Uric acid analogue as a possible xenobiotic marker of uric acid transporter Urat1 in rats

Arakawa, Hiroshi; Amezawa, Natsumi; Katsuyama, Tomomichi; Nakanishi, Takeo; Tamai, Ikumi

doi:10.1016/j.dmpk.2018.12.003

Cited by 6 publications

(4 citation statements)

References 11 publications

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“…This view is supported by in vitro transport data, human disease mutations, and GWAS studies. It is considered a major drug target for the treatment of hyperuricemia [ 46 , 47 ].…”

Section: Discussionmentioning

confidence: 99%

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Loss of the Kidney Urate Transporter, Urat1, Leads to Disrupted Redox Homeostasis in Mice

2023

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High uric acid is associated with gout, hypertension, metabolic syndrome, cardiovascular disease, and kidney disease. URAT1 (SLC22A12), originally discovered in mice as Rst, is generally considered a very selective uric acid transporter compared to other closely-related kidney uric acid transporters such as OAT1 (SLC22A6, NKT) and OAT3 (SLC22A8). While the role of URAT1 in regulating human uric acid is well-established, in recent studies the gene has been linked to redox regulation in flies as well as progression of renal cell carcinoma. We have now identified over twenty metabolites in the Urat1 knockout that are generally distinct from metabolites accumulating in the Oat1 and Oat3 knockout mice, with distinct molecular properties as revealed by chemoinformatics and machine learning analysis. These metabolites are involved in seemingly disparate aspects of cellular metabolism, including pyrimidine, fatty acid, and amino acid metabolism. However, through integrative systems metabolic analysis of the transcriptomic and metabolomic data using a human metabolic reconstruction to build metabolic genome-scale models (GEMs), the cellular response to loss of Urat1/Rst revealed compensatory processes related to reactive oxygen species handling and maintaining redox state balances via Vitamin C metabolism and cofactor charging reactions. These observations are consistent with the increasingly appreciated role of the antioxidant properties of uric acid. Collectively, the results highlight the role of Urat1/Rst as a transporter strongly tied to maintaining redox homeostasis, with implications for metabolic side effects from drugs that block its function.

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“…This view is supported by in vitro transport data, human disease mutations, and GWAS studies. It is considered a major drug target for the treatment of hyperuricemia [ 46 , 47 ].…”

Section: Discussionmentioning

confidence: 99%

“…Our analyses provide much needed physiological context to the widely-held view of uric acid as a modulator of redox state [ 45 , 46 ]. However, we do not propose a direct link between uric acid transport by Urat1 and our analysis of tissue and whole animal metabolic state.…”

Section: Discussionmentioning

confidence: 99%

Loss of the Kidney Urate Transporter, Urat1, Leads to Disrupted Redox Homeostasis in Mice

2023

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“…Dotinurad is a novel, selective urate reabsorption inhibitor (SURI), which reduces serum uric acid levels via selective inhibition of urate transporter 1 (URAT1). URAT1 are expressed on the proximal renal tubules and is responsible for reabsorption of uric acid [9].…”

Section: Introductionmentioning

confidence: 99%

Dotinurad: a clinical pharmacokinetic study of a novel, selective urate reabsorption inhibitor in subjects with hepatic impairment

et al. 2019

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Background Dotinurad is a novel, selective urate reabsorption inhibitor, which reduces serum uric acid levels by inhibiting the urate transporter 1 (URAT1). We compared the pharmacokinetics (PK), pharmacodynamics (PD), and safety of dotinurad in subjects with hepatic impairment and normal hepatic function. Methods This was a multicenter, open-label, single dose study. A total of 24 subjects were divided into four groups: the normal hepatic function group and the mild, moderate, and severe hepatic impairment groups. The primary endpoints were changes in plasma dotinurad levels and PK parameters. Results The geometric mean ratio of the maximum plasma concentration (C max) [two-sided 90% confidence interval (CI)] of dotinurad in in the mild, moderate, and severe hepatic impairment groups relative to that in the normal hepatic function group was 0.840 (0.674-1.047), 0.798 (0.653-0.976), and 0.747 (0.570-0.979), respectively, showing a lower C max in the moderate and severe hepatic impairment groups. Following adjustment for body weight, only the moderate hepatic impairment group had a lower C max than the normal hepatic function group. No meaningful differences in other PK parameters were observed between the groups. Regarding the PD of dotinurad, the changes in serum uric acid levels after dosing were similar in all groups. As for safety, no noteworthy concerns were raised in relation to any group. Conclusion The study revealed no clinically meaningful influence of hepatic impairment on the PK, PD, or safety of dotinurad. These findings indicate possibility that dotinurad can be used without dose adjustment in patients with hepatic impairment.

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“…In the proximal tubular (PT) cells, apical urate transporters form a super-molecular structure called urate transportsome, which are organized by a PDZ scaffold (23). Uric acid reabsorption transporters play an important role in regulating serum uric acid levels, and inhibitors of these transporters such as lesinurad and dotinurad attenuate hyperuricemia (24)(25)(26)(27).…”

Section: Introductionmentioning

confidence: 99%

Human URAT1/SLC22A12gene promoter is regulated by 27-hydroxycholesterol through estrogen response elements

Matsubayashi

Sakaguchi

Sahara

et al. 2019

Preprint

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Elevated levels of uric acid, a metabolite of purine in humans, is related to various diseases, such as gout, atherosclerosis and renal dysfunction. The excretion and reabsorption of uric acid to/from urine is tightly regulated by uric acid transporters. The amino acid sequences of uric acid reabsorption transporters, URAT1/SLC22A12, OAT4/SLC22A11, and OAT10/SLC22A13, share closer phylogenic relationship, whereas the gene promoter sequences are distant phylogenic relationship. Through the single-cell RNA-sequencing analysis of an adult human kidney, we found that only a small number of cells express these transporters, despite their role in the regulation of serum uric acid levels. Transcriptional motif analysis on these transporter genes, revealed that the URAT1/SLC22A12 gene promoter displayed the most conserved estrogen response elements (EREs) among the three transporters. The endogenous selective estrogen receptor modulator (SERM) 27-hydroxycholesterol (27HC) had positive effects on the transcriptional activity of URAT1/SLC22A12. We also found that 27HC increased the protein and gene expression of URAT1/SLC22A12 in mouse kidneys and human kidney organoids, respectively. These results strongly suggest the role of 27HC for URAT1/SLC22A12 expression in renal proximal tubules and upregulation of serum uric acid levels and also show the relationship between cholesterol metabolism and serum uric acid regulation.Significance StatementThe elevated levels of serum uric acid cause various diseases, and the excretion/reabsorption of uric acid to/from urine is tightly regulated by the uric acid transporters. We found that despite the role in serum uric acid regulation, only a small number of cells express URAT1/SLC22A12. We also found that URAT1/SLC22A12 gene promoter region has effective estrogen response elements, and endogenous selective estrogen receptor (ER) modulator 27-hydroxycholesterol (27HC) increased URAT1/SLC22A12 expression in the mice kidneys and human kidney organoids. These suggest that 27HC increases URAT1/SLC22A12 expression and upregulate serum uric acid levels. Since 27HC connects cholesterol metabolism, our study indicates the important link between cholesterol metabolism and serum uric acid regulation, and also provides a novel therapeutic approach to hyperuricemia.

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Uric acid analogue as a possible xenobiotic marker of uric acid transporter Urat1 in rats

Cited by 6 publications

References 11 publications

Loss of the Kidney Urate Transporter, Urat1, Leads to Disrupted Redox Homeostasis in Mice

Loss of the Kidney Urate Transporter, Urat1, Leads to Disrupted Redox Homeostasis in Mice

Dotinurad: a clinical pharmacokinetic study of a novel, selective urate reabsorption inhibitor in subjects with hepatic impairment

Human URAT1/SLC22A12gene promoter is regulated by 27-hydroxycholesterol through estrogen response elements

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