Accelerated Cytotoxicity Mechanism Screening

By discovering how chemical compounds/xenobiotics cytotoxicity is affected when their metabolic pathways are inhibited or activated, the metabolic pathways that activate versus detoxify chemical compound can be identified. Reactive metabolites contributing to cytotoxicity can also be identified. In this lecture, the pretreatment of inhibitors and activators of xenobiotic metabolizing enzymes as well as other xenobiotic cellular targets in freshly isolated rat hepatocytes for the accelerated cytotoxicity mechanism screening (ACMS) of xenobiotics (a technique used in our laboratory) are discussed. This technique is useful for determining toxicity mechanisms. The inhibitors/ activators have been selected on the basis of their selectivity, modulator effectiveness, and their lack of toxicity. The use of these inhibitors/activators with other cells or subcellular fractions (e.g. mitochondria) for assessing target organ toxicity mechanisms is also reviewed.