Identifying human toxicity potential
Dolores Diaz · 2006
Besides lowering cholesterol levels, the statins exert multiple effects on cellular functions such as cell proliferation, differentiation and survival and regulation of cell shape and motility. Statins inhibit proliferation and induce apoptosis in a variety of cell lines, and they also show antitumour effects in animal tumour models, slowing cell growth and inhibiting the metastatic process. Although statins are well tolerated in general, due likely to these multiple effects on cell function, they can have undesirable side effects. Certain statins have been shown to cause toxicity, which for one statin was fatal. Cerivastatin, one of the first marketed statins, was withdrawn in 2001 after the drug was associated with more than 100 deaths due to toxicity. The mechanism for statin-induced injury is still the subject of debate, but there seems to be a common pathway, which is consistent with apoptotic cell death. The apoptotic trigger has been attributed to various events, like the blocking of cholesterol biosynthesis, the reduction in the levels of isoprenoids such as ubiquinone and most likely the reduction in mevalonate metabolites such as farnesol and geranylgeraniol. These metabolites are involved in the prenylation and subsequent targeting and activation of regulatory proteins, which promote cell survival by inhibiting apoptosis. High Content Screening (HCS) allows the measurement of multiple cellular end-points on a cell-by-cell basis. This is possible through the use of multi-colour probe fluorescence and quantitative microscopy linked to sophisticated image-analysis software. HCS was first introduced as a tool for early drug discovery, and it also has potential applications in drug safety evaluation, making it a HCS