Acute and subacute toxicity study of water-soluble polyalkylsulfonated C60 in rats
Acute and subacute toxicity study of water-soluble polyalkylsulfonated C60 in rats
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DOI：
10.1177/019262339802600117
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发表时间：
1998-01-01
影响因子：
1.5
通讯作者：
Chiang, LY
中科院分区：
文献类型：
--
作者：
Chen, HHC;Yu, C;Chiang, LY
聚烷基磺化C-60，或FC 4S，一种高度水溶性的笼状富勒烯衍生物，被认为是生物系统中的自由基去除剂或抗氧化剂。制备50 mg/ml水溶液作为主溶液，并在单次给药急性毒性研究或12天亚急性毒性研究中给予雌性Sprague-Dawley CD（Cr 1：CD（R）（SD）BR）大鼠，其中大鼠每天给予该溶液。在半数致死量（LD 50）研究中，大鼠经口给药后无死亡，因此认为FC 4S经口给药无毒。在一项LD 50腹腔注射研究中，大鼠在注射后30小时内死亡; LD 50经测定约为600 mg/kg体重。经腹膜内或静脉注射化合物的大鼠立即通过肾脏消除化合物;肾脏似乎是主要靶器官。该化合物诱导了一种明显的溶酶体过载肾病，一种吞噬溶酶体肾病，其特征在于外皮质与内皮质和髓质之间的着色差异。受累的外皮质表现为弥漫性变性，肾小管上皮细胞中存在大量大空泡和细胞质聚集体。在急性暴露后的大鼠中以及在1次腹腔注射500 mg/kg或静脉注射100 mg/kg后的存活大鼠中检测到吞噬溶酶体肾病。超微结构研究显示，肾小管上皮细胞质中存在大量吞噬溶酶体和/或溶酶体包涵体特征性的膜性聚集物。这些团块局限于液泡中，电子致密，染色不均匀。它们的大小和形状各不相同，并融合或聚集。偶见管周丛内皮细胞吞噬溶酶体。微粒体酶活性分析的初步研究显示，肝脏细胞色素P-450依赖性单加氧酶活性（包括细胞色素P-450、细胞色素B（5）和苯并（a）芘羟化酶）受到抑制，但肾脏细胞色素P-450依赖性单加氧酶活性（包括NADPH-细胞色素P-450还原酶）水平升高。这些酶变化的意义还没有很好地确定。微粒体酶活性的改变与溶酶体超负荷引起的肾病之间的相关性有待进一步研究。这些变化可以作为这类化合物毒性筛选试验的生物标志物。
Polyalkylsulfonated C-60, or FC4S, a highly water-soluble caged fullerene derivative, is believed to be a free radical remover or an antioxidant in biological systems. A 50 mg/ml aqueous solution was prepared as a master solution and administered to female Sprague-Dawley CD(Cr1:CD(R)(SD)BR) rats in a single-dose acute toxicity study or a 12-day subacute toxicity study where rats were given the solution daily. In a study of the median lethal dose (LD50), no rats died after oral administration, and thus FC4S was considered to nontoxic if administered orally. In an LD50 intraperitoneal injection study, rats died within 30 hr after injection; the LD50 was determined to be approximately 600 mg per kilogram of body weight. Rats injected with the compound intraperitoneally or intravenously immediately eliminated the compound through the kidney; the kidney appeared to be the primary target organ. The compound induced a distinct lysosome-overload nephrosis, a phagolysosomal nephropathy characterized by a tinctorial difference between the outer cortex and the inner cortex and the medulla. The affected outer cortex showed a diffuse degeneration, with the presence of numerous large vacuoles and cytoplasmic aggregates in the tubular epithelium. The phagolysosomal nephropathy was detected in rats after acute exposure as well as in the surviving rats following 1 intraperitoneal injection of 500 mg/kg or intravenous injection of 100 mg/kg. Ultrastructural investigation revealed numerous membranous conglomerates characteristic of phagolysosomal and/or lysosomal inclusions in the cytoplasm of the renal tubular epithelium. These conglomerates were confined to the vacuole, electron-dense, and unevenly stained. They varied in size and shape and were fused or aggregated. Occasional phagolysosomes were also observed in the;endothelial cells of the peritubular plexus. A preliminary study of microsomal enzyme activity analysis revealed a suppression effect of liver cytochrome P-450-dependent monooxygenase activities, including cytochrome P-450, cytochrome b(5), and benzo(a)pyrene hydroxylase, but an increased level of kidney cytochrome P-450-dependent monooxygenase activities, including NADPH-cytochrome P-450 reductase. The significance of these enzyme alterations was not well determined. Further study is needed to clarify the correlation between the alterations of microsomal enzyme activity and the nephropathy of lysosomal overload-induced changes. These changes may serve as a biological marker in toxicity screening tests for this class of compound.