Toxicity evaluation of 6-mercaptopurine using accelerated cytotoxicity mechanism screening (ACMS) techniques

6-mercaptopurine (6-mp) is widely used in clinic as an immunosuppressive for treatment of acute lymphocytic leukemia,crohn’s disease,and ulcerative colitis with documented unpredictable hepatotoxicity. the potential molecular cytotoxic mechanisms of 6-mp against isolated rat hepatocytes were searched in this study using ―accelerated cytotoxicity mechanism screening (acms)‖ techniques. the concentration of 6-mp required to cause 50% cytotoxicity in 2 hour at 37∘c was detected to be 400 µm. a significant increase in 6-mp induced cytotoxicity and reactive oxygen species (ros) formation,% mitochondrial membrane potential (mmp),lysosomal damage were observed. the addition of chloroquine (lysosomotropic agent),l-carnitine (inhibitor of membrane permeability transition (mpt),diphenyleneiodonium (dpi) as an inhibitor of production of superoxide,and h2o2 by mitochondria and dimethyl sulfoxide (dmso) as a radical scavenger decreased 6-mp-induced cytotoxicity,ros formation,collapse of mmp,and lysosomal damage. results from this study suggest that 6-mp-induced cytotoxicity in isolated rat hepatocytes due to ros formation,mitochondrial and lysosomal damages that resulted in crosstalk toxicity between mitochondrial and lysosomal damage and finally cell death. © 2016,iranian association of pharmaceutical scientists. all rights reserved.