LST-2, A human liver-specific organic anion transporter, determines methotrexate sensitivity in gastrointestinal cancers

Abe, Takaaki; Unno, Michiaki; Onogawa, Tohru; Tokui, Taro; Kondo, Tohru Noriko; Nakagomi, Rie; Adachi, Hisanobu; Fujiwara, Koh; Okabe, Mitsunori; Suzuki, Takehiro; Nunoki, Kazuo; Satô, Eiichi; Kakyo, Masayuki; Nishio, Takeshi; Sato, Junichi; Asano, Naoki; Tanemoto, Masayuki; Seki, Makoto; Date, Fumiko; Ono, Koji; Kondo, Yoshiaki; Shiiba, Kenichi; Suzuki, Masanori; Ohtani, Haruo; Shimosegawa, Tooru; Iinuma, Kazuie; Nishimura, Hiroshi; Ito, Sadayoshi; Matsuno, Seiki

doi:10.1053/gast.2001.24804

Cited by 311 publications

(274 citation statements)

References 29 publications

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“…The anticancer and antirheumatic drug MTX is transported in vitro by various members of the OATP1A/1B family (12)(13)(14). To determine the role of Oatp1a/1b transporters in MTX disposition in vivo, we administered MTX (10 mg/kg) i.v.…”

Section: Figurementioning

confidence: 99%

“…This suggests not only that Oatp1a/1b transporters have a high capacity to transport these drugs, but also that they may actively concentrate these drugs in the liver. In vitro studies have shown that MTX is a substrate for Oatp1a4, OATP1B1, OATP1B3, and OATP1A2 (12)(13)(14). FEX is transported in vitro by Oatp1a1, -1a4, -1a5 and -1b2, and OATP1A2 (38,39), but in vitro studies of OATP1B1 and -1B3-mediated uptake of FEX are quite inconsistent (39)(40)(41).…”

Section: Figurementioning

confidence: 99%

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Organic anion transporting polypeptide 1a/1b–knockout mice provide insights into hepatic handling of bilirubin, bile acids, and drugs

Steeg

Wagenaar²,

Kruijssen³

et al. 2010

J. Clin. Invest.

198

196

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Organic anion transporting polypeptides (OATPs) are uptake transporters for a broad range of endogenous compounds and xenobiotics. To investigate the physiologic and pharmacologic roles of OATPs of the 1A and 1B subfamilies, we generated mice lacking all established and predicted mouse Oatp1a/1b transporters (referred to as Slco1a/1b -/-mice, as SLCO genes encode OATPs). Slco1a/1b -/-mice were viable and fertile but exhibited markedly increased plasma levels of bilirubin conjugated to glucuronide and increased plasma levels of unconjugated bile acids. The unexpected conjugated hyperbilirubinemia indicates that Oatp1a/ 1b transporters normally mediate extensive hepatic reuptake of glucuronidated bilirubin. We therefore hypothesized that substantial sinusoidal secretion and subsequent Oatp1a/1b-mediated reuptake of glucuronidated compounds can occur in hepatocytes under physiologic conditions. This alters our perspective on normal liver functioning. Slco1a/1b -/-mice also showed drastically decreased hepatic uptake and consequently increased systemic exposure following i.v. or oral administration of the OATP substrate drugs methotrexate and fexofenadine. Importantly, intestinal absorption of oral methotrexate or fexofenadine was not affected in Slco1a/1b -/-mice. Further analysis showed that rifampicin was an effective and specific Oatp1a/1b inhibitor in controlling methotrexate pharmacokinetics. These data indicate that Oatp1a/1b transporters play an essential role in hepatic reuptake of conjugated bilirubin and uptake of unconjugated bile acids and drugs. Slco1a/1b -/-mice will provide excellent tools to study further the role of Oatp1a/1b transporters in physiology and drug disposition.

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Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Organic anion transporting polypeptide 1a/1b–knockout mice provide insights into hepatic handling of bilirubin, bile acids, and drugs

Steeg

Wagenaar²,

Kruijssen³

et al. 2010

J. Clin. Invest.

198

196

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“…First, overexpression of this gene has been clearly observed in a variety of tumors, including breast, prostate, and gastrointestinal cancers (10,11). Second, this gene has been reported to code for the key methotrexate transporter in colorectal cancer (12). Finally, SLCO1B3 has been seen to be frequently mutated in colorectal cancer (Table S1) (13).…”

Section: Genes With a Restricted Expression In Normal Tissues And Difmentioning

confidence: 99%

Bioinformatics construction of the human cell surfaceome

Cunha

Galante

Souza

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

117

125

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Cell surface proteins are excellent targets for diagnostic and therapeutic interventions. By using bioinformatics tools, we generated a catalog of 3,702 transmembrane proteins located at the surface of human cells (human cell surfaceome). We explored the genetic diversity of the human cell surfaceome at different levels, including the distribution of polymorphisms, conservation among eukaryotic species, and patterns of gene expression. By integrating expression information from a variety of sources, we were able to identify surfaceome genes with a restricted expression in normal tissues and/or differential expression in tumors, important characteristics for putative tumor targets. A high-throughput and efficient quantitative real-time PCR approach was used to validate 593 surfaceome genes selected on the basis of their expression pattern in normal and tumor samples. A number of candidates were identified as potential diagnostic and therapeutic targets for colorectal tumors and glioblastoma. Several candidate genes were also identified as coding for cell surface cancer/testis antigens. The human cell surfaceome will serve as a reference for further studies aimed at characterizing tumor targets at the surface of human cells.colorectal tumors ͉ CT antigens ͉ glioblastoma ͉ transmembrane ͉ tumor cell surface antigens W ith the availability of the human genome sequence, an important goal of current biological research is a more specific and accurate annotation of human genes. One critical property is the subcellular localization of gene products, because this affects their use as potential diagnostic and therapeutic targets. In this respect, the identification of cell surface proteins is of particular interest (1-3) because these proteins represent ideal therapeutic targets. Indeed, cell surface proteins have proved to be relevant to many areas of medicine, and a number of monoclonal antibodies against them are approved for therapeutic applications by the Food and Drug Administration, particularly in cancer therapy. Furthermore, cell surface proteins are also excellent targets for diagnostic assays, especially in biological fluids. On the other hand, there are several issues that make cell surface proteins difficult to manipulate biochemically. First, their hydrophobic transmembrane (TM) domain makes them insoluble. Second, several posttranslational modifications are not executed in commonly used expression systems. Finally, interactions involving cell surface proteins usually have an extremely short half-life (on the order of milliseconds), which has an effect on the development of purification protocols. Despite these limitations, decades of intensive research of cell surface proteins have generated a significant information base. Ideally, this information should be analyzed in a genome-wide context.We generated here a catalog of more than 3,700 genes believed to encode proteins located at the surface of human cells. For the sake of simplicity, we will call this catalog the ''human cell surfaceome.'' An integrated ...

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“…There is no evidence as yet indicating that these carriers are widely expressed in malignant cells and play a role in drug resistance. However, LST-2 has been shown to be highly expressed in a variety of GI cancers (Abe et al, 2001). The physiological role of these carriers with respect to folates, beyond mediating transport in liver and kidney, is not clear.…”

Section: Role Of Membrane Transport Of Antifolates In Drug Resistancementioning

confidence: 99%

Resistance to antifolates

2003

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LST-2, A human liver-specific organic anion transporter, determines methotrexate sensitivity in gastrointestinal cancers

Cited by 311 publications

References 29 publications

Organic anion transporting polypeptide 1a/1b–knockout mice provide insights into hepatic handling of bilirubin, bile acids, and drugs

Organic anion transporting polypeptide 1a/1b–knockout mice provide insights into hepatic handling of bilirubin, bile acids, and drugs

Bioinformatics construction of the human cell surfaceome

Resistance to antifolates

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