Allopurinol induces renal toxicity by impairing pyrimidine metabolism in mice

We investigated the relationship between the toxic effect of allopurinol an d pyrimidine metabolism in mice. Allopurinol-induced increases in plasma tr ansaminase levels in dinitrofluorobenzene (DNFB)-sensitized mice were not a ffected by uridine. In contrast, plasma creatinine and BUN tended to decrea se 18 hr after the last injection of uridine. Both plasma and urinary oroti dine (OD) were detected in DNFB-sensitized mice after administration of a s ingle dose of allopurinol. In contrast, TEI-6720, a newly synthesized xanth ine oxidase/xanthine dehydrogenase inhibitor, caused neither pyrimidine met abolism abnormality nor renal impairment in DNFB-sensitized mice. Also, nor mal mice administered high doses of allopurinol showed abnormal pyrimidine metabolism together with renal toxicity which could be ameliorated by uridi ne, indicating that allopurinol essentially causes pyrimidine metabolism ab normality leading to renal impairment. In DNFB-sensitized mice, allopurinol increased urinary OD excretion to an extent similar to that in normal mice administered the same dose of allopurinol. However, renal impairment by al lopurinol was more striking in DNFB-sensitized mice than in normal mice. Hi stopathological observations showed that allopurinol induced calculus forma tion in the collecting tubules and papillary duct. Calculus formation was i ncreased by DNFB and decreased by uridine. These observations indicate that the enhancement of the renal toxicity of allopurinol by DNFB-sensitization may be due to some biological interactions between DNFB and allopurinol. I n humans, it is possible that there are some biological interactions which serve to enhance the toxicity of allopurinol, resulting in the development of allopurinol hypersensitivity syndrome (AHS). In contrast, TEI-6720, had no effect on pyrimidine metabolism and showed no toxic effect.