O'Brien Peter J, Chan Katie, Silber Paul M
Graduate Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Toronto, 19 Russell St., Toronto, Ont., Canada M5S 2S2.
Chem Biol Interact. 2004 Nov 1;150(1):97-114. doi: 10.1016/j.cbi.2004.09.003.
Human and animal hepatocytes are now being used as an in vitro technique to aid drug discovery by predicting the in vivo metabolic pathways of drugs or new chemical entities (NCEs), identifying drug-metabolizing enzymes and predicting their in vivo induction. Because of the difficulty of establishing whether the cytotoxic susceptibility of human hepatocytes to xenobiotics/drugs in vitro could be used to predict in vivo human hepatotoxicity, a comparison of the susceptibility of the hepatocytes of human and animal models to six chemical classes of drugs/xenobiotics in vitro have been related to their in vivo hepatotoxicity and the corresponding activity of their metabolizing enzymes. This study showed that the cytotoxic effectiveness of 16 halobenzenes towards rat hepatocytes in vitro using higher doses and short incubation times correlated well with rat hepatotoxic effectiveness in vivo with lower doses/longer times. The hepatic/hepatocyte xenobiotic metabolizing enzyme activities of various animal species and human have been reviewed for use by veterinarians and research scientists. Where possible, recommendations have been made regarding which animal hepatocyte model is most applicable for modeling the susceptibility to xenobiotic induced hepatotoxicity of those humans with slow versus rapid metabolizing enzyme polymorphisms. These recommendations are based on the best human fit for animal drug/xenobiotic metabolizing enzymes in terms of activity, kinetics and substrate/inhibitor specificity. The use of human hepatocytes from slow versus rapid metabolizing individuals for drug metabolism/cytotoxicity studies; and the research use of freshly isolated rat hepatocytes and "Accelerated Cytotoxicity Mechanism Screening" (ACMS) techniques for identifying drug/xenobiotic reactive metabolites are also described. Using these techniques the molecular hepatocytotoxic mechanisms found in vitro for seven classes of xenobiotics/drugs were found to be similar to the rat hepatotoxic mechanisms reported in vivo.
目前，人和动物肝细胞正被用作一种体外技术，通过预测药物或新化学实体（NCEs）的体内代谢途径、识别药物代谢酶并预测其体内诱导作用，来辅助药物研发。由于难以确定人肝细胞在体外对异生物素/药物的细胞毒性敏感性是否可用于预测体内人肝毒性，因此已将人和动物模型的肝细胞在体外对六类化学药物/异生物素的敏感性与其体内肝毒性及其代谢酶的相应活性进行了比较。这项研究表明，16种卤代苯在体外使用较高剂量和较短孵育时间对大鼠肝细胞的细胞毒性效力与在体内使用较低剂量/较长时间的大鼠肝毒性效力密切相关。已综述了各种动物物种和人类的肝脏/肝细胞异生物素代谢酶活性，以供兽医和研究科学家使用。在可能的情况下，已就哪种动物肝细胞模型最适用于模拟具有慢代谢酶多态性与快代谢酶多态性的人类对异生物素诱导的肝毒性的易感性提出了建议。这些建议基于在活性、动力学和底物/抑制剂特异性方面对动物药物/异生物素代谢酶的最佳人类拟合。还描述了使用来自慢代谢个体与快代谢个体的人肝细胞进行药物代谢/细胞毒性研究；以及使用新鲜分离的大鼠肝细胞和“加速细胞毒性机制筛选”（ACMS）技术来鉴定药物/异生物素反应性代谢产物的研究用途。使用这些技术发现，七类异生物素/药物在体外发现的分子肝细胞毒性机制与体内报道的大鼠肝毒性机制相似。
