Zicca Antonio, Cafaggi Sergio, Mariggiò Maria A, Vannozzi Maria O, Ottone Massimo, Bocchini Vittorio, Caviglioli Gabriele, Viale Maurizio
Dipartimento di Medicina Sperimentale, Sezione di Anatomia Umana, Università di Genova, Via De Toni, 14, 16132 Genoa, Italy.
Eur J Pharmacol. 2002 May 10;442(3):265-72. doi: 10.1016/s0014-2999(02)01537-6.
In preceding papers, we proposed that procainamide hydrochloride, a class I antiarrhythmic agent, was able to protect mice and rats from cisplatin-induced nephrotoxicity and that it could exert its action through accumulation in kidneys followed by coordination with cisplatin (or its hydrolysis metabolites) and formation of a less toxic platinum compound similar to the new platinum(II) triamine complex cis-diamminechloro-[2-(diethylamino)ethyl 4-amino-benzoate, N4]-chlorideplatinum(II) monohydrochloride monohydrate, obtained by the reaction of cisplatin with procaine hydrochloride. Hepatotoxicity is not considered as a dose-limiting toxicity for cisplatin, but liver toxicity can occur when the antineoplastic drug is administered at high doses. Here, we report that procainamide hydrochloride, at an i.p. dose of 100 mg/kg, reduces cisplatin-induced hepatotoxicity, as evidenced by the normalization of plasma activity of glutamic oxalacetic transaminase and gamma-glutamyl transpeptidase, as well as by histological examination of the liver tissue. Twenty-four hours after i.p. treatment with the combination of 7.5 mg/kg cisplatin and 100 mg/kg procainamide, a significant increase of procainamide (+56%, P<0.05), total platinum (+31%, P<0.05), platinum-DNA adducts (+31%, P<0.05) and percent DNA-DNA interstrand cross-links (+69%, P<0.02) was found in liver tissue, as compared to animals treated with cisplatin alone. Moreover, in accordance with these findings, we also observed a slightly lower concentration and cumulative excretion of platinum in the feces. Since mitochondrial injury is considered a central event in the early stages of the nephrotoxic effect of cisplatin, the distribution of platinum in these subcellular organelles obtained from hepatocytes was determined after treatment with cisplatin with or without procainamide hydrochloride, together with platinum concentration in their cytosolic fraction. Our data show that the coadministration of procainamide hydrochloride produced a rearrangement of subcellular platinum distribution in hepatocytes with a slight decrease in mitochondria (-15%, P<0.10) and a slight increase in the cytosolic fraction (+40%, P<0.10) of platinum content, compared to the treatment with cisplatin alone. In analogy with our previous results in the kidney, confirmed here by our data in vitro, we suggest that the hepatoprotective activity of procainamide hydrochloride is linked to the formation of a less toxic platinum complex, which leads to inactivation of cisplatin itself and/or its highly toxic hydrolysis metabolites and to a different subcellular distribution of platinum.
在之前的论文中，我们提出盐酸普鲁卡因胺（一种I类抗心律失常药物）能够保护小鼠和大鼠免受顺铂诱导的肾毒性，并且它可以通过在肾脏中蓄积，随后与顺铂（或其水解代谢产物）配位并形成一种毒性较小的铂化合物来发挥作用，这种铂化合物类似于通过顺铂与盐酸普鲁卡因反应得到的新型铂（II）三胺配合物顺 - 二氨氯 - [2 - （二乙氨基）乙基4 - 氨基 - 苯甲酸酯，N4] - 氯铂（II）盐酸盐一水合物。肝毒性不被认为是顺铂的剂量限制性毒性，但当以高剂量施用这种抗肿瘤药物时可能会发生肝毒性。在此，我们报告，腹腔注射剂量为100 mg/kg的盐酸普鲁卡因胺可降低顺铂诱导的肝毒性，这通过谷氨酸草酰乙酸转氨酶和γ - 谷氨酰转肽酶的血浆活性正常化以及肝组织的组织学检查得以证实。在用7.5 mg/kg顺铂和100 mg/kg盐酸普鲁卡因胺联合腹腔注射治疗24小时后，与单独用顺铂治疗的动物相比，肝组织中盐酸普鲁卡因胺显著增加（+56%，P<0.05）、总铂显著增加（+31%，P<0.05）、铂 - DNA加合物显著增加（+31%，P<0.05）以及DNA - DNA链间交联百分比显著增加（+69%，P<0.02）。此外，与这些发现一致，我们还观察到粪便中铂的浓度和累积排泄量略低。由于线粒体损伤被认为是顺铂肾毒性早期阶段的核心事件，在用顺铂或顺铂与盐酸普鲁卡因胺联合处理后，测定了从肝细胞获得的这些亚细胞器中铂的分布以及它们胞质部分中的铂浓度。我们的数据表明，与单独用顺铂处理相比，联合施用盐酸普鲁卡因胺使肝细胞中亚细胞铂分布发生重排，线粒体中铂含量略有下降（-15%，P<0.10），胞质部分中铂含量略有增加（+40%，P<0.10）。与我们之前在肾脏中的结果类似（这里通过我们的体外数据得到证实），我们认为盐酸普鲁卡因胺的肝保护活性与形成毒性较小的铂配合物有关，这导致顺铂本身和/或其高毒性水解代谢产物失活，并导致铂在亚细胞中的不同分布。
