Renal Reabsorptive Transport of Uric Acid Precursor Xanthine by URAT1 and GLUT9

Arakawa, Hiroshi; Amezawa, Natsumi; Kawakatsu, Yu; Tamai, Ikumi

doi:10.1248/bpb.b20-00597

Cited by 16 publications

(7 citation statements)

References 37 publications

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“…4) Likewise, canine kidney MDCKII cells co-expressing both uptake and efflux transporters were used to evaluate transcellular transport across epithelial cells that mimic renal reabsorption and hepatobiliary excretion. [5][6][7] As detailed above, in vitro transcellular transport assays are invaluable for the evaluation of pharmacokinetic characteristics. However, transport assays which use inserts to culture such cells have their limitations.…”

Section: Introductionmentioning

confidence: 99%

Drug Transcellular Transport Assay Using a High Porosity Honeycomb Film

Nakazono

Arakawa

Nishino

et al. 2021

Biological & Pharmaceutical Bulletin

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In vitro transport studies across cells grown on culture inserts are widely used for evaluating pharmacokinetic characteristics such as intestinal membrane permeability. However, measurements of the apparent permeability coefficient of highly lipophilic compounds are often limited by transport across the membrane filters, not by transport across the cultured cells. To overcome this concern, we have investigated the utility of a high-porosity membrane honeycomb film (HCF) for transcellular transport studies. Using the HCF inserts, the apparent permeability coefficient (P app ) of the drugs tested in LLC-PK1 and Caco-2 cells tended to increase with an increase in lipophilicity, reaching a maximum P app value at Log D higher than 2. In contrast, using the commercially available Track-Etched membrane (TEM) inserts, a maximum value was observed at Log D higher than 1. The basolateral to apical transport permeability P app(BL→AP) of rhodamine 123 across LLC-PK1 cells that express P-glycoprotein (P-gp) cultured on HCF inserts and TEM inserts was 2.33 and 2.39 times higher than the reverse directional P app(AP→BL) permeability, respectively. The efflux ratio (P app(B-A) / P app(A-B) ) of rhodamine 123 in LLC-PK1 expressing P-gp cells using HCF inserts was comparable to that obtained using TEM inserts, whereas the transported amount in both directions was significantly higher when using the HCF inserts. Accordingly, due to the higher permeability and high porosity of HCF membranes, it is expected that transcellular transport of high lipophilic as well as hydrophilic compounds and substrate recognition of transporters can be evaluated more accurately by using HCF inserts.

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Section: Introductionmentioning

confidence: 99%

Drug Transcellular Transport Assay Using a High Porosity Honeycomb Film

Nakazono

Arakawa

Nishino

et al. 2021

Biological & Pharmaceutical Bulletin

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“…[26] Xanthine and hypoxanthine are vital intermediates in purine metabolism, and they are turned into uric acid through XOR (xanthine oxidoreductase). [27] The trend of biomarkers revealed that xanthine, L-glutamine, hypoxanthine, and inosine demonstrated a decreasing trend in the GZFL group. Thus, the protection of myocardial ischemia by purine metabolism could be due to decreased uric acid levels.…”

Section: Discussionmentioning

confidence: 94%

“…However, when uric acid levels are higher than physiological concentrations, it can instead elevate oxidative stress [26] . Xanthine and hypoxanthine are vital intermediates in purine metabolism, and they are turned into uric acid through XOR (xanthine oxidoreductase) [27] . The trend of biomarkers revealed that xanthine, L‐glutamine, hypoxanthine, and inosine demonstrated a decreasing trend in the GZFL group.…”

Section: Discussionmentioning

confidence: 99%

Integrated Metabolomics and Network Pharmacology to Reveal the Mechanisms of Guizhi‐Fuling Treatment for Myocardial Ischemia

Yan

Duan

Zhou

et al. 2022

Chemistry & Biodiversity

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Myocardial ischemia is a cardio-physiological condition due to a decrease in blood perfusion to the heart, leading to reduced oxygen supply and abnormal myocardial energy metabolism. Guizhi-Fuling (GZFL) is effective in treating Myocardial ischemia. However, its mechanism of action is unclear and requires further exploration. We attempt to decipher the mechanisms behind GZFL treating Myocardial ischemia by integrating metabolomics and network pharmacology. In this study, myocardial metabolomic analysis was performed using GC/MS to identify the potential mechanism of action of GZFL during myocardial ischemia. Then, network pharmacology was utilized to analyze key pathways and construct a pathway-core target network. Molecular docking was incorporated to validate core targets within network pharmacological signaling pathways. Finally, western blots were utilized to verify core targets of metabolomics, network pharmacology integrated pathways, and key signaling targets. Thus, 22 critical biomarkers of GZFL for treating myocardial ischemia were identified. Most of these metabolites were restored using modulation after GZFL treatment. Based on the network pharmacology, 297 targets of GZFL in treating myocardial ischemia were identified. The further comprehensive analysis focused on three key targets, such as Tyrosine hydroxylase (TH), myeloperoxidase (MPO), and phosphatidylinositol 3kinases (PIK3CA), and their related metabolites and pathways. Compared with the model group, the protein expression levels of TH, MPO and PIK3CA were reduced in GZFL. Therefore, the mechanism of GZFL for treating myocardial ischemia could inhibit myocardial inflammatory factors, reduce myocardial inflammation, and restore endothelial function while controlling norepinephrine release and uric acid concentration.

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“…Although SLC43A3 has been identified as a transporter involved in HX transport, the details of transporters involved in HX transport in the kidney are not yet known [ 34 ]. At least, it has been reported that URAT1 does not directly transport HX [ 35 ], indicating that loss of URAT1 indirectly regulates the activity or expression of HX transporters, resulting in increased HX excretion. Further analysis, including the identification of HX transporters, will be necessary in the future.…”

Section: Discussionmentioning

confidence: 99%

Analysis of Purine Metabolism to Elucidate the Pathogenesis of Acute Kidney Injury in Renal Hypouricemia

Miyamoto

Sato²,

Nagata³

et al. 2022

Biomedicines

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Renal hypouricemia is a disease caused by the dysfunction of renal urate transporters. This disease is known to cause exercise-induced acute kidney injury, but its mechanism has not yet been established. To analyze the mechanism by which hypouricemia causes renal failure, we conducted a semi-ischemic forearm exercise stress test to mimic exercise conditions in five healthy subjects, six patients with renal hypouricemia, and one patient with xanthinuria and analyzed the changes in purine metabolites. The results showed that the subjects with renal hypouricemia had significantly lower blood hypoxanthine levels and increased urinary hypoxanthine excretion after exercise than healthy subjects. Oxidative stress markers did not differ between healthy subjects and hypouricemic subjects before and after exercise, and no effect of uric acid as a radical scavenger was observed. As hypoxanthine is a precursor for adenosine triphosphate (ATP) production via the salvage pathway, loss of hypoxanthine after exercise in patients with renal hypouricemia may cause ATP loss in the renal tubules and consequent tissue damage.

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Renal Reabsorptive Transport of Uric Acid Precursor Xanthine by URAT1 and GLUT9

Cited by 16 publications

References 37 publications

Drug Transcellular Transport Assay Using a High Porosity Honeycomb Film

Drug Transcellular Transport Assay Using a High Porosity Honeycomb Film

Integrated Metabolomics and Network Pharmacology to Reveal the Mechanisms of Guizhi‐Fuling Treatment for Myocardial Ischemia

Analysis of Purine Metabolism to Elucidate the Pathogenesis of Acute Kidney Injury in Renal Hypouricemia

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