Cresol isomers: comparison of toxic potency in rat liver slices.
Cresol isomers: comparison of toxic potency in rat liver slices.
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DOI：
10.1006/taap.1994.1048
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发表时间：
1994-03
影响因子：
3.8
通讯作者：
D. Thompson;K. Perera;R. Fisher;K. Brendel
中科院分区：
文献类型：
--
作者：
D. Thompson;K. Perera;R. Fisher;K. Brendel
使用精密切割的大鼠肝切片作为试验系统，对甲酚异构体（邻、间和对甲基苯酚）的毒性进行了比较。在等摩尔浓度下，对甲酚是毒性最大的异构体。要观察到与对甲酚相同程度的细胞杀伤作用，需要浓度高5- 10倍的邻位或间位异构体。巯基前体N-乙酰半胱氨酸可抑制对甲酚的毒性，而马来酸二乙酯预处理肝片可使谷胱甘肽耗竭，从而增强对甲酚的毒性。然而，这些治疗对邻甲酚或间甲酚毒性的影响很小。对甲酚迅速耗尽细胞内谷胱甘肽水平，而邻位和间位异构体耗尽谷胱甘肽的程度较低。[14 C]对甲酚代谢为一种反应性中间体，该中间体与切片蛋白共价结合，并被N-乙酰半胱氨酸抑制。在微粒体孵育中，还观察到[14 C]对甲酚代谢产物的共价结合。这种结合被谷胱甘肽抑制，并导致谷胱甘肽结合物的形成。在谷胱甘肽的情况下，对羟基苯甲醇是主要的微粒体代谢产物形成的对甲酚，但这种化合物是没有毒性的肝切片在2 mM的浓度。这些结果表明，对甲酚是最有毒的甲酚异构体在大鼠肝组织和它的毒性是依赖于反应中间体的形成。结果还表明，邻位和间位异构体的毒性机制可能与对甲酚不同。
A comparison of the toxicity of cresol isomers (o-, m-, and p-methylphenol) was carried out using precision-cut rat liver slices as a test system. At equimolar concentrations p-cresol was the most toxic isomer. A 5- to 10-fold higher concentration of either the o- or m-isomers was required to observe the same degree of cell killing as p-cresol. The toxicity of p-cresol was inhibited by the thiol precursor N-acetylcysteine and was enhanced by pretreatment of liver slices with diethyl maleate to deplete glutathione. These treatments, however, had little effect on either o- or m-cresol toxicity. p-Cresol rapidly depleted intracellular glutathione levels, while the o- and m-isomers depleted glutathione to a lesser extent. [14C]p-cresol was metabolized to a reactive intermediate which covalently bound to slice protein and was inhibited by N-acetylcysteine. In microsomal incubations covalent binding of [14C]p-cresol metabolites was also observed. This binding was inhibited by glutathione and resulted in the formation of a glutathione conjugate. In the absence of glutathione, p-hydroxybenzyl alcohol was the major microsomal metabolite formed from p-cresol, but this compound was not toxic to liver slices at a concentration of 2 mM. These results demonstrate that p-cresol is the most toxic cresol isomer in rat liver tissue and that its toxicity is dependent on the formation of a reactive intermediate. The results also suggest that the mechanism(s) of toxicity of the o- and m-isomers may differ from that of p-cresol.