A new approach on valproic acid induced hepatotoxicity: involvement of lysosomal membrane leakiness and cellular proteolysis

Toxicology in Vitro : an International Journal Published in Association with BIBRA
Jalal PourahmadJavad Khalili Fard

Abstract

Although valproic acid (VPA) a proven anticonvulsant agent thought to have relatively few side-effects VPA has been referred as the third most common xenobiotic suspected of causing death due to liver injury. In this study the cellular pathways involved in VPA hepatotoxicity were investigated in isolated rat hepatocytes. Accelerated cytotoxicity mechanism screening (ACMS) techniques using fluorescent probes including, ortho-phthalaldehyde, rhodamine 123 and acridine orange were applied for measurement of ROS formation, glutathione depletion, mitochondrial membrane potential and Lysosomal membrane damage, respectively. Our results showed that cytotoxic action of VPA is mediated by lysosomal membrane leakiness along with reactive oxygen species (ROS) formation and decline of mitochondrial membrane potential before cell lysis ensued. Incubation of hepatocytes with VPA also caused rapid hepatocyte glutathione (GSH) depletion which is another marker of cellular oxidative stress. Most of the VPA induced GSH depletion could be attributed to the expulsion of GSSG. Our results also showed that CYP2EI is involved in the mechanism of VPA cytotoxicity. We finally concluded that VPA hepatotoxicity is a result of metabolic activation by CYP2...Continue Reading

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Citations

Sep 10, 2013·Toxicological Sciences : an Official Journal of the Society of Toxicology·Jenny M PedersenPer Artursson
Apr 25, 2013·Marine Environmental Research·Jafar ShahrakiJalal Pourahmad
Sep 15, 2015·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Aziz EftekhariMohammad Ali Eghbal
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Apr 2, 2019·Current Pharmaceutical Design·Hong-Li GuoTengfei Wang
Dec 15, 2020·Journal of Biochemical and Molecular Toxicology·Gehad MekkyAnthony Atala
Dec 12, 2020·Toxicology Reports·Mahmoud HashemzaeiJafar Shahraki
Mar 23, 2021·Journal of Neuroimmune Pharmacology : the Official Journal of the Society on NeuroImmune Pharmacology·Koffi L LakpaJonathan D Geiger
Jul 2, 2019·Journal of the American Chemical Society·Penghui ChengKanyi Pu

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