Søderlund E J, Omichinski J G, Dahl J E, Nelson S D, Dybing E
Department of Toxicology, National Institute of Public Health, Oslo 4, Norway.
Pharmacol Toxicol. 1988 Mar;62(3):142-9. doi: 10.1111/j.1600-0773.1988.tb01862.x.
Selectively deuterated and methylated analogues of the flame retardant tris(2,3-dibromopropyl)phosphate (Tris-BP) and its nephrotoxic metabolite bis(2,3-dibromopropyl)phosphate (Bis-BP) were compared to Tris-BP and Bis-BP in inducing acute renal damage in rats. None of the deuterated Tris-BP or Bis-BP analogues significantly altered morphological evidence of nephrotoxicity compared to the protio compounds. On the other hand, some of the selectively methylated analogues were much less nephrotoxic. Although the C1-methyl analogues of both Tris-BP and Bis-BP were as potent nephrotoxicants as Tris-BP and Bis-BP, respectively, neither the C2-methyl nor the C3-methyl analogues were significantly nephrotoxic. Interestingly, whereas the 3,4-dibromobutyl homologue of Tris-BP was not nephrotoxic, the corresponding 3,4-dibromobutyl-Bis homologue was as nephrotoxic as Bis-BP. Additional investigations with treatments that are known to decrease nephrotoxicity caused by several halogenated alkenes, showed that L-(alpha S,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (AT-125) and aminooxyacetic acid were without effects on Tris-BP induced renal damage. Probenecid pretreatment led to a reduction in Tris-BP and Bis-BP tubular necrosis, these effects may be related to inhibition of Bis-BP uptake in the kidney. It appears that the cysteine conjugate beta-lyase pathway is not involved in the generation of nephrotoxic metabolites of Tris-BP.
将阻燃剂磷酸三（2,3 - 二溴丙基）酯（Tris - BP）及其肾毒性代谢物磷酸双（2,3 - 二溴丙基）酯（Bis - BP）的选择性氘代和甲基化类似物与Tris - BP和Bis - BP进行比较，观察它们对大鼠急性肾损伤的诱导作用。与原型化合物相比，氘代的Tris - BP或Bis - BP类似物均未显著改变肾毒性的形态学证据。另一方面，一些选择性甲基化类似物的肾毒性要小得多。尽管Tris - BP和Bis - BP的C1 - 甲基类似物分别与Tris - BP和Bis - BP一样具有强大的肾毒性，但C2 - 甲基和C3 - 甲基类似物均无明显肾毒性。有趣的是，虽然Tris - BP的3,4 - 二溴丁基同系物无肾毒性，但相应的3,4 - 二溴丁基 - Bis同系物与Bis - BP一样具有肾毒性。对已知可降低几种卤代烯烃所致肾毒性的治疗方法进行的进一步研究表明，L -（αS，5S）-α - 氨基 - 3 - 氯 - 4,5 - 二氢 - 5 - 异恶唑乙酸（AT - 125）和氨基氧乙酸对Tris - BP诱导的肾损伤无影响。丙磺舒预处理可减轻Tris - BP和Bis - BP引起的肾小管坏死，这些作用可能与抑制肾脏对Bis - BP的摄取有关。看来半胱氨酸共轭β - 裂解酶途径不参与Tris - BP肾毒性代谢物的生成。
