Elucidating mechanism of drug induced toxicity
Drug toxicity may cause liver injury, resulting in damage to cells and tissues.This damage can lead to cytotoxic events that may result in an activation of poly (ADP-ribose) polymerase (PARP).Motivation: Drug-induced toxicity related proteins (DITRPs) are proteins that mediate adverse drug reactions (ADRs) or toxicities through their binding to drugs or reactive metabolites.Collection of these proteins facilitates better understanding of the molecular mechanisms of drug-induced toxicity and the rational drug discovery.Environ 3000 manuscrits des chercheurs financés par les Instituts de recherche en santé du Canada (IRSC) seront transférés sous peu au dépôt numérique du Conseil national de recherches du Canada (CNRC) et formeront la Collection des IRSC.Toxicity has been estimated to be responsible for the attrition of approximately one-third of drug candidates and is a major contributor to the high cost of drug development, particularly when not recognized until late in clinical trials or post-marketing.A PARP inhibition analysis was conducted with cocaine and (APAP) to understand the impact of a PARP inhibitor, 1,5-dihydroxyisoquinoline (DIQ), on PARP activity in the liver.
A dose-response analysis for cocaine concluded that a dose as low as 20 mg/kg resulted in elevated ALT levels.
DIQ was effective in reducing drug-induced hepatotoxicity and preserving organ function.
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A higher dose of 60 mg/kg was tested for analyses but resulted in severe hemorrhaging.
The dose-response analyses for APAP resulted in no elevated liver enzyme levels for a 75 mg/kg and 150 mg/kg dose.
Drug-induced toxicity related protein database (DITOP) is such a database that is intending to provide comprehensive information of DITRPs.