Toxicity Evaluation of 6-Mercaptopurine Using Accelerated Cytotoxicity Mechanism Screening (ACMS) techniques
Iranian Journal of Pharmaceutical Sciences,
Vol. 12 No. 3 (2016),
1 July 2016
,
Page 65-74
https://doi.org/10.22037/ijps.v12.40770
Abstract
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.
- ACMS
- Hepatotoxicity
- lysosome
- Mercaptopurine
- Mitochondria
- Reactive Oxygen Species
How to Cite
References
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