Differences in the localization and extent of the renal proximal tubular necrosis caused by mercapturic acid and glutathione conjugates of 1,4-naphthoquinone and menadione.
Differences in the localization and extent of the renal proximal tubular necrosis caused by mercapturic acid and glutathione conjugates of 1,4-naphthoquinone and menadione.
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硫醇尿酸和1,4-萘醌和甲萘醌的谷胱甘肽缀合物引起的肾近端肾小管坏死的定位和程度存在差异。
DOI：
10.1016/0041-008x(90)90307-g
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发表时间：
1990
影响因子：
3.8
通讯作者：
Monks,TJ
中科院分区：
文献类型：
--
作者：
Lau,SS;Jones,TW;Highet,RJ;Hill,BA;Monks,TJ
我们先前已经证明，给大鼠注射不同的苯喹酚-谷胱甘肽(GSH)结合物会导致肾近端小管坏死，最初的损害似乎位于S3节段外髓(OSOM)内的那部分。这种毒性可能是由于对苯二酚的偶联物氧化成对苯二酚，然后与组织大分子共价结合的结果。因此，我们合成了2-甲基-1，4-萘醌和1，4-萘醌的GSH和N-乙酰半胱氨酸结合物。所得的结合物与苯喹酚-GSH结合物有一定的相似之处，但主要的不同之处在于与硫醇反应生成的结合物仍以苯醌的形式存在。2-Methyl-3-(N-acetylcystein-S-yl)-1，4-naphthoquinone可使近端肾小管上皮细胞发生剂量依赖性(50-200mmol.μ/kg)的坏死。病变累及延髓内S2节段和S3节段终末部分。在较低剂量时，S3节段外延髓外条的那部分没有显示出坏死的证据。相反，2-methyl-3-(glutathion-S-yl)-1，4-naphthoquinone(200mmol.kg-1)对肾脏无明显的组织学改变。2-(谷胱甘肽-S基)-1，4-萘酚和2，3-(二谷硫基-S基)-1，4-萘酚(200moL/kg)是较弱的近端肾小管毒性物质，病变累及延髓与OSOM交界处的S3段。本文讨论了甲奈酮的N-乙酰半胱氨酸结合物的毒性与谷胱甘肽结合物的毒性有显著差异的一个可能原因(S)。2-methyl-3-(N-acetylcystein-S-yl)-1，4-naphthoquinone所致病变的定位依据有待进一步研究。
We have previously demonstrated that administration of various benzoquinol-glutathione (GSH) conjugates to rats causes renal proximal tubular necrosis and the initial lesion appears to lie within that portion of the S3segment within the outer stripe of the outer medulla (OSOM). The toxicity may be a consequence of oxidation of the quinol conjugate to the quinone followed by covalent binding to tissue macromolecules. We have therefore synthesized the GSH and N-acetylcysteine conjugates of 2-methyl-1,4-naphthoquinone (menadione) and 1,4-naphthoquinone. The resulting conjugates have certain similarities to the benzoquinol-GSH conjugates, but the main difference is that reaction with the thiol yields a conjugate which remains in the quinone form. 2-Methyl-3-(N-acetylcystein-S-yl)-1,4-naphthoquinone caused a dose-dependent (50–200 μmol/kg) necrosis of the prximal tubular epithelium. The lesion involved the terminal portion of the S2segment and the S3segment within the medullary ray. At the lower doses, that portion of the S3segment in the outer stripe of the outer medulla displayed no evidence of necrosis. In contrast, 2-methyl-3-(glutathion-S-yl)-1,4-naphthoquinone (200 μmol/kg) caused no apparent histological alterations to the kidney. 2-(Glutathion-S-yl)-1,4-naphthoquinone and 2,3-(diglutathion-S-yl)-1,4-naphthoquinone (200 μmol/kg) were relatively weak proximal tubular toxicants and the lesion involved the S3segment at the junction of the medullary ray and the OSOM. A possible reason(s) for the striking difference in the toxicity of the N-acetylcysteine conjugate of menadione, as opposed to the lack of toxicity of the GSH conjugate of menadione, is discussed. The basis for the localization of the lesion caused by 2-methyl-3-(N-acetylcystein-S-yl)-1,4-naphthoquinone requires further study.