Sultatos L G, Minor L D, Murphy S D
J Pharmacol Exp Ther. 1985 Mar;232(3):624-8.
Mouse liver perfusion studies in situ revealed that the cholinesterase inhibitor chlorpyrifos oxon produced by the liver from the phosphorothioate pesticide chlorpyrifos was quickly detoxified within the liver, thereby preventing it's exit from the liver in the effluent. In contrast, when the pesticide parathion was perfused as a substrate a substantial amount of the toxic metabolite paraoxon was found in exiting perfusate. Pesticide concentrations (5-15 microM) used in the perfusion studies in situ were similar to their hepatic portal blood concentrations in vivo (2.32-12.95 microM) after i.p. administration of lethal or near lethal doses. Moreover, the half-life for elimination of paraoxon by mouse blood in vitro was 8.6 min, a rate sufficiently low to allow passage of paraoxon to extrahepatic target tissues from liver in vivo. These results suggest that in the mouse, the acute toxicity of chlorpyrifos is mediated by extrahepatic production of oxon, whereas that of parathion is likely mediated by both hepatic and extrahepatic activation.
原位小鼠肝脏灌注研究表明，肝脏从硫代磷酸酯农药毒死蜱产生的胆碱酯酶抑制剂毒死蜱氧磷在肝脏内迅速解毒，从而阻止其随流出物离开肝脏。相比之下，当灌注农药对硫磷作为底物时，在流出的灌注液中发现了大量有毒代谢物对氧磷。原位灌注研究中使用的农药浓度（5 - 15 microM）与腹腔注射致死或接近致死剂量后体内肝门静脉血浓度（2.32 - 12.95 microM）相似。此外，小鼠血液在体外消除对氧磷的半衰期为8.6分钟，该速率足够低，足以使对氧磷在体内从肝脏传递到肝外靶组织。这些结果表明，在小鼠中，毒死蜱的急性毒性是由肝外产生的氧磷介导的，而对硫磷的急性毒性可能是由肝脏和肝外激活共同介导的。
