Mechanisms involved in the valproic acid-induced hepatotoxicity: A Comprehensive review.

Adverse drug reactions (ADR) remain a challenge in modern healthcare, particularly given the increasing complexity of therapeutics. WHO's definition of an adverse drug reaction as a response to a drug that is noxious and unintended and occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease, or for modification of physiological function. This definition underscores the importance of monitoring and mitigating unintended drug effects, particularly for widely used medications like valproic acid (VPA). An anticonvulsant medicine which is frequently used in treatment of epilepsy and other neurological conditions is valproic acid (VPA), is frequently associated with hepatotoxicity, a severe ADR that complicates its clinical use, which can take two different forms: Type I, which is defined by dose-dependent and reversible liver damage, and Type II, an idiosyncratic reaction that can result in severe liver failure, frequently complicates its clinical application. Oxidative stress, the creation of reactive metabolites, mitochondrial dysfunction, carnitine shortage, immune-mediated reactions, glutathione depletion, and blockage of the bile salt export pump (BSEP) are some of the numerous underlying mechanisms of Valproic acid-induced hepatic damage. The production of reactive oxygen species and the liver's antioxidant protection are out of balance as a cause of oxidative stress, which is a significant factor in VPA intoxication. Reactive oxygen species (ROS) are defined as "a collective term for a variety of reactive molecules and free radicals derived from molecular oxygen". This includes species such as superoxide anion, hydrogen peroxide, hydroxyl radical, and singlet oxygen, have long been implicated in oxidative damage inflicted on fatty acids, DNA and proteins as well as other cellular components. The integrity of the hepatocyte may be compromised by the over production of ROS, which can create cellular damage such as protein oxidation and lipid peroxidation. Liver damage is further exacerbated by reactive metabolites produced by VPA metabolism, which have the ability to covalently attach to biological macromolecules. As VPA reduces mitochondrial bioenergetics, it causes ATP depletion and consequent cellular death, which is another important component of VPA-induced hepatotoxicity. Increased urea cycle activity leads to hyperammonemia, which aggravates the liver and causes neurotoxicity. VPA can also accelerate the build-up of fatty acids, which increases the risk of steatosis, due to its interaction with the metabolism of carnitine. Immune-mediated processes have been shown to increase liver injury, implying that the immunity system may possibly be involved in VPA hepatotoxicity. Hepatocyte injury and cholestasis are caused by BSEP inhibition, which impairs bile flow. As another point of view, glutathione depletion, a result of oxidative stress, reduces the liver's ability to neutralize toxic compounds. The complex interaction between biochemical and cellular mechanisms that underlie valproic acid's hepatotoxic potential calls for additional research to clarify the precise pathways implicated and create mitigation techniques for this ADR.