Valproic acid induced liver injury: An insight into molecular toxicological mechanism |
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| Institution: | 1. Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu 600 077, India;2. Animal House Division, CSIR-Central Leather Research Institute, Adyar, Chennai 600 020, India;1. Department of Pharmacology, Faculty of Medicine, Kahramanmaras Sutcu Imam University, Kahramanmaras, Turkey;2. Department of Medical Biology, Faculty of Medicine, Kahramanmaras Sutcu Imam University, Kahramanmaras, Turkey;3. Department of Anatomy, Faculty of Medicine, Kahramanmaras Sutcu Imam University, Kahramanmaras, Turkey;4. Department of Pathology, Faculty of Medicine, Gaziosmanpasa University, Tokat, Turkey;1. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA;2. School of Public Health, University of California, Berkeley, CA, USA;3. National Institute of Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing, China;4. Division of Environmental Epidemiology, Institute for Risk Assessment Sciences, Utrecht University, Utrecht, the Netherlands;5. Cancer Control and Population Sciences, University of New Mexico Comprehensive Cancer Center, Albuquerque, NM, USA;6. Division of Epidemiology, Biostatistics, and Preventive Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, University of New Mexico Comprehensive Cancer Center, Albuquerque, NM, USA;7. Chaoyang Center for Disease Control and Prevention, Chaoyang, Liaoning, China;8. School of Public Health, The University of Hong Kong, Hong Kong Special Administrative Region;9. China Medical University, Shenyang, Liaoning, China;10. Division of Epidemiology, Albert Einstein College of Medicine, New York, NY, USA;11. School of Public Health, Qingdao University, Qingdao, China;1. Division of Gastroenterology/Hepatology, Scripps Clinic, and Scripps Translational Science Institute, 10666 North Torrey Pines Road, La Jolla, CA 92037, USA;2. Division of Gastroenterology/Hepatology, Liver Disease Center, Scripps Clinic, and Scripps Translational Science Institute, 10666 North Torrey Pines Road, La Jolla, CA 92037, USA;1. Department of Occupational Health and Occupational Diseases, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan, China;2. The Key Laboratory of Nanomedicine and Health Inspection of Zhengzhou, Zhengzhou 450001, Henan, China;3. Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450052, Henan, China;1. Department of Cardiovascular Biomedicine, National Institute of Cardiology Ignacio Chávez, Mexico City 14080, Mexico;2. Department of Pharmacology, National Institute of Cardiology Ignacio Chávez, Mexico City 14080, Mexico;3. Department of Plant Molecular Biology, Institute of Biotechnology, National Autonomous University of Mexico, Cuernavaca 62210, Morelos, Mexico;1. Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER) – Guwahati, Changsari, Kamrup, Assam 781101, India;2. Danylo Halytsky Lviv National Medical University, Lviv, Ukraine;3. National University of Pharmacy, Kharkiv, Ukraine;4. School of Pharmaceutical Sciences, Lovely Professional University, Phagwara 144411, India;5. Ivan Franko National University of Lviv, Lviv, Ukraine;6. Andrei Krupynskyi Lviv Medical Academy, Lviv, Ukraine |
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| Abstract: | Valproic acid (VPA) is an anti-seizure drug that causes idiosyncratic liver injury. 2-propyl-4-pentenoic acid (Δ4VPA), a metabolite of VPA, has been implicated in VPA-induced hepatotoxicity. This review summarizes the pathogenesis involved in VPA-induced liver injury. The VPA induce liver injury mainly by i) liberation of Δ4VPA metabolites; ii) decrease in glutathione stores and antioxidants, resulting in oxidative stress; iii) inhibition of fatty acid β-oxidation, inducing mitochondrial DNA depletion and hypermethylation; a decrease in proton leak; oxidative phosphorylation impairment and ATP synthesis decrease; iv) induction of fatty liver via inhibition of carnitine palmitoyltransferase I, enhancing nuclear receptor peroxisome proliferator-activated receptor-gamma and acyl-CoA thioesterase 1, and inducing long-chain fatty acid uptake and triglyceride synthesis. VPA administration aggravates liver injury in individuals with metabolic syndromes. Therapeutic drug monitoring, routine serum levels of transaminases, ammonia, and lipid parameters during VPA therapy may thus be beneficial in improving the safety profile or preventing the progression of DILI. |
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| Keywords: | Sodium valproate Carnitine palmitoyltransferase Anti-epileptic drugs Drug induced liver injury |
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