Effects of Uremic Serum Residue on OATP1B1‐ and OATP1B3‐Mediated Pravastatin Uptake in OATP‐Expressing HEK293 Cells and Human Hepatocytes

Uchiyama, Hiroo; Tsujimoto, Masayuki; Kimura, Akari; Yuki, Eriko; Saiki, Takashi; Yoshida, Takuya; Furukubo, Taku; Yamakawa, Tomoyuki; Tachiki, Hidehisa; Minegaki, Tetsuya; Nishiguchi, Kohshi

doi:10.1111/1744-9987.12758

Cited by 4 publications

(4 citation statements)

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“…The transfection rate was determined to be greater than 80% and met the requirement of our design. HEK293T cells are currently one of the commonly used in vitro models for studying the relationship between drug transporters and substrates 25,26 . OATP1B1 transfected HEK-293T cells can express OATP1B1 and bind to transport ions.…”

Section: Discussionmentioning

confidence: 99%

“…Because hepatocyte only accounts for 10% of rosuvastatin metabolism 29 and scutellarin has such a significant pharmacokinetic effect on rosuvastatin uptake, suggesting that this effect is more likely to occur on cell surface transporters. HEK293 cells do not express OATP1B1, and it is a model cell that is commonly used to investigate OATP1B1 transport 26 . In this study, we showed that OATP1B1 can mediate the inhibition of scutellarin on rosuvastatin uptake transfected HEK293T cells with high expression of OATP1B1.…”

Section: Discussionmentioning

confidence: 99%

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Scutellarin inhibition of the rosuvastatin uptake in rat hepatocytes and the competition for organic anion transporting polypeptide 1B1 in HEK293T cells

Liu

Guo²,

Liu³

et al. 2020

Sci Rep

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www.nature.com/scientificreports www.nature.com/scientificreports/ by hepatocytes 13 . However, the mechanism of OATP1B1 involvement remains unclear, or whether scutellarin and rosuvastatin compete for OATP1B1. Therefore, in this study, we treated rats with rosuvastatin alone, or with a combination of rosuvastatin and a series concentration of scutellarin, to examine the plasma and hepatic levels of rosuvastatin in rats, as well as in OATP1B1 transfected HEK293T cells. Materials and MethodsAnimals. A total of 48 healthy male Sprague-Dawley rats weighing 230-270 g were obtained by the Experimental Animal Center of Nanchang University Medical College. Animals were housed in individual cages in an air-conditioned room at room temperature of 25 ± 1 °C with a 12 h light: 12 h dark period. The study was approved by the Ethical Committee of JiangXi Medical College, and all experiments were carried out with humane care according the Animal Care and Use Committee (ACUC) of Nanchang University Medical College. Rats were given free access to drinking water, after experiments, rats were euthanized by intraperitoneal injection of sodium pentobarbital with a dose of 200 mg/kg. Treatment and sampling. The rats were randomly divided into two groups with 24 rats in each group: the rosuvastatin group (rosuvastatin 10 mg/kg) and the combination treatment group (rosuvastatin 10 mg/kg + scutellarin 50 mg/kg), the concentrations used in the animal were transformed from clinical dose. The treatment was administered by gavage in the morning before feeding, and scutellarin was administered immediately following the rosuvastatin administration for the combination treatment group. In each group, 6 rats were maintained throughout the study and used for orbital vein blood sampling (0.15 ml) at 0 (before), 0.5, 1.0, 1.5, 2.0, 3.0, 5.0, 8.0, 12.0, 18.0, 24.0 h post treatment, to obtain the concentration-time profile data. Six of the remaining rats in each group were sacrificed at 1 h, 2 h, and 6 h post treatment (each time point) to sample the 0.5 ml of eyeball blood and the liver tissues. Blood was stored in heparinized tubes and the plasma was separated by centrifugation, then stored at −80 °C for further analysis. Scientific RepoRtS |(2020) 10:1308 | https://doi.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Scutellarin inhibition of the rosuvastatin uptake in rat hepatocytes and the competition for organic anion transporting polypeptide 1B1 in HEK293T cells

Liu

Guo²,

Liu³

et al. 2020

Sci Rep

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“…We have previously shown uremic toxins concentration, indoxyl sulfate (total: 163.8 ± 6.2 µM, unbound: 26.3 ± 2.4 µM) and hippuric acid (total: 208.7 ± 2.6 µM, unbound 106.1 ± 1.5 µM) (Values represent the mean ± S.E.) 16 . These K i and IC 50 are higher than concentration of uremic toxins in our uremic serum, in other words, BCRP seems not to be inhibited by sole uremic toxin, but uremic toxins and other components in uremic serum may co-inhibit that.…”

Section: Discussionmentioning

confidence: 93%

Uremic serum residue decreases SN-38 sensitivity through suppression of organic anion transporter polypeptide 2B1 in LS-180 colon cancer cells

Ozawa

Tsujimoto

Uchiyama

et al. 2019

Sci Rep

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Pharmacokinetics of SN-38 in patients with end-stage kidney disease (ESKD) is partially varied because of fluctuations in transporters expression and/or function by high protein bound-uremic toxins concentration. The fluctuations may induce variations in anticancer drugs sensitivity to cancer cells. We aimed to clarify the variations in sensitivity of SN-38 to cancer patients with ESKD and investigate this mechanism, by human colon cancer cells exposed to uremic serum residue. LS180 cells were exposed to normal or uremic serum residue (LS/NSR or LS/USR cells) for a month. IC50 values of SN-38 in LS/NSR or LS/USR cells were calculated from viability of each cells treated SN-38. mRNA expression and intracellular SN-38 accumulation was evaluated by RT-PCR and HPLC-fluorescence methods, respectively. The IC50 value in LS/USR cells was higher than that in LS/NSR cells. Organic anion transporter polypeptide (OATP) 2B1 mRNA expression was lower in LS/USR cells than in LS/NSR cells, and SN-38 accumulation in LS/USR cells was lower than that in LS/NSR cells. Only co-treatment baicalin, which is OATP2B1 inhibitor, almost negated the difference in SN-38 accumulation between LS/NSR and LS/USR. Anticancer effects of substrates of OATP2B1, such as SN-38, were reduced in ESKD patients at the same plasma substrate concentration.

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“…The organic anion transporting polypeptides (OATPs) are a different category of organic anion transporters involved in the uptake of uremic toxins in the endothelium. OATPs belong to the SLCO superfamily and they have been detected in various tissues, such as lung, liver, kidney, and brain [ 102 , 103 ]. Grube et al [ 104 ] showed that these transporters are expressed in the cardiac endothelium.…”

Section: Transporters and Receptors Of Uremic Toxins In The Endothmentioning

confidence: 99%

How do Uremic Toxins Affect the Endothelium?

Cunha

Santos

Barreto

et al. 2020

Toxins

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Uremic toxins can induce endothelial dysfunction in patients with chronic kidney disease (CKD). Indeed, the structure of the endothelial monolayer is damaged in CKD, and studies have shown that the uremic toxins contribute to the loss of cell–cell junctions, increasing permeability. Membrane proteins, such as transporters and receptors, can mediate the interaction between uremic toxins and endothelial cells. In these cells, uremic toxins induce oxidative stress and activation of signaling pathways, including the aryl hydrocarbon receptor (AhR), nuclear factor kappa B (NF-κB), and mitogen-activated protein kinase (MAPK) pathways. The activation of these pathways leads to overexpression of proinflammatory (e.g., monocyte chemoattractant protein-1, E-selectin) and prothrombotic (e.g., tissue factor) proteins. Uremic toxins also induce the formation of endothelial microparticles (EMPs), which can lead to the activation and dysfunction of other cells, and modulate the expression of microRNAs that have an important role in the regulation of cellular processes. The resulting endothelial dysfunction contributes to the pathogenesis of cardiovascular diseases, such as atherosclerosis and thrombotic events. Therefore, uremic toxins as well as the pathways they modulated may be potential targets for therapies in order to improve treatment for patients with CKD.

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Effects of Uremic Serum Residue on OATP1B1‐ and OATP1B3‐Mediated Pravastatin Uptake in OATP‐Expressing HEK293 Cells and Human Hepatocytes

Cited by 4 publications

References 27 publications

Scutellarin inhibition of the rosuvastatin uptake in rat hepatocytes and the competition for organic anion transporting polypeptide 1B1 in HEK293T cells

Scutellarin inhibition of the rosuvastatin uptake in rat hepatocytes and the competition for organic anion transporting polypeptide 1B1 in HEK293T cells

Uremic serum residue decreases SN-38 sensitivity through suppression of organic anion transporter polypeptide 2B1 in LS-180 colon cancer cells

How do Uremic Toxins Affect the Endothelium?

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