The Superfamily of Organic Anion Transporting Polypeptides

Division of Clinical Pharmacology and Toxicology, Department of Medicine, University Hospital, CH-8091 Zurich, Switzerland.
Biochimica et Biophysica Acta (Impact Factor: 4.66). 02/2003; 1609(1):1-18. DOI: 10.1016/S0005-2736(02)00633-8
Source: PubMed


Organic anion transporting polypeptides (Oatps/OATPs) form a growing gene superfamily and mediate transport of a wide spectrum of amphipathic organic solutes. Different Oatps/OATPs have partially overlapping and partially distinct substrate preferences for organic solutes such as bile salts, steroid conjugates, thyroid hormones, anionic oligopeptides, drugs, toxins and other xenobiotics. While some Oatps/OATPs are preferentially or even selectively expressed in one tissue such as the liver, others are expressed in multiple organs including the blood-brain barrier (BBB), choroid plexus, lung, heart, intestine, kidney, placenta and testis. This review summarizes the actual state of the rapidly expanding OATP superfamily and covers the structural properties, the genomic classification, the phylogenetic relationships and the functional transport characteristics. In addition, we propose a new species independent and open ended nomenclature and classification system, which is based on divergent evolution and agrees with the guidelines of the Human Genome Nomenclature Committee.

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Available from: Bruno Hagenbuch
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    • "MCs are mainly excreted by the hepatocytes, but up to 9 % can be eliminated by urine (Bischoff, 2001) which makes the kidneys a potential target for MC-LR toxicity (Menezes et al., 2013). Furthermore, OATP-A, one of the known MC active transporters, has been identified recently at mRNA level in the human kidney (Hagenbuch & Meier, 2003). Thus, the kidney might also be an important target organ for MCs (Dias et al., 2009). "
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    ABSTRACT: Microcystin-LR (MC-LR) is a potent hepatotoxin, and increasing evidence suggests that it might also induce kidney injury. The aim of present work was to evaluate the cytotoxicity and possible apoptotic effects of MC-LR on human embryonic kidney cell line (HEK-293) and human kidney adenocarcinoma cell line (ACHN). Cells were exposed for 24 h to pure MC-LR (1.0-200 µM) and the cytotoxic effects were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and Sulphorhodamine B (SRB) cell viability assays. Cell viability in both cell lines were significantly decreased after treatment with MC-LR at 50 µM for 24 h (p<0.001). Moreover, MC-LR treated ACHN and HEK-293 cells exhibited a marked dose dependant loss of confluence as judged by phase contrast microscopy. Similarly, fluorescence microscopic observations following Acridine Orange-Ethidium Bromide (AO/EB) staining confirmed that both cell types were undergoing apoptosis after treatment with MC-LR for 24 h. Expression of three apoptosis related genes namely, Bax, Survivin and p53 was analyzed by quantitative RT-PCR analysis. Both Bax and p53 genes were functioned as promoters of MC-LR mediated apoptosis in ACHN and HEK-293 cells. Survivin gene was act as suppressor of apoptosis in lower MC-LR concentration (1 µM) and the gene was up regulated at higher MC-LR concentration (10 µM) tested (p< 0.001). It was detected that the significant increase of caspase 3 (p<0.0001) and caspase 9 (p<0.0001) activity in both cell lines after exposure to MC-LR for 24 h indicating the MC-LR induces cytotoxicity and a marked apoptosis in both ACHN and HEK-293 kidney cell lines.
    Full-text · Article · Jan 2015 · Microbiology
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    • "Microcystins are unable to directly penetrate the lipid membranes of cells, thus, membrane transporters are necessary to ensure the uptake of these toxins. Organic anion transporter peptides (OATPs) were shown to be responsible for this transport in mammals [44] and potential OATPs were also identified in C. elegans [45]. Therefore, this mechanism is also very likely responsible for the uptake of MC-LR in C. elegans. "
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    ABSTRACT: Cyanobacterial blooms in aquatic environments are frequently characterized by elevated levels of microcystins, a potent hepatotoxin. Here we exposed the nematode Caenorhabditis elegans with environmentally realistic concentrations of MC-LR to explore its non-hepatic toxicity. Lifespan, reproduction and growth assays confirmed the toxic potential of 100 μg/L MC-LR even in this liver-lacking invertebrate. Whole-genome microarray analysis revealed that a neuromodulating action was the dominant response in nematodes challenged with 100 μg/L MC-LR. Indeed, most of the 201 differentially expressed genes were associated with neurobehavior, neurogenesis, and signaling associated pathways. In addition, a whole-genome miRNA-microarray highlighted that, in particular, members of the let-7 family were differentially regulated. These miRNAs are involved in the developmental timing of cell fates, including neurons, and are probably also part of the stress response system. To conclude, neurological modulation is the main transcriptional stress response in C. elegans exposed to MC-LR.
    Full-text · Article · Sep 2014 · Chemico-Biological Interactions
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    • "Additionally, simvastatin and its hydrolysate simvastatin acid are substrates of organic anion transporting polypeptide 1B1 (OATP1B1/Oatp2)11,12,13,14, an influx transporter expressed on the sinusoidal membrane of hepatocytes. Recent studies have shown that OATP1B1 plays a clinically important role in the hepatic elimination of several drugs including statins, via mediating the hepatic uptake11,12,13,14,15. Both clinical trials and animal experiments have demonstrated that DM may alter the pharmacokinetic behaviors of some drugs via regulating the expressions and activities of cytochrome P450s (CYP450s) and drug transporters in the liver16,17,18,19,20,21,22. Breast cancer resistance protein (Bcrp) and multidrug resistance-associated protein 2 (Mrp2) have also been reported to mediate statin transport11,23,24. "
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    ABSTRACT: Aim: Simvastatin is frequently administered to diabetic patients with hypercholesterolemia. The aim of the study was to investigate the pharmacokinetics of simvastatin and its hydrolysate simvastatin acid in a rat model of type 2 diabetes. Methods: Diabetes was induced in 4-week-old rats by a treatment of high-fat diet combined with streptozotocin. After the rats received a single dose of simvastatin (20 mg/kg, po, or 2 mg/kg, iv), the plasma concentrations of simvastatin and simvastatin acid were determined. Simvastatin metabolism and cytochrome P4503A (Cyp3a) activity were assessed in hepatic microsomes, and its uptake was studied in freshly isolated hepatocytes. The expression of Cyp3a1, organic anion transporting polypeptide 2 (Oatp2), multidrug resistance-associated protein 2 (Mrp2) and breast cancer resistance protein (Bcrp) in livers was measured using qRT-PCR. Results: After oral or intravenous administration, the plasma concentrations and areas under concentrations of simvastatin and simvastatin acid were markedly decreased in diabetic rats. Both simvastatin metabolism and Cyp3a activity were markedly increased in hepatocytes of diabetic rats, accompanied by increased expression of hepatic Cyp3a1 mRNA. Furthermore, the uptake of simvastatin by hepatocytes of diabetic rats was markedly increased, which was associated with increased expression of the influx transporter Oatp2, and decreased expression of the efflux transporters Mrp2 and Bcrp. Conclusion: Diabetes enhances the metabolism of simvastatin and simvastatin acid in rats via up-regulating hepatic Cyp3a activity and expression and increasing hepatic uptake.
    Full-text · Article · Aug 2014 · Acta Pharmacologica Sinica
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