有機(jī)磷（OP）引起的遲發(fā)性神經(jīng)毒性（OPIDN）是一種神經(jīng)退行性疾病,，其主要特征是周圍神經(jīng)軸突的變性降解,。具有溶血磷脂酶（LysoPLA）和磷脂酶B（PLB）活性的神經(jīng)病靶酯酶（NTE）被認(rèn)為是OPIDN的主要靶標(biāo)。OPIDN的發(fā)生具有動(dòng)物種屬敏感性差異：成年雞在對(duì)神經(jīng)毒性O(shè)P的易感性以及隨后表現(xiàn)出來(lái)的毒性癥狀方面與人極為相似,，故其一直被用作研究OPIDN的動(dòng)物模型,，而醫(yī)學(xué)研究中最常用的實(shí)驗(yàn)動(dòng)物小鼠，在接觸神經(jīng)毒性O(shè)P后通常不出現(xiàn)典型的OPIDN癥狀,。然而,，這種OPIDN敏感性的動(dòng)物種屬差異的原因迄今未能闡明。
中國(guó)科學(xué)院動(dòng)物研究所伍一軍研究組的科研人員近年來(lái)開展了OPIDN的敏感性動(dòng)物種屬差異的研究,，他們分別以成年雞和小鼠為實(shí)驗(yàn)動(dòng)物,，比較研究了這兩種對(duì)OPIDN敏感性完全不同的動(dòng)物在染毒OPIDN的經(jīng)典藥物¾三鄰甲苯基磷酸酯（TOCP）后其神經(jīng)系統(tǒng)（腦、脊髓和坐骨神經(jīng)）不同時(shí)間點(diǎn)的NTE、LysoPLA和PLB活性及其底物卵磷脂（PC）和溶血卵磷脂（LPC）穩(wěn)態(tài)變化,。結(jié)果發(fā)現(xiàn),，TOCP對(duì)雞和小鼠神經(jīng)組織中PC和LPC的穩(wěn)態(tài)并沒(méi)有影響，說(shuō)明以前關(guān)于“NTE被OP抑制后其生理底物PC/LPC濃度變化可能是這兩種動(dòng)物接觸OP后神經(jīng)毒性不同的原因”的假設(shè)并不成立,。進(jìn)一步分析發(fā)現(xiàn),，TOCP對(duì)這兩種動(dòng)物神經(jīng)組織中NTE、LysoPLA和PLB活性的抑制表現(xiàn)出不同的特點(diǎn),，小鼠神經(jīng)組織中這三種絲氨酸水解酶受TOCP抑制及其后恢復(fù)的速率均較在母雞中的高,，提示OP在小鼠體內(nèi)代謝速率及其代謝物的消除都比雞的要快，而起動(dòng)OPIDN的發(fā)生則需要OP抑制這些酶達(dá)到一定程度并保持一定的時(shí)間,。根據(jù)上述比較研究的結(jié)果,，研究小組首次提出雞和小鼠這兩種動(dòng)物對(duì)OPIDN易感性不同及其毒性癥狀的差異可能與OP對(duì)這兩種動(dòng)物神經(jīng)組織中的NTE、LysoPLA和 PLB的抑制模式不同有關(guān),。
以上研究結(jié)果分別發(fā)表在毒理學(xué)國(guó)際權(quán)威學(xué)術(shù)期刊 Toxicological Sciences（Hou W-Y, Long D-X, Wu Y-J. Toxicological Sciences. 2009, 109:276-285）和 Toxicology （Hou W-Y, Long D-X, Wang H-P, Wang Q, Wu Y-J. Toxicology. 2008, 252:56-63.）上,。論文第一作者侯威遠(yuǎn)為已畢業(yè)的博士研究生，聯(lián)系作者伍一軍為分子毒理學(xué)研究組組長(zhǎng),。
該研究工作得到了國(guó)家自然科學(xué)基金項(xiàng)目（30470228；30870537）的資助,。（生物谷Bioon.com）
生物谷推薦原始出處：
Toxicological Sciences 2009 109(2):276-285; doi:10.1093/toxsci/kfp068
The Homeostasis of Phosphatidylcholine and Lysophosphatidylcholine in Nervous Tissues of Mice was not Disrupted after Administration of Tri-o-cresyl Phosphate
Wei-Yuan Hou*,, Ding-Xin Long* and Yi-Jun Wu*,1
* Laboratory of Molecular Toxicology, State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, P.R. China Graduate School of the Chinese Academy of Sciences, Beijing 100039, P.R. China
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.
