HPRT高活性Urat1-Uoxダブルノックアウトマウスの確立とキサンチン酸化還元酵素阻害剤の効果

It is known that there are species differences in the purine metabolic system between humans and rodents (e.g. urate oxidase (Uox), and hypoxanthine phosphoribosyltransferase (HPRT), etc.). URAT1 (SLC22A12) is renal urate (UA) reabsorption transporter and the target for UA-lowering therapies. In hum...

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Published in日本薬理学会年会要旨集 p. 3-P-299
Main Authors 内田, 俊也, 細谷, 拓司, 柴田, 茂, 富岡, 直子, 細山田, 真
Format Journal Article
LanguageJapanese
Published 公益社団法人 日本薬理学会 2020
Subjects
excretion
transporter
uric acid
xanthine oxidase
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ISSN2435-4953
DOI10.1254/jpssuppl.93.0_3-P-299

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Abstract It is known that there are species differences in the purine metabolic system between humans and rodents (e.g. urate oxidase (Uox), and hypoxanthine phosphoribosyltransferase (HPRT), etc.). URAT1 (SLC22A12) is renal urate (UA) reabsorption transporter and the target for UA-lowering therapies. In humans, URAT1 deficiency has a significant UA-lowering effect (ULE), but not in Urat1-knokout (KO) mice. The aim of this study is the establishment and urate kinetic profiling of high HPRT activity Urat1-Uox double knockout (DKO) mice and the investigation of the effect of xanthine oxidoreductase inhibitor (XOI), topiroxostat in this model mice. Topiroxostat 1 mg/kg (Top) was administered to DKO mice for 7 days by feeding diet. Oxypurines (UA, hypoxanthine and xanthine) and creatinine in plasma and urine were measured by HPLC. DKO mice showed a significant decrease in plasma UA levels, increased fractional excretion of UA (FEUA), and enhanced Top-induced ULEs, compared with Uox-KO only. Thus, high HPRT activity seems to be important for producing ULE by URAT1 inhibition. The combination therapy of URAT1 inhibition and XOI showed an effective ULEs, suggesting that it is useful for the treatment of hyperuricemia.
AbstractList It is known that there are species differences in the purine metabolic system between humans and rodents (e.g. urate oxidase (Uox), and hypoxanthine phosphoribosyltransferase (HPRT), etc.). URAT1 (SLC22A12) is renal urate (UA) reabsorption transporter and the target for UA-lowering therapies. In humans, URAT1 deficiency has a significant UA-lowering effect (ULE), but not in Urat1-knokout (KO) mice. The aim of this study is the establishment and urate kinetic profiling of high HPRT activity Urat1-Uox double knockout (DKO) mice and the investigation of the effect of xanthine oxidoreductase inhibitor (XOI), topiroxostat in this model mice. Topiroxostat 1 mg/kg (Top) was administered to DKO mice for 7 days by feeding diet. Oxypurines (UA, hypoxanthine and xanthine) and creatinine in plasma and urine were measured by HPLC. DKO mice showed a significant decrease in plasma UA levels, increased fractional excretion of UA (FEUA), and enhanced Top-induced ULEs, compared with Uox-KO only. Thus, high HPRT activity seems to be important for producing ULE by URAT1 inhibition. The combination therapy of URAT1 inhibition and XOI showed an effective ULEs, suggesting that it is useful for the treatment of hyperuricemia.
Author 細谷, 拓司
富岡, 直子
細山田, 真
内田, 俊也
柴田, 茂
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SubjectTerms excretion
transporter
uric acid
xanthine oxidase
Title HPRT高活性Urat1-Uoxダブルノックアウトマウスの確立とキサンチン酸化還元酵素阻害剤の効果
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