Xanthine oxidoreductase knockout mice with high HPRT activity were not rescued by NAD⁺ replenishment

Abstract

Although xanthinuria is nonfatal in human, xanthine oxidoreductase knockout (Xor-KO) mice have only a short lifespan. Hypoxanthine phosphoribosyltransferase activity (HPRT) in human and wild mice is higher than in laboratory mice. The aim of this study was to investigate the underlying mechanisms that give rise to the longer lifespan of high-HPRT/Xor-KO mice. Before Xor-KO mice die, urinary excretion of hypoxanthine increased with a corresponding decrease in excretion of xanthine. The switch of excretion from xanthine to hypoxanthine might be a cause of death for Xor-KO mice, suggesting inhibition of NAD⁺-dependent IMP dehydrogenase. Because hypoxanthine inhibits the synthesis of nicotinamide mononucleotide (NMN), a precursor of NAD⁺, the accumulation of hypoxanthine in Xor-KO mice may cause a depletion in the levels of NAD⁺. Moreover, urinary excretion of urate in high-HPRT/Uox-KO/Xor-KO mice means urate derived from gut microbiota is absorbed by the intestine. Likewise, over excretion of oxypurine in mice may be caused by intestinal absorption of oxypurine. For NAD⁺ replenishment, oral supplementation with 1% L-tryptophan, an alternative precursor of NAD⁺, resulted in a recovery of body weight gain in high-HPRT/Uox-KO/Xor-KO mice. In conclusion, the death of Xor-KO mice by renal failure seems to be caused by a depletion in NAD⁺ levels due to the intracellular accumulation of hypoxanthine. NAD⁺ replenishment by oral supplementation of NMN or tryptophan was complicated by the effect of gut microbiota and failed to rescue high-HPRT/Xor-KO mice. The attenuation of intestinal absorption of oxypurines seems to be necessary to avoid hypoxanthine accumulation and over excretion of oxypurine.

Keywords:

• Hypoxanthine
• tryptophan
• nicotinamide adenine dinucleotide
• enzymology
• xanthine oxidoreductase
• xanthine

Additional information

Funding

This study was supported by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology (# 26460347) and from the Gout Research Foundation.