Pharmacodynamics and toxicodynamics of drug action: Signaling in cell survival and cell death

In therapeutic response to drugs, the plasma concentration range leads to t he establishment of a safe and effective dosage regimen. Our hypothesis is that by studying drug concentration-dependent effect on signal transduction mechanisms, a better understanding of the beneficial pharmacodynamic and a dverse toxicodynamic responses elicited by the drug may be achieved. Using two classes of chemopreventive compounds (phenolic antioxidants and isothio cyanates), we illustrate the potential utility of two signal transduction p athways elicited by these agents to predict the pharmacodynamic effect (ind uction of Phase II drug metabolizing enzymes) and the potential toxicodynam ic response (stimulation of caspase activity and cytotoxic cell death). At lower concentration. phenolic antioxidants and isothiocyanates activate mit ogen-activated protein kinase (MAPK: extracellular signal-regulated protein kinase 2, ERK2; and c-Jun N-terminal kinase 1,JNK1) in a concentration-and time-dependent manner. The activation of MAPK by these compounds may lead to the induction of cell survival/protection genes such as c-jun,, c-fos, o r Phase II drug metabolizing enzymes. However, at higher concentrations, th ese agents activate another signaling molecule, ICE/Ced3 cysteine protease enzymes (caspases) leading to apoptotic cell death. The activation of these pathways may dictate the fate of the cells/tissues upon exposure to drugs or chemicals. At lower concentrations, these compounds activate MAPK leadin g to the induction of Phase II genes, which may protect the cells/tissues a gainst toxic insults and therefore may enhance cell survival. On the other hand, at higher concentrations, these agents may activate the caspases, whi ch may lead to apoptotic cell death, and have toxicity. Understanding the a ctivation of these and other signal transduction events elicited by various drugs and chemicals may yield insights into the regulation of gene express ion of drug metabolizing enzymes and cytotoxicity. Thus, the study of signa ling events in cell survival (hemeostasis) and cell death (cytotoxicity) ma y have practical application during pharmaceutical drug development.