Abou-Donia M B, Lapadula D M, Suwita E
Department of Pharmacology, Duke University Medical Center, Durham, NC 27710.
Toxicology. 1988 May;49(2-3):469-77. doi: 10.1016/0300-483x(88)90033-9.
Concurrent exposures to organophosphorus insecticide leptophos and the industrial solvents n-hexane and toluene were implicated in causing an outbreak of neuropathy in workers. Although both leptophos and n-hexane produce central-peripheral distal axonopathy, the morphology and distribution of neuropathic lesions are distinct, reflecting different modes of action. The molecular mechanisms of organophosphorus compound-induced delayed neurotoxicity (OPIDN) and aliphatic hexacarbon-induced neurotoxicity have been investigated utilizing various biochemical techniques, (i.e. one- and two-dimensional gel electrophoresis, immunoblotting, peptide mapping). Oral administration of tri-o-cresyl phosphate (TOCP) produced delayed neurotoxicity and increased in vitro Ca2+ and calmodulin-dependent kinase protein phosphorylation of cytoskeletal proteins in brain, spinal cord, and sciatic nerve of chickens. This enhanced protein phosphorylation correlated well with the following characteristics of OPIDN: test chemical, whether an OPIDN-producing or not; dose-dependence and time course of the effect; and the animal sex sensitivity, age selectivity, and species susceptibility. The proteins that showed an increased phosphorylation were identified to be; alpha- and beta-tubulin, microtubule-associated protein-2 (MAP-2), and the 3 neurofilament proteins 70 kDa, 160 kDa, and 210 kDa. Further studies suggested that the increased protein phosphorylation is not related to an effect on protein phosphatase or ATPase activity, but rather to altered Ca2+-calmodulin kinase II activity. Aliphatic hexacarbon-induced neurotoxicity is characterized by an accumulation of 10 nm neurofilaments above the nodes of Ranvier in the spinal cord and peripheral nerve. Treatment of rats with 2,5-hexanedione, the active neurotoxic metabolite of n-hexane, produced protein crosslinking in a dose-dependent manner. This treatment also decreased protein phosphorylation of neurofilament proteins as well as MAP-2. These studies demonstrate the involvement of cytoskeletal proteins in the molecular pathogenesis of chemical-induced neurotoxicity.
同时接触有机磷杀虫剂溴苯磷以及工业溶剂正己烷和甲苯被认为是导致工人神经病变暴发的原因。尽管溴苯磷和正己烷都会引发中枢 - 外周远端轴索性神经病，但神经病变的形态和分布是不同的，这反映了不同的作用方式。利用各种生化技术（即一维和二维凝胶电泳、免疫印迹、肽图谱分析）对有机磷化合物诱导的迟发性神经毒性（OPIDN）和脂肪族六碳化合物诱导的神经毒性的分子机制进行了研究。给鸡口服磷酸三邻甲苯酯（TOCP）会产生迟发性神经毒性，并增加鸡脑、脊髓和坐骨神经中细胞骨架蛋白的体外Ca2+和钙调蛋白依赖性激酶蛋白磷酸化。这种增强的蛋白磷酸化与OPIDN的以下特征密切相关：受试化学物质是否产生OPIDN；效应的剂量依赖性和时间进程；以及动物的性别敏感性、年龄选择性和物种易感性。显示磷酸化增加的蛋白质被鉴定为α - 和β - 微管蛋白、微管相关蛋白 - 2（MAP - 2）以及三种神经丝蛋白70 kDa、160 kDa和210 kDa。进一步的研究表明，蛋白磷酸化增加与对蛋白磷酸酶或ATP酶活性的影响无关，而是与Ca2+ - 钙调蛋白激酶II活性的改变有关。脂肪族六碳化合物诱导的神经毒性的特征是脊髓和周围神经中朗飞结上方10 nm神经丝的积累。用正己烷的活性神经毒性代谢物2,5 - 己二酮处理大鼠会以剂量依赖性方式产生蛋白质交联。这种处理还会降低神经丝蛋白以及MAP - 2的蛋白磷酸化。这些研究证明了细胞骨架蛋白参与化学诱导的神经毒性的分子发病机制。
