Journal of Drug Metabolism & Toxicology
Open Access

Liver cell death induced by 4-aminopyridine in a repeated dose (28 days) oral toxicity study in rats: Gene expression profile of hybrid cell death

International Conference on Toxicogenomics and Drug Monitoring

August 25-27, 2015 Valencia, Spain

Javier del Pino1, Mar�­a Teresa Frejo1, Mar�­a Jes�ºs D�­az1, Mar�­a Jos�© Anad�³n1, Paula Moyano1, Margarita Lobo1, Jimena Garc�­a2 and Miguel Andr�©s Capo1

1Complutense University, Spain 2Alfonso X University, Spain

Posters-Accepted Abstracts: J Drug Metab Toxicol

Abstract :

4-Aminopyridine (4-AP) is an orphan drug indicated for the treatment of neuromuscular disorders. Thereis a great controversy around the use of this drug because of its narrow safety index and because a large number of adverse affects that have been reported. Moreover, it was shown to induce cell death in different cell lines, being reported mainly apoptosis and necrosis as the principal pathways of cell death mediated by blockage of K channels or the Na, K-ATPase, but until now it was not described in vivo cell death induced by 4-aminipyridine. To provide that 4-AP is able to induce cell death in vivo and the main pathways related to it, a repeated dose (28 days) oral toxicity study, at therapeutic range of doses, was conducted in rat livers. The caspases 3/7 activation, LDH release a real-time PCR array analysis was developed. The caspases 3/7 were activated and the lactate dehydrogenase (LDH) release was increased at all doses confirming that 4-AP induce cell death in rat liver in vivo. Moreover, this data suggest that both necrotic and apoptotic process take place at the same time. Furthermore, the the real-time PCR array on liver tissue expressed a gene expression profile of necrotic and apoptotic induced cell death which support our biochemical results. The present work shows for the first time in vivo cell death on liver induced by 4-AP and the biochemical and the gene expression profile shows that the cell death is mediated by necrotic and apoptotic pathways.

Biography :

Javier del Pino received his PharmD degree at the University Complutense University of Madrid in 2004. He has two Masters in Sciences 2009 and 2010. He specialized in neurotoxicology and neurodevelopmental toxicology and received his PhD in Toxicology in 2009. In 2010 he worked in Institute of Health Carlos III in the National Center of Environmental Health. From 2010 to 2012 he was Associated Researcher at University of Massachusetts (UMASS) working in Sandra Petersen´s Lab in a National Institute of Health (NIH) project on developmental effects of TCDD endocrine disruptor on sexual differentiation. In 2012 he got a position as Assistant Professor of Toxicology at the Complutense University of Madrid.

Email: jdelpino@pdi.ucm.es