X-ray microanalysis and ultrastructural localization of cisplatin in liver and kidney of the rat.

Cisplatin or cis-diamminedichloroplatinum(II) is a platinum coordination compound showing clinically useful antitumor activity, but the major dose-limiting factor is a dose-dependent cumulative nephrotoxicity. At the electron microscopic level, platinum has been localized in the nucleus, microsomes and cytoplasm of cells of the kidney and liver in rats. This report confirms the subcellular localization of platinum and adds one more site of platinum accumulation, the microbody, based on results obtained with an energy-dispersive X-ray microanalyzer (EDX). After daily administration of cisplatin (0.5 mg/ml/kg body weight) successively for 5 weeks, accumulated platinum was detected in microbodies of hepatocytes and epithelial cells of proximal convoluted tubules of the rat. The major site of metal deposition in the kidney was the matrix of many microbodies in the epithelial cells of proximal convoluted tubules. EDX revealed the presence of platinum in those metallic deposits. The matrix of the nucleus also had metallic deposits but they were rather diffuse and platinum could not readily be detected on individual grains in the nucleus. In the liver, major damage was concentrated in hepatocytes, and other types of cells such as Kupffer cells, Ito cells and endothelial cells of capillaries were less affected. Metallic fine grains were localized in the cisterna of smooth-surfaced endoplasmic reticulum and in the matrix of microbodies. The nucleus of hepatocytes had few, if any, metallic precipitates. A specific type of metallic deposition was round aggregations of dense tubules in which platinum was detected by EDX. There was no evidence of platinum precipitation in mitochondria or Golgi complex. These findings suggest that the microbody may play an important role in degradation of the platinum complex both in hepatocytes and epithelial cells of proximal convoluted tubules.