Fukuoka M, Takahashi T, Naito K, Takada K
Division of Medical Chemistry, National Institute of Hygienic Sciences, Tokyo, Japan.
J Appl Toxicol. 1988 Feb;8(1):43-52. doi: 10.1002/jat.2550080108.
The mechanism of Tris-BP or Bis-BP (a metabolite of Tris-BP) induced nephrotoxicity was investigated by determining urinary excretion of enzymes and selected metabolites. Rats received single oral doses of 0, 71.7, 143.4 and 286.8 mumol/kg tris (2,3-dibromopropyl) phosphate (Tris-BP) or bis (2,3-dibromopropyl) phosphate (Bis-BP). Urine was collected over a 24 h period and subjected to biochemical examinations. Comparative studies on Tris-BP- and Bis-BP-induced nephrotoxicities were carried out for abnormal patterns of urinary excretion. The urinary excretion of glucose was higher in Bis-BP than Tris-BP at a dose of 143.4 mumol/kg, but this pattern reversed at a dose of 286.8 mumol/kg. Peak lactate excretion occurred later than peak glucose excretion with 143.4 and 286.8 mumol/kg Tris BP and 143.4 mumol/kg Bis-BP. Bis-BP 286.8 mumol/kg caused a transient urinary elevation of lactate on Day 2. Uric acid was excreted at higher levels for Bis-BP than Tris-BP on day 2 of urine collection. Activities of urinary enzymes including alkaline phosphatase, aspartate aminotransferase and gamma-glutamyltransferase, were different on the first day of post-treatment for Tris-BP and Bis-BP. Leucine aminopeptidase and lactate dehydrogenase levels differed on the second day. Activities of the former enzymes on the day 2 urine suggested a transformation of Tris-BP to Bis-BP. Urinary patterns of lactate dehydrogenase isoenzymes (LDH-1-LDH-5) were different between Tris-BP and Bis-BP when rats were treated with the dose of 286.8 mumol/kg: Tris-BP caused a higher excretion of LDH-4 and LDH-5 in urine on day 1 and all five isoenzymes into the day 2 urine. Bis-BP caused slightly higher excretion of LDH-5 and LDH-4 into the day 1 and 3 urine, respectively. Bis-BP but not Tris-BP caused abnormally urinary excretion of sodium ion. Histopathologically, the nephrotoxic effect of Tris-BP appeared one day later and was more obvious than that of Bis-BP in rats after single oral administration.
通过测定酶和特定代谢物的尿排泄情况，研究了三（2,3 - 二溴丙基）磷酸酯（Tris - BP）或双（2,3 - 二溴丙基）磷酸酯（Bis - BP，Tris - BP的一种代谢产物）诱导肾毒性的机制。大鼠单次口服剂量分别为0、71.7、143.4和286.8 μmol/kg的三（2,3 - 二溴丙基）磷酸酯（Tris - BP）或双（2,3 - 二溴丙基）磷酸酯（Bis - BP）。收集24小时尿液并进行生化检查。针对Tris - BP和Bis - BP诱导的肾毒性异常排泄模式进行了对比研究。在剂量为143.4 μmol/kg时，Bis - BP组的葡萄糖尿排泄量高于Tris - BP组，但在剂量为286.8 μmol/kg时这种模式发生逆转。当给予143.4和286.8 μmol/kg Tris - BP以及143.4 μmol/kg Bis - BP时，乳酸排泄峰值出现的时间晚于葡萄糖排泄峰值。286.8 μmol/kg的Bis - BP在第2天导致尿液中乳酸短暂升高。在收集尿液的第2天，Bis - BP组的尿酸排泄水平高于Tris - BP组。包括碱性磷酸酶、天冬氨酸氨基转移酶和γ - 谷氨酰转移酶在内的尿酶活性，在Tris - BP和Bis - BP处理后的第一天有所不同。亮氨酸氨肽酶和乳酸脱氢酶水平在第二天存在差异。第2天尿液中前几种酶的活性表明Tris - BP向Bis - BP发生了转化。当大鼠以286.8 μmol/kg剂量处理时，Tris - BP和Bis - BP的乳酸脱氢酶同工酶（LDH - 1 - LDH - 5）尿排泄模式不同：Tris - BP在第1天导致尿液中LDH - 4和LDH - 5排泄增加，在第2天导致所有五种同工酶排泄增加。Bis - BP分别在第1天和第3天导致尿液中LDH - 5和LDH - 4排泄略有增加。Bis - BP而非Tris - BP导致尿液中钠离子排泄异常。组织病理学上，单次口服给药后，Tris - BP在大鼠体内的肾毒性作用比Bis - BP出现晚一天且更明显。
