Life span extension of XDH knockout mouse with high HPRT activity

Although xanthinuria is asymptomatic in humans, xanthine dehydrogenase knockout (XdhKO) mice die from renal failure. The activities of hypoxanthine phosphoribosyl transferase (HPRT) of human and wild mice are higher than those of labolatory mice. The aim of this study is to compare the life span between the XdhKO mice with high and low HPRT activity. High HPRT activity XdhKO mice were produced by crossbreeding with a consomic C57BL/6 mice whose Hprt allele is derived from wild mice. Urinary substances of high or low HPRT activity XdhKO mice were separated by HPLC. In a low HPRT mice, which died at 7 weeks of age, the excretion of xanthine (XA) decreased with increasing excretion of hypoxanthine (HX) without changing the total amount of urinary oxypurine excretion. At one week before death, HX excretion of low HPRT mice were 2.5 times higher than those of high HPRT mice. Prior to death of high HPRT activity mice, the excretion of XA and its precursor xanthosine decreased as HX excretion increased. In conclusion, the change of urinary oxypurine excretion from xanthine to hypoxanthine might be a cause of death of XdhKO mice, suggesting involvement of the reduction of IMP dehydrogenase activity due to NAD+ deficiency or competitive inhibition.