STRUCTURE ACTIVITY STUDIES OF THE NEPHROTOXIC AND MUTAGENIC ACTION OF CYSTEINE CONJUGATES OF CHLOROALKENES AND FLUOROALKENES
STRUCTURE ACTIVITY STUDIES OF THE NEPHROTOXIC AND MUTAGENIC ACTION OF CYSTEINE CONJUGATES OF CHLOROALKENES AND FLUOROALKENES
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DOI：
10.1016/s0009-2797(85)80149-6
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发表时间：
1985-01-01
影响因子：
5.1
通讯作者：
ODUM, J
中科院分区：
文献类型：
--
作者：
GREEN, T;ODUM, J
肾毒素六氯丁二烯 (HCBD)、四氟乙烯 (TFE) 和六氟丙烯 (HFP) 缀合物的半胱氨酸以及三氯乙烯和全氯乙烯的缀合物已被化学合成，并确定了它们的结构与其肾毒性和致突变性之间的关系。 体外。所有缀合物对大鼠肾切片中有机阴离子对氨基马尿酸（PAH）和阳离子四乙基溴化铵（TEA）的吸收都有显着影响，表明切片中的缀合物被激活为干扰离子转运的有毒物质。这一观察结果与已知的六氯丁二烯、TFE 和 HFP 体内肾毒性一致。发现每种缀合物被大鼠肾切片和半纯化的大鼠肾β-裂合酶代谢为丙酮酸、氨和未鉴定的反应性代谢物。当使用半纯化的β-裂解酶时，产生化学计量的丙酮酸和氨。尽管所有缀合物均被β-裂合酶激活并且对离子转运具有相似的作用，但它们的致突变性显着不同。在 Ames 细菌突变试验中，六氯丁二烯、三氯乙烯和全氯乙烯的缀合物被大鼠肾 S9 激活时具有致突变性。不需要代谢辅助因子，这表明激活是由于酶β-裂解酶所致。在同一测定中，TFE 和 HFP 的缀合物在存在或不存在大鼠肾 S9 和辅因子的情况下均不具有诱变性。通过有限数量的半胱氨酸缀合物，已鉴定出氟代烯烃缀合物之间的明显区别，它们具有类似的肾毒性但不具有诱变性。六氯丁二烯半胱氨酸缀合物的致突变性与该化学品已知的肾致癌性一致。
The cysteine of conjugates of the nephrotoxins hexachlorobutadiene (HCBD), tetrafluoroethylene (TFE) and hexafluoropropene (HFP), together with those of tricholoroethylene and perchloroethylene, have been chemically synthesized and a relationship was determined between their structures and their nephrotoxicity and mutagenicity in vitro. All of the conjugates had a marked effect on the uptake of both the organic anion p-aminohippuric acid (PAH) and the cation tetraethylammonium bromide (TEA) into rat kidney slices, suggesting activation of the conjugates in the slices to a toxic species which interferes with ion transport. This observation is consistent with the known nephrotoxicity of HCBD, TFE and HFP in vivo. Each of the conjugates was found to be metabolized by rat kidney slices and by semi-purified rat kidney .beta.-lyase to pyruvate, ammonia and an unidentified reactive metabolite. When semi-purified .beta.-lyase was used stoichiometric amounts of pyruvate and ammonia were produced. Although all of the conjugates were activated by .beta.-lyase and had a similar effect on ion transport, their mutagenicity differed markedly. The conjugates of HCBD, trichloroethylene and perchloroethylene were mutagenic in the Ames bacterial mutation assay when activated by rat kidney S9. Metabolic cofactors were not required suggesting that activation was due to the nzyme .beta.-lyase. In the same assay the conjugates of TFE and HFP were not mutagenic either in the presence or absence of rat kidney S9 and cofactors. With a limited number of cysteine conjugates a clear distinction has been identified between the conjugates of fluoroalkenes which were similarly nephrotoxic but were not mutagenic. The mutagenicity of the cysteine conjugate of HCBD is consistent with the known renal carcinogenicity of this chemical.