Allopurinol induces renal toxicity by impairing pyrimidine metabolism in mice.
We investigated the relationship between the toxic effect of allopurinol and pyrimidine metabolism in mice. Allopurinol-induced increases in plasma transaminase levels in dinitrofluorobenzene (DNFB)-sensitized mice were not affected by uridine. In contrast, plasma creatinine and BUN tended to decrease 18 hr after the last injection of uridine. Both plasma and urinary orotidine (OD) were detected in DNFB-sensitized mice after administration of a single dose of allopurinol. In contrast, TEI-6720, a newly synthesized xanthine oxidase/xanthine dehydrogenase inhibitor, caused neither pyrimidine metabolism abnormality nor renal impairment in DNFB-sensitized mice. Also, normal mice administered high doses of allopurinol showed abnormal pyrimidine metabolism together with renal toxicity which could be ameliorated by uridine, indicating that allopurinol essentially causes pyrimidine metabolism abnormality 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 allopurinol was more striking in DNFB-sensitized mice than in normal mice. Histopathological observations showed that allopurinol induced calculus formation in the collecting tubules and papillary duct. Calculus formation was increased 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. In 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.
Horiuchi
H
H
Pharmaceuticals Development Research Laboratories, Teijin Institute for Bio-Medical Research, Hino, Tokyo, Japan. h.horiuchi@teijin.co.jp
Ota
M
M
Nishimura
S
S
Kaneko
H
H
Kasahara
Y
Y
Ohta
T
T
Komoriya
K
K
D000493:Allopurinol / Q000633:toxicity*; D000818:Animals; D000963:Antimetabolites / Q000633:toxicity*; D004139:Dinitrofluorobenzene / Q000494:pharmacology; D004342:Drug Hypersensitivity; D004347:Drug Interactions; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011743:Pyrimidines / Q000378:metabolism*; D014529:Uridine / Q000494:pharmacology
D000963:Antimetabolites; D011743:Pyrimidines; D000493:Allopurinol; D004139:Dinitrofluorobenzene; D014529:Uridine