Hou Wei-Yuan, Long Ding-Xin, Wu Yi-Jun
Laboratory of Molecular Toxicology, State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, PR China.
Toxicol Sci. 2009 Jun;109(2):276-85. doi: 10.1093/toxsci/kfp068. Epub 2009 Apr 6.
Neuropathy target esterase (NTE) is proven to act as a lysophospholipase (LysoPLA) in mice and phospholipase B (PLB) in cultured mammalian cells. In sensitive species, organophosphate (OP)-induced delayed neurotoxicity is initiated when NTE is inhibited by > 70% and then aged. It is hypothesized that homeostasis of phosphatidylcholine (PC) and/or lysophosphatidylcholine (LPC) in mice might be disrupted by the OPs since NTE and other phospholipases could be inhibited. To test this hypothesis, we treated mice using tri-o-cresyl phosphate (TOCP), which can inhibit and age NTE. Phenylmethylsulfonyl fluoride (PMSF), which inhibits NTE but cannot age, was used as a negative control. Effects on activity of NTE, LysoPLA, and PLB, the levels of PC, LPC, and glycerophosphocholine (GPC), and the aging of NTE in the brain, spinal cord, and sciatic nerve were examined. The results showed that the activities of NTE, NTE-LysoPLA, LysoPLA, NTE-PLB, and PLB were significantly inhibited in both TOCP- and PMSF-treated mice, and the inhibition of NTE and NTE-LysoPLA or NTE-PLB showed a high correlation coefficient. The NTE inhibited by TOCP was of the aged type, while nearly all NTE inhibited by PMSF was of the unaged type. Although the GPC level was remarkedly decreased, no significant change of PC and LPC levels was observed. However, the inhibition of these enzymes in mice by TOCP exhibited different characteristics from the TOCP-treated hens that we previously reported, which indicates that these enzymes were inhibited and then recovered more rapidly in mice than in hens. All results suggest that PC and LPC homeostasis was not disrupted in mice after exposure to TOCP. Differences in inhibition of NTE, LysoPLA, and PLB activities by TOCP between mice and hens may elucidate why these two species display different signs after exposure to the same neuropathic OPs.
已证实神经病变靶酯酶（NTE）在小鼠体内作为溶血磷脂酶（LysoPLA）发挥作用，在培养的哺乳动物细胞中作为磷脂酶B（PLB）发挥作用。在敏感物种中，当NTE被抑制超过70%并随后老化时，有机磷酸酯（OP）诱导的迟发性神经毒性就会引发。据推测，由于NTE和其他磷脂酶可能被抑制，小鼠体内磷脂酰胆碱（PC）和/或溶血磷脂酰胆碱（LPC）的稳态可能会被OP破坏。为了验证这一假设，我们用磷酸三邻甲苯酯（TOCP）处理小鼠，TOCP可以抑制NTE并使其老化。苯甲基磺酰氟（PMSF）可抑制NTE但不能使其老化，用作阴性对照。检测了对大脑、脊髓和坐骨神经中NTE、LysoPLA和PLB的活性、PC、LPC和甘油磷酸胆碱（GPC）的水平以及NTE老化的影响。结果表明，TOCP和PMSF处理的小鼠中NTE、NTE-LysoPLA、LysoPLA、NTE-PLB和PLB的活性均受到显著抑制，并且NTE与NTE-LysoPLA或NTE-PLB的抑制呈现出高相关系数。TOCP抑制的NTE是老化型，而PMSF抑制的几乎所有NTE都是未老化型。尽管GPC水平显著降低，但未观察到PC和LPC水平的显著变化。然而，TOCP对小鼠中这些酶的抑制表现出与我们之前报道的TOCP处理母鸡不同的特征，这表明这些酶在小鼠中被抑制后比在母鸡中恢复得更快。所有结果表明，暴露于TOCP后小鼠体内PC和LPC的稳态未被破坏。TOCP对小鼠和母鸡中NTE、LysoPLA和PLB活性抑制的差异可能解释了为什么这两个物种在暴露于相同的神经性OP后表现出不同的症状。
