Tolman K G, Gray P D, el Masry S, Luther R R, Janicki R S
Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City.
Biochem Pharmacol. 1989 Apr 1;38(7):1181-4. doi: 10.1016/0006-2952(89)90266-9.
Several aryloxyacetic acid diuretics have shown hepatotoxicity in humans, yet there continues to be interest in developing these compounds because of the uricosuric properties of some of them. This study was designed to test the utility of the hepatocyte monolayer culture as a model for studying these compounds. In addition, an attempt was made to define the structural components that are common to hepatotoxicity. Ticrynafen, indacrinone, ethacrynic acid and A-49816, an investigational compound, were found to be toxic in hepatocyte cultures; thus, with the exception of indacrinone, paralleling the experience in humans. The toxic compounds share a ketodichlorophenoxyacetic acid chemical structure. A-56234, an investigational uricosuric, was also found to be toxic in cultures but has not been demonstrated to be hepatotoxic in humans in limited clinical experience. It does not possess the ketodichlorophenoxyacetic acid structure proper but may be metabolized to a closely related structure. Furosemide, which does not have the ketodichlorophenoxyacetic acid structure, was not toxic in hepatocyte cultures and has not been hepatotoxic in humans. Thus, the structure common to the toxic compounds is ketodichlorophenoxyacetic acid or a closely related compound. The hepatocyte monolayer system appears to be a good model for demonstrating toxicity and, perhaps, for predicting toxicity of new compounds under development.
几种芳氧基乙酸类利尿剂已在人体中显示出肝毒性，但由于其中一些化合物具有促尿酸排泄特性，人们仍对开发这些化合物感兴趣。本研究旨在测试肝细胞单层培养作为研究这些化合物的模型的实用性。此外，还试图确定肝毒性共有的结构成分。发现替可克生、茚达立酮、依他尼酸和一种研究用化合物A - 49816在肝细胞培养中具有毒性；因此，除茚达立酮外，与人体中的情况相似。有毒化合物具有酮二氯苯氧基乙酸化学结构。一种研究用促尿酸排泄剂A - 56234在培养中也被发现具有毒性，但在有限的临床经验中尚未证明其对人体具有肝毒性。它不具有适当的酮二氯苯氧基乙酸结构，但可能代谢为密切相关的结构。呋塞米不具有酮二氯苯氧基乙酸结构，在肝细胞培养中无毒，在人体中也无肝毒性。因此，有毒化合物共有的结构是酮二氯苯氧基乙酸或密切相关的化合物。肝细胞单层系统似乎是一个很好的模型，可用于证明毒性，或许还可用于预测正在开发的新化合物的毒性。
