毒死蜱对成年大鼠羧酸酯酶和胆碱酯酶活性的组织特异性影响:体外和体内比较。

S M Chanda, S R Mortensen, V C Moser, S Padilla
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引用次数: 0

摘要

有机磷农药可以与羧酸酯酶(CaE)结合,从而降低靶位酶乙酰胆碱酯酶(ChE)上有机磷农药的浓度。从文献中尚不清楚是CaE对OP的亲和力和/或CaE分子的数量是决定CaE保护潜力的主要因素。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体内给药毒死蜱(CPF)后的抑制模式;80 mg/kg, p.o.)。对于大脑,体外对CPF-oxon的敏感性确实预测了体内抑制模式:体外,脑ChE对活性代谢物CPF-oxon的敏感性约为脑CaE的25倍,体内脑ChE比脑CaE更受抑制。相比之下,血浆ChE和CaE的体外敏感性与体内抑制模式没有很好的相关性:在体外,血浆ChE对CPF-oxon的敏感性约为血浆CaE的6.5倍,但在体内,血浆ChE比CaE更受抑制。为了了解CaE在体外保护脑ChE免受CPF-oxon抑制的作用,我们在成年大鼠肝组织存在和不存在的情况下,对成年大鼠纹状体组织进行孵育,测定CPF-oxon的ic50。在肝脏存在的情况下,纹状体CPF-oxon IC50值的增加表明CaE结合CPF-oxon并限制其进入ChE。男性肝脏CaE对CPF-oxon的结合亲和力与女性肝脏CaE相同,但结合位点是女性肝脏CaE的两倍,导致纹状体CPF-oxon IC50的增加高于女性肝脏,这表明结合位点的数量确实在组织的解毒潜力中起作用。综上所述,我们发现(1)基础ChE和CaE活性存在组织和性别相关差异;(2) CaE或ChE对CPF-oxon的体外敏感性具有高度的组织特异性;(3)体内给药CPF后ChE和CaE的抑制模式不一定能从这些酶的体外IC50来预测;(4)CaE分子的数量可能在CPF的毒性调节中起作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Tissue-specific effects of chlorpyrifos on carboxylesterase and cholinesterase activity in adult rats: an in vitro and in vivo comparison.

Organophosphate (OP) 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 IC50s 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.

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