Podprasart Varaporn, Satayavivad Jutamaad, Riengrojpitak Suda, Wilairat Prapin, Wananukul Winai, Chavalittumrong Pranee, Chivapat Songpol, Yoovathaworn Krongtong
Graduate Program in Toxicology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand.
Toxicol Lett. 2007 May 15;170(3):193-202. doi: 10.1016/j.toxlet.2007.03.006. Epub 2007 Mar 13.
Paraquat (PQ) is a well-known toxic bipyridyl herbicide commonly used in agricultural countries. Pulmonary toxicity is the main cause of death but damage to other organs has also been reported. PQ is also classified as a "direct hepatotoxicant" following an acute high dose exposure. The evidence of multi-low dose toxicity of PQ was scarce. Therefore, the aim of this study was to examine the effect of multiple low doses of PQ on the liver function and xenobiotic-metabolizing enzyme activities including CYP1A1, 2E1, and 3A4, and to correlate the effects with its tissue accumulation. PQ, at the dose range 4.0-6.0 mg/kg day, was subcutaneously administered to male Wistar rats for seven consecutive days. The prominent feature of toxic response was lung toxicity. Interestingly, PQ-treatment caused a dose- and time-dependent reduction of plasma transaminase activity. Hypobilirubinemia and hypoalbuminemia were also observed without significant alteration in the liver morphology. Of all the xenobiotic-metabolizing enzymes being studied, only the activity of CYP1A1-related 7-ethoxyresorufin-O-deethylase was reduced following the highest dose of PQ administration. Plasma and tissue concentrations and accumulation of PQ analyzed by HPLC were dose-dependent showing much higher concentration (approximately 13 times) in the lung than that in the liver whereas it was undetectable in the plasma at the same time point. It can be concluded that multi-low dose PQ might affect certain synthetic function of the liver or activity of some hepatic xenobiotic-metabolizing enzymes. Minimal PQ accumulation in the liver is one of the explanations for the lack of cytotoxic hepatic injury in this study. Plasma PQ concentration may not be a good marker of exposure and toxicity after a prolonged exposure to PQ.
百草枯（PQ）是一种在农业国家常用的知名有毒双吡啶类除草剂。肺毒性是主要死因，但也有其他器官受损的报道。急性高剂量暴露后，PQ也被归类为“直接肝毒性物质”。关于PQ多低剂量毒性的证据很少。因此，本研究的目的是研究多次低剂量PQ对肝功能以及包括CYP1A1、2E1和3A4在内的外源性代谢酶活性的影响，并将这些影响与其组织蓄积相关联。将剂量范围为4.0 - 6.0 mg/kg·天的PQ连续7天皮下注射给雄性Wistar大鼠。毒性反应的突出特征是肺毒性。有趣的是，PQ处理导致血浆转氨酶活性呈剂量和时间依赖性降低。还观察到低胆红素血症和低白蛋白血症，而肝脏形态无明显改变。在所有研究的外源性代谢酶中，仅在给予最高剂量PQ后，CYP1A1相关的7 - 乙氧基异吩恶唑酮 - O - 脱乙基酶的活性降低。通过高效液相色谱法分析的血浆和组织中PQ的浓度及蓄积呈剂量依赖性，肺中的浓度（约13倍）远高于肝脏，而在同一时间点血浆中未检测到。可以得出结论，多次低剂量PQ可能会影响肝脏的某些合成功能或一些肝脏外源性代谢酶的活性。肝脏中PQ蓄积极少是本研究中缺乏细胞毒性肝损伤的原因之一。长时间接触PQ后，血浆PQ浓度可能不是暴露和毒性的良好标志物。
