Tissue-specific effects of chlorpyrifos on carboxylesterase and cholinesterase activity in adult rats: An in vitro and in vivo comparison
Tissue-specific effects of chlorpyrifos on carboxylesterase and cholinesterase activity in adult rats: An in vitro and in vivo comparison
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DOI：
10.1006/faat.1997.2329
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发表时间：
1997-08-01
期刊：
影响因子：
--
通讯作者：
Padilla, S
中科院分区：
文献类型：
--
作者：
Chanda, SM;Mortensen, SR;Padilla, S
有机磷农药能与羧酸酯酶结合，降低乙酰胆碱酯酶的活性。从文献中还不清楚CaE对OP的亲和力和/或CaE分子的数量是否是决定CaE保护潜力的主导因素。我们对CaE和ChE进行了详细的体外和体内调查，以确定CaE和ChE的体外敏感性是否预测了体内给药毒死蜱（CPF; 80 mg/ kg，p.o.）在雄性或雌性成年Long-Evans大鼠中。对于大脑，体外敏感性CPF-oxon预测在体内模式的抑制：在体外，脑胆碱酯酶是大约25倍更敏感的活性代谢产物，CPF-oxon，比脑钙，在体内脑胆碱酯酶比脑钙抑制。与此相反，在体外的敏感性，血浆胆碱酯酶和钙没有相关性以及在体内的抑制模式：在体外，血浆胆碱酯酶是约6.5倍的敏感性CPF-氧磷比血浆钙，但在体内，血浆胆碱酯酶的抑制比钙。为了解CaE对CPF-oxon体外抑制脑ChE的保护作用，用成年大鼠纹状体组织与肝组织孵育，测定CPF-oxon的IC（50）。在存在肝脏的情况下，ChE的纹状体CPF-oxon IC 50值增加，表明CaE结合CPF-oxon并限制其进入ChE。男性肝脏钙，它具有相同的亲和力结合CPF-氧磷作为女性肝脏钙，但有两倍多的结合位点，造成了更大的增加纹状体CPF-氧磷IC 50比女性肝脏，这表明结合位点的数量确实发挥了作用，在解毒潜力的组织。综上所述，我们发现（1）基础ChE和CaE活性存在组织和性别差异：（2）CaE或ChE对CPF-oxon的体外敏感性具有高度的组织特异性;（3）体内给予CPF后ChE和CaE抑制的模式不一定能从这些相同酶的体外IC 50预测，（4）CaE分子的数量可能对CPF的毒性起一定的调节作用。
Organophosphate (OF) pesticides can bind to carboxylesterase (CaE), which may lower the concentration of OPs at the target site enzyme, acetylcholinesterase (ChE). It is unclear from the literature whether it is the CaE's affinity for the OP and/or the number of CaE molecules which is the dominant factor in determining the protective potential of CaE. We undertook a detailed, in vitro and in vivo survey of both CaE and ChE to ascertain if in vitro sensitivity of CaE and ChE predicted the pattern of inhibition seen after in vivo dosing with chlorpyrifos (CPF; 80 mg/ kg, p.o.) in male or female adult Long-Evans rats. For the brain, the in vitro sensitivity to CPF-oxon did predict the in vivo patterns of inhibition: In vitro, brain ChE was approximately 25 times more sensitive to the active metabolite, CPF-oxon, than brain CaE, and in vivo brain ChE was more inhibited than brain CaE. In contrast, the in vitro sensitivity of plasma ChE and CaE did not correlate well with the in vivo pattern of inhibition: In vitro, plasma ChE was approximately 6.5 times less sensitive to CPF-oxon than plasma CaE, but in vivo, plasma ChE was more inhibited than CaE. In order to understand the role of CaE in protecting the brain ChE from inhibition by CPF-oxon in vitro, adult rat striatal tissue was incubated in the presence and absence of adult rat liver tissue and IC(50)s of CPF-oxon were determined. The increase in the striatal CPF-oxon IC50 value noted for ChE in the presence of liver suggested that CaE was binding the CPF-oxon and limiting its access to ChE. Male liver CaE, which has the same affinity for binding CPF-oxon as female liver CaE but has twice as many binding sites, caused a greater increase in the striatal CPF-oxon IC50 than female liver, suggesting that the number of binding sites does play a role in the detoxification potential of a tissue. In summary, we found that (1) there are tissue and gender-related differences for basal ChE and CaE activity; (2) the in vitro sensitivity of CaE or ChE to CPF-oxon is highly tissue-specific; (3) the pattern of ChE and CaE inhibition after in vivo dosing with CPF is not necessarily predictable from the in vitro IC50 for these same enzymes, and (4) the number of CaE molecules may play a role in modifying the toxicity of CPF.