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Perfecting a high hypoxanthine phosphoribosyltransferase activity–uricase KO mice to test the effects of purine‐ and non‐purine‐type xanthine dehydrogenase (XDH) inhibitors
Author(s) -
Hosoya Takuji,
Uchida Shunya,
Shibata Shigeru,
Tomioka Naoko H.,
Hosoyamada Makoto
Publication year - 2020
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.14978
Subject(s) - allopurinol , hypoxanthine , xanthine , purine , hypoxanthine phosphoribosyltransferase , hypoxanthine guanine phosphoribosyltransferase , xanthine dehydrogenase , chemistry , biochemistry , uric acid , medicine , endocrinology , xanthine oxidase , pharmacology , biology , enzyme , mutant , gene
Background and Purpose Purine metabolism in mice and human differ in terms of uricase ( Uox ) activity as well as hypoxanthine phosphoribosyltransferase (HPRT) activity. The aim of this study was the establishment of high HPRT activity– Uox knockout (KO) mice as a novel hyperuricaemic model. Then to investigate the effects of purine‐type xanthine dehydrogenase (XDH) inhibitor, allopurinol, and non‐purine‐type XDH inhibitor, topiroxostat, on purine metabolism. Experimental Approach A novel hyperuricaemic mouse model was established by mating B6‐ChrXC MSM mice with uricase KO mice. The pharmacological effects of allopurinol and topiroxostat were explored by evaluating urate, hypoxanthine, xanthine and creatinine in the plasma and urine of these model mice. Furthermore, we analysed the effect of both drugs on erythrocyte hypoxanthine phosphoribosyltransferase activity. Key Results Plasma urate level and urinary urate/creatinine ratio significantly decreased after administration of allopurinol 30 mg·kg −1 or topiroxostat 1 mg·kg −1 for 7 days. The urate‐lowering effect was equivalent for allopurinol and topiroxostat. However, the urinary hypoxanthine/creatinine ratio and xanthine/creatinine ratio after treatment with topiroxostat were significantly lower than for allopurinol. In addition, the urinary oxypurine/creatinine ratio was significantly lowered after treatment with topiroxostat, but allopurinol elicited no such effect. Furthermore, allopurinol inhibited mouse erythrocyte hypoxanthine phosphoribosyltransferase, while topiroxostat did not. Conclusions and Implications High hypoxanthine phosphoribosyltransferase activity– uricase KO mice were established as a novel hyperuricaemic animal model. In addition, topiroxostat, a non‐purine‐type xanthine dehydrogenase inhibitor, elicited a potent plasma urate‐lowering effect. However, unlike allopurinol, topiroxostat did not perturb the salvage pathway, resulting in lowered total oxypurine excretion.