Human Organic Anion Transporting Polypeptide-C (SLC21A6) Is a Major Determinant of Rifampin-Mediated Pregnane X Receptor Activation

Tirona, Rommel G.; Leake, Brenda F.; Wolkoff, Allan W.; Kim, Richard B.

doi:10.1124/jpet.102.043026

Cited by 292 publications

(221 citation statements)

References 38 publications

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“…Indeed, the 521T4C (V174A) variant of SLCO1B1 is associated with changes in the transporter activity of estrone sulfate, 17b-D-glucuronide and pravastatin in vitro. [4][5][6][7] Moreover, the 521C/C genotype has been associated with increased plasma concentrations of statins and glinides in human studies. [8][9][10] In SLCO1B3, several single-nucleotide polymorphisms (SNPs) have been identified in coding and noncoding regions.…”

Section: Introductionmentioning

confidence: 99%

Association study of genetic polymorphisms of drug transporters, SLCO1B1, SLCO1B3 and ABCC2, in African-Americans, Hispanics and Caucasians and olmesartan exposure

et al. 2012

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It has been reported that organic anion-transporting polypeptide (OATP) 1B1, OATP1B3 and multidrug resistance-associated protein 2 are involved in the hepatobiliary transport of olmesartan. We investigated the association of SLCO1B1, SLCO1B3 and ABCC2 polymorphisms with the pharmacokinetics of olmesartan. We sequenced all exons, exon-intron junctions and the 5 0 and 3 0 flanking regions of the three genes in 115 individuals from African-American, Hispanic and Caucasian populations who had participated in our clinical studies. A total of 348 single-nucleotide polymorphisms (SNPs) were identified with a minor allele frequency of X0.01 in at least one population; 132 SNPs were detected in SLCO1B1, 130 in SLCO1B3 and 86 in ABCC2. We characterized the linkage disequilibrium (LD) and haplotypes shared across the populations and then evaluated the association between the haplotypes and the pharmacokinetics of olmesartan. Seven inter-ethnic LD blocks were observed in SLCO1B1, while three in SLCO1B3 and four in ABCC2. Although extensive variability in the sequences of SLCO1B1, SLCO1B3 and ABCC2 existed across the three populations, there was no remarkable difference in any pharmacokinetic parameters of olmesartan between subjects with and without any major haplotypes in the three transporter genes we tested.

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Section: Introductionmentioning

confidence: 99%

Association study of genetic polymorphisms of drug transporters, SLCO1B1, SLCO1B3 and ABCC2, in African-Americans, Hispanics and Caucasians and olmesartan exposure

et al. 2012

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“…3 OATP1B1 can uptake structurally diverse drugs, such as 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), 1 SN-38 4 and rifampicin, 5 from circulation in a sodium-independent manner. With its high level of expression in the liver and its substrate polyspecificity, OATP1B1 is one of the major determinants of pharmacokinetics of various drugs.…”

Section: Introductionmentioning

confidence: 99%

Functional analysis of a mutation in the SLCO1B1 gene (c.1628T>G) identified in a Japanese patient with pravastatin-induced myopathy

et al. 2009

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In the present study, we analyzed the function of a novel mutation (c.1628T4G, p.Leu543Trp) in the solute carrier organic anion transporter (SLCO) 1B1 gene, encoding organic anion transporting polypeptide (OATP) 1B1, which was identified in a patient with pravastatin-induced myopathy. OATP1B1 variants carrying the mutation (OATP1B1*1a þ c.1628T4G or *1b þ c.1628T4G) showed a reduced transporting activity toward typical substrates and pravastatin compared with the activity of the references (OATP1B1*1a or *1b). This was due to reduction in V max values of the variants, not due to change in their K m values. OATP1B1*1b þ c.1628T4G was normally expressed on the plasma membrane of HEK293 cells at the same level as that of OATP1B1*1b. Taken together, our results suggest that the mutation c.1628T4G (p.Leu543Trp) reduced the function of OATP1B1 probably due to decrease in turnover rate of one OATP1B1 molecule rather than impairment of protein sorting to the plasma membrane.

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“…It is expressed predominantly at the basolateral membrane of hepatocytes [5]. Substrates of human OATP-C include bromosulfophthalein (BSP), estradiol-17b-D-glucuronide (E 2 17bG), estrone-3-sulfate, dehydroepiandrosterone sulfate (DHEAS), thyroid hormone, leukotriene C 4 , rifampin, pravastatin, bile salts, eicosanoids, peptides, and other organic anions [6][7][8][9][10]. OATP-C has also been shown to mediate cellular uptake of bilirubin and its glucuronide conjugates [11].…”

Section: Introductionmentioning

confidence: 99%

Organic anion transporting polypeptide-C mediates arsenic uptake in HEK-293 cells

Lu¹,

Tamai²,

Nezu³

et al. 2006

J Biomed Sci

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SummaryArsenic is an established human carcinogen. The role of aquaglyroporins (AQPs) in arsenic disposition was recently identified. In order to examine whether organic anion transporting polypeptide-C (OATP-C) also plays a role in arsenic transport, OATP-C cDNA was transfected into cells of a human embryonic kidney cell line (HEK-293). Transfection increased uptake of the model OATP-C substrate, estradiol-17b-D-glucuronide, by 10-fold. In addition, we measured uptake and cytotoxicity of arsenate, arsenite, monomethylarsonate(MMA V ), and dimethylarsinate (DMA V ). Transfection of OATP-C increased uptake and cytotoxicity of arsenate and arsenite, but not of MMA V or DMA V . Rifampin and taurocholic acid (a substrate of OATP-C) reversed the increased toxicity of arsenate and arsenite seen in OATP-C-transfected cells. The increase in uptake of inorganic arsenic was not as great as that of estradiol-17b-D-glucuronide. Our results suggest that OATP-C can transport inorganic arsenic in a (GSH)-dependent manner. However, this may not be the major pathway for arsenic transport.

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Human Organic Anion Transporting Polypeptide-C (SLC21A6) Is a Major Determinant of Rifampin-Mediated Pregnane X Receptor Activation

Abstract: Rifampin, a member of the rifamycin class of antibiotics, is well known for its ability to induce drug-metabolizing enzymes and transporters, through activation of the pregnane X receptor.

Cited by 292 publications

References 38 publications

Association study of genetic polymorphisms of drug transporters, SLCO1B1, SLCO1B3 and ABCC2, in African-Americans, Hispanics and Caucasians and olmesartan exposure

Association study of genetic polymorphisms of drug transporters, SLCO1B1, SLCO1B3 and ABCC2, in African-Americans, Hispanics and Caucasians and olmesartan exposure

Functional analysis of a mutation in the SLCO1B1 gene (c.1628T>G) identified in a Japanese patient with pravastatin-induced myopathy

Organic anion transporting polypeptide-C mediates arsenic uptake in HEK-293 cells

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