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磷酸三(2,3-二溴丙基)酯的诱变活化作用:微粒体氧化代谢的作用

Mutagenic activation of tris(2,3-dibromopropyl)phosphate: the role of microsomal oxidative metabolism.

作者信息

Søderlund E J, Nelson S D, Dybing E

出版信息

Acta Pharmacol Toxicol (Copenh). 1979 Aug;45(2):112-21. doi: 10.1111/j.1600-0773.1979.tb02370.x.

DOI:10.1111/j.1600-0773.1979.tb02370.x
PMID:40390
Abstract

The flame retardant tris(2,3-dibromopropyl)phosphate (Tris-BP) is converted to products which are mutagenic for Salmonella typhimurium TA 100 in the presence of rat liver microsomes, NADPH and oxygen. Other bromopropyl-compounds were also mutagenic; 2,3-dibromopropene and 2,3-dibromopropionic acid were directly mutagenic, whereas 2,3-dibromopropanol and tris(2-bromopropyl)phosphate were weakly mutagenic after addition of liver microsomes and cofactors. Typical in vivo and in vitro inhibitors of cytochrome P-450 inhibited Tris-BP mutagenicity. The effects of inducers of cytochrome P-450 on Tris-BP mutagenicity was dependent on the concentration of mutagen and microsomal protein in the assay, indicating complexity in the kinetics involved when dealing with possible multiple pathways that lead to mutagenicity. Addition of glutathione strongly inhibited Tris-BP mutagenicity. It is suggested that Tris-BP is oxidized to a reactive electrophile, possibly the 2-keto derivative, which could react with nucleophilic groups in DNA and thus lead to mutagenic events.

摘要

阻燃剂磷酸三(2,3 - 二溴丙基)酯(Tris - BP)在大鼠肝微粒体、NADPH和氧气存在的情况下,会转化为对鼠伤寒沙门氏菌TA 100具有致突变性的产物。其他溴丙基化合物也具有致突变性;2,3 - 二溴丙烯和2,3 - 二溴丙酸具有直接致突变性,而2,3 - 二溴丙醇和磷酸三(2 - 溴丙基)酯在添加肝微粒体和辅助因子后具有弱致突变性。典型的细胞色素P - 450体内和体外抑制剂可抑制Tris - BP的致突变性。细胞色素P - 450诱导剂对Tris - BP致突变性的影响取决于测定中诱变剂和微粒体蛋白的浓度,这表明在处理可能导致致突变性的多种途径时,所涉及的动力学较为复杂。添加谷胱甘肽可强烈抑制Tris - BP的致突变性。有人提出Tris - BP被氧化为一种活性亲电试剂,可能是2 - 酮衍生物,它可与DNA中的亲核基团反应,从而导致致突变事件。

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