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首页> 外文期刊>Life sciences >Allopurinol induces renal toxicity by impairing pyrimidine metabolism in mice.
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Allopurinol induces renal toxicity by impairing pyrimidine metabolism in mice.

机译：别嘌醇通过损害小鼠的嘧啶代谢来诱导肾脏毒性。

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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.
机译：我们调查了别嘌醇的毒性作用与嘧啶代谢在小鼠之间的关系。在二硝基氟苯（DNFB）致敏的小鼠中，别嘌呤醇诱导的血浆转氨酶水平升高不受尿苷的影响。相反，最后一次注射尿苷后18小时血浆肌酐和BUN趋于下降。给予单剂量别嘌呤醇后，在DNFB致敏的小鼠中检测到血浆和尿中的尿苷（OD）。相反，新合成的黄嘌呤氧化酶/黄嘌呤脱氢酶抑制剂TEI-6720在DNFB致敏的小鼠中既不引起嘧啶代谢异常，也不引起肾功能损害。同样，给予高剂量别嘌呤醇的正常小鼠显示出嘧啶代谢异常，并且肾毒性可以被尿苷改善，这表明别嘌醇本质上引起嘧啶代谢异常，从而导致肾脏损害。在DNFB致敏的小鼠中，别嘌呤醇可增加尿OD排泄，其程度与施用相同剂量别嘌呤醇的正常小鼠相似。但是，与普通小鼠相比，DNFB致敏的小鼠中别嘌呤醇对肾脏的损害更为明显。组织病理学观察表明，别嘌呤醇在收集管和乳头管中诱导牙结石形成。 DNFB增加了结石形成，尿苷减少了。这些观察结果表明，DNFB-致敏作用增强了别嘌呤醇的肾脏毒性，这可能是由于DNFB和别嘌呤醇之间存在某些生物学相互作用。在人类中，可能存在一些生物相互作用，这些相互作用可增强别嘌呤醇的毒性，从而导致别嘌呤醇超敏综合征（AHS）的发展。相反，TEI-6720对嘧啶的代谢没有影响，也没有毒性作用。

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