Histopathological, ultrastructural, and biochemical traits of apoptosis induced by peroxisomicine A1 (toxin T-514) from Karwinskia parvifolia in kidney and lung

Abstract

Peroxisomicine A1 (PA1) is a toxin isolated from the Karwinskia genus plants whose target organs are the liver, kidney, and lung. In vitro studies demonstrated the induction of apoptosis by PA1 in cancer cell lines, and in vivo in the liver. Apoptosis has a wide range of morphological features such as cell shrinkage, plasma membrane blistering, loss of microvilli, cytoplasm, and chromatin condensation, internucleosomal DNA fragmentation, and formation of apoptotic bodies that are phagocytized by resident macrophages or nearby cells. Early stages of apoptosis can be detected by mitochondrial alterations. We investigated the presence of apoptosis in vivo at the morphological, ultrastructural, and biochemical levels in two target organs of PA1: kidney and lung. Sixty CD-1 mice were divided into three groups (n = 20): untreated control (ST), vehicle control (VH), and PA1 intoxicated group (2LD50). Five animals of each group were sacrificed at 4, 8, 12, and 24 h post-intoxication. Kidney and lung were examined by morphometry, histopathology, ultrastructural, and DNA fragmentation analysis. Pre-apoptotic mitochondrial alterations were present at 4 h. Apoptotic bodies were observed at 8 h and increased over time. TUNEL positive cells were detected as early as 4 h, and the DNA ladder pattern was observed at 12 h and 24 h. The liver showed the highest value of fragmented DNA, followed by the kidney and the lung. We demonstrated the induction of apoptosis by a toxic dose of PA1 in the kidney and lung in vivo. These results could be useful in understanding the mechanism of action of this compound at toxic doses in vivo.