A Novel Human Hepatic Organic Anion Transporting Polypeptide (OATP2)

Hsiang, Bonnie C.; Zhu, Yingjie; Wang, Zhaoqing; Wu, Yuli; Sasseville, Vito G.; Yang, Wen-Pin; Kirchgessner, Todd G.

doi:10.1074/jbc.274.52.37161

Cited by 579 publications

(111 citation statements)

References 38 publications

Supporting

Mentioning

105

Contrasting

Order By: Relevance

“…They confirm previous studies that demonstrated complete protection of lethal intoxications in mice by the known OATP1B1 and OATP1B3 substrate rifampin (Hermansky et al, 1991;Vavricka et al, 2002). Therefore, one can speculate that any drug with reasonable high affinity for OATP, for example, statins (Hsiang et al, 1999), could prevent lowdose microcystin intoxication, provided it is given simultaneously with or shortly after the intoxication.…”

Section: Discussionsupporting

confidence: 74%

“…It has previously been shown that hepatocellular uptake of microcystins is inhibited by bile salts and BSP Runnegar et al, 1995), suggesting that Oatps/OATPs could be involved in microcystin transport. Furthermore, several Oatps/OATPs that are expressed at the sinusoidal membrane of hepatocytes (Abe et al, 1999(Abe et al, , 2001Cattori et al, 2000;Hsiang et al, 1999;König et al, 2000aKönig et al, , 2000b are able to transport cyclic peptides such as the endothelin antagonist BQ-123, the opioid peptide [d-penicillamin 2,5] enkephalin, and the mushroom toxin phalloidin (Meier-Abt et al, 2004). Therefore, we tested these hepatic Oatps/OATPs in the X. laevis oocyte expression system and could demonstrate that rat Oatp1b2, human OATP1B1, and human OATP1B3 indeed mediate uptake of radiolabeled microcystin-LR (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Oatps/OATPs that are expressed in the brain (bloodbrain barrier, choroid plexus) as well as in the liver include rat Oatp1a1 (Jacquemin et al, 1994), rat Oatp1a4 (Abe et al, 1998;Noé et al, 1997), human OATP1A2 (Kullak-Ublick et al, 1995, and human OATP2B1 (Kullak-Ublick et al, 2001). Rat Oatp1b2 (Cattori et al, 2000), human OATP1B1 (Abe et al, 1999;Hsiang et al, 1999;König et al, 2000b), and human OATP1B3 (König et al, 2000a) are primarily expressed in the liver. In the present study, we used the radiolabeled dihydromicrocystin-LR epimer ]microcystin-LR , which was previously shown to have similar characteristics as native microcystins .…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Organic anion transporting polypeptides expressed in liver and brain mediate uptake of microcystin

Fischer

Altheimer

Cattori

et al. 2005

Toxicology and Applied Pharmacology

435

276

View full text Add to dashboard Cite

Microcystins are toxins produced by freshwater cyanobacteria. They are cyclic heptapeptides that exhibit hepato-and neurotoxicity. However, the transport systems that mediate uptake of microcystins into hepatocytes and across the blood-brain barrier have not yet been identified. Using the Xenopus laevis oocyte expression system we tested whether members of the organic anion transporting polypeptide superfamily (rodent: Oatps; human: OATPs) are involved in transport of the most common microcystin variant microcystin-LR by measuring uptake of a radiolabeled derivative dihydromicrocystin-LR. Among the tested Oatps/OATPs, rat Oatp1b2, human OATP1B1, human OATP1B3, and human OATP1A2 transported microcystin-LR 2-to 5-fold above water-injected control oocytes. This microcystin-LR transport was inhibited by co-incubation with the known Oatp/OATP substrates taurocholate (TC) and bromosulfophthalein (BSP). Microcystin-LR transport mediated by the human OATPs was further characterized and showed saturability with increasing microcystin-LR concentrations. The apparent K m values amounted to 7 F 3 AM for OATP1B1, 9 F 3 AM for OATP1B3, and 20 F 8 AM for OATP1A2. No microcystin-LR transport was observed in oocytes expressing Oatp1a1, Oatp1a4, and OATP2B1. These results may explain some of the observed organ-specific toxicity of microcystin-LR. Oatp1b2, OATP1B1, and OATP1B3 are responsible for microcystin transport into hepatocytes, whereas OATP1A2 mediates microcystin-LR transport across the blood-brain barrier.

show abstract

Section: Discussionsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Organic anion transporting polypeptides expressed in liver and brain mediate uptake of microcystin

Fischer

Altheimer

Cattori

et al. 2005

Toxicology and Applied Pharmacology

435

276

View full text Add to dashboard Cite

show abstract

“…Human organic anion-transporting polypeptide 1B1 (OATP1B1), transporter of pravastatin, is expressed on the basolateral membrane in the hepatocytes responsible for the hepatocellular uptake of pravastatin (Hsiang et al 1999). The major site of cholesterol synthesis, the liver, is the main target organ of statins.…”

Section: Introductionmentioning

confidence: 99%

Pharmacogenetic determinants of variability in lipid-lowering response to pravastatin therapy

et al. 2006

View full text Add to dashboard Cite

Pravastatin is mainly taken up from the circulation into the liver via organic anion-transporting polypeptide 1B1 (SLCO1B1 gene product). We examined the contribution of genetic variants in the SLCO1B1 gene and other candidate genes to the variability of pravastatin efficacy in 33 hypercholesterolemic patients. In the initial phase of pravastatin treatment (8 weeks), heterozygous carriers of the SLCO1B1*15 allele had poor low-density lipoprotein cholesterol (LDL-C) reduction relative to non-carriers (percent reduction: -14.1 vs -28.9%); however, the genotype-dependent difference in the cholesterol-lowering effect disappeared after 1 year of treatment. Cholesterol 7a-hydroxylase (CYP7A1) and apolipoprotein E (APOE) are known to contribute to lipid metabolism. Homozygous carriers of the CYP7A1 -204C allele or heterozygotes for both CYP7A1 -204C and APOE 4 alleles showed significantly poorer LDL-C reduction compared to that in other genotypic groups after 1 year of treatment (-24.3 vs -33.1%). These results suggest that the SLCO1B1*15 allele is associated with a slow response to pravastatin therapy, and the combined genotyping of CYP7A1 and APOE genes is a useful index of the lipid-lowering effect of pravastatin.

show abstract

“…12) Oatp2, exclusively expressed in the liver, has been identified to transport taurocholic acid, pravastatin and fluorescein-methotrexate. 13,14) We previously reported that MTX treatment downregulated the expression levels of Mrp2, Oat1 and Oat3 in rats. 15) Alterations in Mrp2 expression and/or function could have a variety of clinically important effects.…”

mentioning

confidence: 99%

Effect of Methotrexate Treatment on Expression Levels of Organic Anion Transporter Polypeptide 2, P-Glycoprotein and Bile Salt Export Pump in Rats

Shibayama

Takeda

Yamada

2009

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

High-dose methotrexate (HDMTX) chemotherapy with leucovorin (LV) rescue has been used as a therapeutic strategy in oncology since the 1970s. Adverse reactions following extension of methotrexate (MTX) elimination are a crucial problem in HDMTX chemotherapy. MTX is a substrate for drug transporters, which are multidrug resistance protein 2 (Mrp2), organic anion transporter polypeptide 2 (Oatp2) and other transporters. We previously reported that MTX treatment downregulated the expression level of Mrp2 in rats. Here we examined the effect of MTX treatment on the expression of Oatp2, P-glycoprotein (P-gp) and bile salt export pump (Bsep) in rats. MTX was single-injected intraperitoneally at a dose of 150 mg/kg, and Western blot analysis was performed. The levels of Oatp2, P-gp and Bsep in the liver on day 4 after treatment were downregulated to 36.3؎6.9%, 51.5؎5.2% and 61.8؎5.5% (mean؎S.E.M.) of controls, respectively. Expression levels of P-gp in the kidney and ileum were also downregulated to 38.5؎1.6% and 16.2؎1.6% of controls, respectively. These effects of MTX were partially recovered by LV, which rescues normal cells from MTX toxicity. In conclusion, the result indicates that MTX treatment downregulates expression levels of Oatp2, P-gp and Bsep.

show abstract

A Novel Human Hepatic Organic Anion Transporting Polypeptide (OATP2)

Cited by 579 publications

References 38 publications

Organic anion transporting polypeptides expressed in liver and brain mediate uptake of microcystin

Organic anion transporting polypeptides expressed in liver and brain mediate uptake of microcystin

Pharmacogenetic determinants of variability in lipid-lowering response to pravastatin therapy

Effect of Methotrexate Treatment on Expression Levels of Organic Anion Transporter Polypeptide 2, P-Glycoprotein and Bile Salt Export Pump in Rats

Contact Info

Product

Resources

About