or luminal membranes (Moller and Sheikh, 1983;Boyer et al, 1992;Pritchard and Miller, 1993;Ullrich and Rumrich, 1993;Petzinger, 1994;Meier, 1995;Bossuyt et al, 1996;Muller and Jansen, 1997;Ullrich, 1997). The proximal tubular cells of the kidney take up organic anions from the blood stream via multispecific organic anion transport pathway(s) in the basolateral membranes (Moller and Sheikh, 1983;Ullrich and Rumrich, 1993;Pritchard and Miller, 1993;Ullrich, 1997).…”

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Isolation, Characterization and Differential Gene Expression of Multispecific Organic Anion Transporter 2 in Mice

et al. 2002

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We isolated cDNA encoding a multispecific organic anion transporter 2 (OAT2) from the mouse kidney cDNA library. Isolated mouse OAT2 (mOAT2) consisted of 1623 base pairs that encoded a 540-amino acid residue protein with 12 putative membrane-spanning domains, and the amino acid sequence was 87% identical to that of rat OAT2 (rOAT2). The gene coding for mOAT2, Slc22a7, is found on chromosome 17C. Northern blot analysis revealed that the mOAT2 mRNA is abundantly expressed in the male mouse kidney, whereas it was predominantly expressed in both the liver and kidney of female mice. When expressed in Xenopus laevis oocytes, mOAT2 mediated the high affinity transport of glutarate (K m ϭ 15.8 Ϯ 3.2 M) and prostaglandin E 2 (K m ϭ 5.2 Ϯ 0.5 nM) in a sodium-independent manner. mOAT2-expressing oocytes also mediated the uptake of ␣-ketoglutarate, glutarate, prostaglandin E 2 , p-aminohippuric acid, methotrexate, ochratoxin A, valproate, and allopurinol. However, we did not observe mOAT2-mediated uptake of salicylate. A wide range of structurally unrelated organic anions inhibited mOAT2-mediated glutarate uptake especially erythromycin, a potent inhibitor. These results indicate that isolated mOAT2 is a multispecific organic anion transporter having some differences in substrate specificity compared with rOAT2. In addition, we found that there exists a sex-and speciesrelated differential gene expression of the OAT2 isoform.Organic anion transporters play central roles in the elimination of a wide range of endogenous and exogenous anionic compounds including drugs, environmental toxicants, and their metabolites. Current extensive molecular studies have identified several families of multispecific organic anion transporters that are involved in the elimination of various organic anions (Moller and Sheikh, 1983;Boyer et al

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Renal transport mechanisms for xenobiotics: chemicals and drugs

Cited by 33 publications

References 29 publications

Molecular Cloning and Characterization of Multispecific Organic Anion Transporter 4 Expressed in the Placenta

Molecular Cloning and Characterization of Multispecific Organic Anion Transporter 4 Expressed in the Placenta

Renal Transport of Organic Compounds Mediated by Mouse Organic Anion Transporter 3 (Moat3): Further Substrate Specificity of Moat3

Isolation, Characterization and Differential Gene Expression of Multispecific Organic Anion Transporter 2 in Mice

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