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656023 
Book/Book Chapter 
Hepatocytes as the gold standard for predicting in vivo hepatotoxicity of xenobiotics using accelerated cytotoxicity mechanism screening techniques 
O'Brien, PJ; Siraki, A; Tafazoli, S; Chan, K 
2006 
Science Publishers 
Enfield, NH 
Liver Diseases: Biochemical Mechanisms and New Therapeutic Insights 
2 
519-530 
A review. It is still not clear whether hepatocytes can predict in vivo hepatic metabolite profiles of xenobiotics and can be regarded as the gold std. for predicting in vivo xenobiotic hepatotoxicity. To det. this, it needs to be demonstrated that the in vitro susceptibility of hepatocytes to xenobiotics does predict whether the same xenobiotic will induce hepatotoxicity in vivo during animal toxicol. testing. Perhaps the largest and most studied chem. class of compds. that cause hepatotoxicity in vivo in rodents is the halobenzenes. Their phase 1 metabolites include epoxides, phenols hydroquinones, catechols and quinones. Using "Accelerated Cytotoxic Mechanism Screening" (ACMS) techniques the order of effectiveness of the 16 halobenzenes tested with isolated rat hepatocytes in vitro at 2 h were found to be similar to liver toxicity reported in rats in vivo at 24 h. Furthermore, although ACMS techniques revealed differences in mol. cytotoxic mechanisms between the halobenzenes, the same mechanism for a particular halobenzene was the same in vitro as in vivo. The LD50 (2 h) detd. by ACMS for hepatocytes in vitro and Quant. Structure activity/toxicity relationships using parameters such as EHOMO, ELUMO, log P, pKa, s and bond dissocn. energy could be used to predict hepatotoxicity and reactive metabolites of a particular xenobiotic, such as halobenzenes. 
S Ali; SL Friedman; DA Mann