Thompson D C, Constantin-Teodosiu D, Moldéus P
Department of Toxicology, Karolinska Institutet, Stockholm, Sweden.
Chem Biol Interact. 1991;77(2):137-47. doi: 10.1016/0009-2797(91)90069-j.
The metabolism and toxic effects of eugenol (4-allyl-2-methoxyphenol) were studies in isolated rat hepatocytes. Incubation of hepatocytes with eugenol resulted in the formation of conjugates with sulfate, glucuronic acid and glutathione. The major metabolite formed was the glucuronic acid conjugate. Covalent binding to cellular protein was observed using [3H]eugenol. Loss of intracellular glutathione and cell death were also observed in these incubations. Concentrations of 1 mM eugenol caused a loss of over 90% of intracellular glutathione and resulted in approximately 85% cell death over a 5-h incubation period. The loss of the majority of glutathione occurred prior to the onset of cell death (2 h). The effects of eugenol were concentration dependent. The addition of 1 mM N-acetylcysteine to incubations containing 1 mM eugenol was able to completely prevent glutathione loss and cell death as well as inhibit the covalent binding of eugenol metabolites to protein. Conversely, pretreatment of hepatocytes with diethylmaleate to deplete intracellular glutathione increased the cytotoxic effects of eugenol. These results demonstrate that eugenol is actively metabolized in hepatocytes and suggest that the cytotoxic effects of eugenol are due to the formation of a reactive intermediate, possibly a quinone methide.
在分离的大鼠肝细胞中研究了丁香酚（4-烯丙基-2-甲氧基苯酚）的代谢和毒性作用。将肝细胞与丁香酚一起孵育会导致形成与硫酸盐、葡萄糖醛酸和谷胱甘肽的结合物。形成的主要代谢产物是葡萄糖醛酸结合物。使用[3H]丁香酚观察到与细胞蛋白质的共价结合。在这些孵育过程中还观察到细胞内谷胱甘肽的损失和细胞死亡。1 mM丁香酚的浓度在5小时的孵育期内导致细胞内谷胱甘肽损失超过90%，并导致约85%的细胞死亡。大多数谷胱甘肽的损失发生在细胞死亡开始之前（2小时）。丁香酚的作用具有浓度依赖性。在含有1 mM丁香酚的孵育物中加入1 mM N-乙酰半胱氨酸能够完全防止谷胱甘肽损失和细胞死亡，并抑制丁香酚代谢产物与蛋白质的共价结合。相反，用马来酸二乙酯预处理肝细胞以耗尽细胞内谷胱甘肽会增加丁香酚的细胞毒性作用。这些结果表明丁香酚在肝细胞中被积极代谢，并表明丁香酚的细胞毒性作用是由于形成了一种反应性中间体，可能是一种醌甲基化物。
