Evidence for a potential protective effect of carnitine-pantothenic acid co-treatment on valproic acid-induced hepatotoxicity

Expert Review of Clinical Pharmacology

Volumn 7, Issue 2, 2014, Pages 211-218

  Felker, Dana ^a   Lynn, Alexandra ^a   Wang, Sue ^a   Johnson, Dale E ^a,b  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b UNIVERSITY OF MICHIGAN   (United States)

Author keywords

1 genotype; 1 ; beta oxidation; carnitine; coenzyme Rfaut; CYP2A6; CYP2B6; CYP2C9; hepatotoxicity; metabolic activation; oxidative stress; pantothenic acid; valproic acid

Indexed keywords

ANIMALS; ANTICONVULSANTS; BIPOLAR DISORDER; CARNITINE; CHILD; DRUG THERAPY, COMBINATION; DRUG-INDUCED LIVER INJURY; HUMANS; OXIDATIVE STRESS; PANTOTHENIC ACID; SEIZURES; VALPROIC ACID;

EID: 84894155729     PISSN: 17512433     EISSN: 17512441     Source Type: Journal    
DOI: 10.1586/17512433.2014.871202     Document Type: Review

References (61)

1. Silva MFB, Aires CCP, Luis PBM, et al. Valproic acid metabolism and its effects on mitochondrial fatty acid oxidation: A review. J Inherit Metab Dis 2008;31(2):205-16 . Excellent review of how valproic acid (VPA) and metabolites affect mitochondrial beta-oxidation.
2. Luis PBM, Ruiter JP, Ofman R, et al. Valproic acid utilizes the isoleucine breakdown pathway for its complete beta-oxidation. Biochem Pharmacol 2011; 82(11):1740-6
3. Pourahmad J, Eskandari MR, Kaghazi A, et al. A new approach on valproic acid induced hepatotoxicity: Involvement of lysosomal membrane leakiness and cellular proteolysis. Toxicol In Vitro 2012;26(4): 545-51 . An animal model shows important evidence for the mechanisms of VPA-induced hepatotoxicity.
4. Price KE, Pearce RE, Garg UC, et al. Effects of valproic acid on organic acid metabolism in children: A metabolic profiling study. Clin Pharmacol Ther 2011; 89(6):867-74
5. National Center for Biotechnology Information, US National Library of Medicine, Rockville, MD, USA; 2005 (PubMed). Available from: Www.ncbi.nlm. nih.gov/pubmed
6. Liu X, Ouyang S, Yu B, et al. PharmMapper server: A web server for potential drug target identification via pharmacophore mapping approach. Nucleic Acids Res 2010.38.W609-14. Available from: Http://59.78.96.61/pharmmapper/
7. Knox C, Law V, Jewison T, et al. DrugBank 3.0: A comprehensive resource for 'omics' research on drugs. Nucleic Acids Res 2011.39:D1035-41. Available from: Www. drugbank.ca/
8. Liu T, Lin Y, Wen X, et al. BindingDB: A web-accessible database of experimentally determined protein-ligand binding affinities. Nucleic Acids Res 2007.35:D198-201. Available from: Www.bindingdb.org/
9. Jensen LJ, Kuhn M, Stark M, et al. STRING: Functional protein association networks. Nucleic Acids Res 2009.37(9.05): D412-16. Available from: Http://string-db. org/
10. Kuhn M, Von Mering C, Campillos M, et al. STITCH: Interaction networks of chemicals and proteins. Nucleic Acids Res 2007.36:D684-8. Available from: Http://stitch.embl.de/
11. Kanehisa M, Goto S. KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res 2000.28:27-30. Available from: Www.genome.jp/kegg/
12. TheHapMap Consortium. The International HapMap Project. Nature 2003.426:789-96. Available from: Http://hapmap.ncbi.nlm.nih. gov/
13. Davis AP, Murphy CG, Johnson R, et al. The comparative toxicogenomics database: Update 2013. Nucleic Acids Res 2013. 41(D1):D1104-14. Available from: Http://ctdbase.org/
14. Preissner S, Kroll K, Dunkel M, et al. SuperCYP: A comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res 2010.38:D237-43. Available from: Http://bioinformatics.charite. de/supercyp/
15. GeneCards Human Gene Database. Weizmann Institute of Science 2013. Available from: Www.genecards.org/
16. Online Mendelian Inheritance in Man, OMIM. McKusick-Nathans Institute of Genetic Medicine, JohnsHopkinsUniversity (Baltimore, MD, USA) Available from: Http://omim.org/
17. Whirl-Carrillo M, McDonagh EM, Hebert JM, et al. Pharmacogenomics Knowledge for Personalized Medicine. Clin Pharmacol Ther 2012.92(4):414-17. Available from: Www.pharmgkb.org/
18. Sushko I, Novotarskyi S, Korner R, et al. Online chemical modeling environment (OCHEM): Web platform for data storage, model development and publishing of chemical information. J Comput Aided Mol Des 2011.25(6):533-54. Available from: Www.ochem.eu
19. Sushko I, Salmina E, Potemkin VA, et al. ToxAlerts: A web server of structural alerts for toxic chemicals and compounds with potential adverse reactions. J ChemInf Model 2012.52(8):2310-16. Available from: Http://ochem.eu/alerts
20. Lim E, Pon A, Djoumbou Y, et al. T3DB: A comprehensively annotated database of common toxins and their targets. Nucleic Acids Res 2010.38:D781-6. Available from: Www.t3db.org/
21. US FDA Archive. FDA, Rockville, MD, USA 2013. Available from: Www.accessdata. fda.gov/scripts/search/index.cfm? action=archive.search
22. Kuhn M, Campillos M, Letunic I, et al. A side effect resource to capture phenotypic effects of drugs. Mol Syst Biol 2010.6:343. Available from: Http://sideeffects.embl.de/
23. Meteor, a predictive search engine of Lhasa Ltd. Available from: Www.lhasalimited.org/
24. Kiang TKL, Tent XW, Karagiozov S, et al. Role of oxidative metabolism in the effect of valproic acid on markers of cell viability. necrosis, and oxidative stress in sandwichcultured rat hepatocytes. Toxicol Sci 2010; 118(2):501-9
25. Pollack GM, McHugh WB, Gengo FM, et al. Accumulation and washout kinetics of valproic acid and its active metabolites. J Clin Pharmacol 1986;26(8):668-76 . An early description of VPA metabolism giving percentages of metabolic processing.
26. Lee MS, Jung BH, Chung BC, et al. Metabolomics study with gas chromatography-mass spectrometry for predicting valproic acid-induced hepatotoxicity and discovery of novel biomarkers in rat urine. Int J Toxicol 2009; 28(5):392-404
27. Testa B. Drug metabolism for the perplexed medicinal chemist. Chem Biodivers 2009; 6(11):2055-70
28. Surendradoss J, Chang TKH, Abbott FS. Assessment of the role of in situ generated (E)-2,4-diene-valproic acid in the toxicity of valproic acid and (E)-2-ene-valproic acid in sandwich-cultured rat hepatocytes. Toxicol Appl Pharmacol 2012;264:413-22
29. Jung BH, Kim BJ, Lee MS, et al. Dose-dependent pharmacokinetics of toxic metabolites is not related to increased toxicity following high-dose valproic acid in rats. J Appl Toxicol 2010;30(8):775-8
30. Becker ML, Leeder JS. Identifying genomic and developmental causes of adverse drug reactions in children. Pharmacogenomics 2010;11(11):1591-602
31. Kochen W, Schneider A, Ritz A. Abnormal metabolism of valproic acid in fatal hepatic failure. Eur J Pediatr 1983;141(1):30-5
32. Ji X, Shi X, Lin R, et al. Participation of lipid transport and fatty acid metabolism in valproate sodium-induced hepatotoxicity in HepG2 cells. Toxicol In Vitro 2010;24(4): 1086-91
33. Kawai Y, Arinze IJ. Valproic acid-induced gene expression through production of reactive oxygen species. Cancer Res 2006; 66(13):6563-9
34. Espandiari P, Zhang J, Schnackenberg L, et al. Age-related differences in susceptibility to toxic effects of valproic acid in rats. J Appl Toxicol 2008;28(5):628-37
35. Amacher DE. The discovery and development of proteomic safety biomarkers for the detection of drug-induced liver toxicity. Toxicol Appl Pharmacol 2010; 245(1):134-42
36. Kiang TKL, Ho PC, Anari MR, et al. Contribution of CYP2C9, CYP2A6, and CYP2B6 to valproic acid metabolism in hepatic microsomes from individuals with CYP2C91/1 genotype. Toxicol Sci 2006; 94(2):261-71
37. McFarland R. Reversible valproate hepatotoxicity due to mutations in mitochondrial DNA polymerase gamma (POLG1). Arch Dis Child 2008;93(2): 151-3
38. Knapp AC, Todesco L, Beier K, et al. Toxicity of valproic acid in mice with decreased plasma and tissue carnitine stores. J Pharmacol Exp Ther 2008;324(2):568-75 . Knockout mice provided clear evidence in this experiment of carnitine deficiency as a risk factor for VPA-induced hepatotoxicity.
39. Indiveri C, Iacobazzi V, Tonazzi A, et al. The mitochondrial carnitine/acylcarnitine carrier: Function, structure and physiopathology. Mol Aspects Med 2011; 32(4-6):223-33
40. Lheureux PE, Hantson P. Carnitine in the treatment of valproic acid-induced toxicity. Clin Toxicol (Phila) 2009;47(2):101-11 . A clear discussion of observed and hypothesized therapeutic and prophylactic effects of carnitine administration in relation to VPA-induced hepatotoxicity.
41. Clay HB, Sillivan S, Konradi C. Mitochondrial dysfunction and pathology in bipolar disorder and schizophrenia. Int J Dev Neurosci 2011;29(3):311-24
42. Waring WS, Nixon AC. Acute liver impairment after sodium valproate overdose. BMJ Case Rep 2009. [Epub ahead of print]
43. Aires CC. Inhibition of hepatic carnitinepalmitoyl-transferase I (CPT IA) by valproyl-CoA as a possible mechanism of valproate-induced steatosis. Biochem Pharmacol 2010;79(5):792-9 . This publication provides crucial evidence of valproyl-CoA's activity as a Carnitine palmitoyltransferase I inhibitor.
44. Goto S, Seo T, Hagiwara T, et al. Potential relationships between transaminase abnormality and valproic acid clearance or serum carnitine concentrations in Japanese epileptic patients. J Pharm Pharmacol 2008; 60(2):267-72
45. Anil M, Helvaci M, Ozbal E, et al. Serum and muscle carnitine levels in epileptic children receiving sodium valproate. J Child Neurol 2009;24(1):80-6
46. Thurston JH, Hauhart RE. Amelioration of adverse effects of valproic acid on ketogenesis and liver Coenzyme A metabolism by cotreatment with pantothenate and carnitine in developing mice. Pediatr Res 1992;31(4):419-23
47. Sugimoto T, Araki A, Nishida N, et al. Hepatotoxicity in rat following administration of valproic acid: Effect of L-carnitine supplementation. Epilepsia 1987;28(4):373-7
48. Bohan TP. Effect of L-carnitine treatment for valproate-induced hepatotoxicity. Neurology 2001;56(10):1405-9
49. Ishikura H, Matsuo N, Matsubara M, et al. Valproic acid overdose and L-carnitine therapy. J Anal Toxicol 1996;20(1):55-8
50. Chaudhry N, Patidar Y, Puri V. Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes unveiled by valproate. J Pediatr Neurosci 2013;8(2):135-7
51. Li LO, Klett EL, Coleman RA. Acyl-CoA synthesis, lipid metabolism and lipotoxicity. Biochim Biophys Acta 2010; 1801(3):246-51
52. Kucharska J. Vitamins in mitochondrial function. In: Gvozdjakova A, editor. Mitochondrial medicine: Mitochondrial metabolism, diseases, diagnosis and therapy. Springer Netherlands; Heidelberg, Germany: 2008. p. 367-84
53. Leonardi R, Zhang Y, Rock C, Jackowski S. Coenzyme A: Back in action. Prog Lipid Res 2005;44(2-3):125-53
54. Nozaki S, Webb ME, Niki H. An activator for pyruvoyl-dependent l-aspartate a-decarboxylase is conserved in a small group of the g-proteobacteria including Escherichia coli. Microbiologyopen 2012; 1(3):298-310
55. Tahiliani G, Keene T, Kaplan RS. Characterization of the inhibitor sensitivity of the Coenzyme A transport system in isolated rat heart mitochondria. J Bioenerg Biomembr 1992;24(6):635-40
56. Keijer J, Bekkenkamp-Grovenstein M, Venema D, Dommels YE. Bioactive food components, cancer cell growth limitation and reversal of glycolytic metabolism. Biochim Biophys Acta 2011;1807(6): 697-706
57. Qin F, Liu YX, Zhao HW, et al. Chinese medicinal formula Guan-Xin-Er-Hao protects the heart against oxidative stress induced by acute ischemic myocardial injury in rats. Phytomedicine 2009;16(2-3):215-21
58. Tung EWY, Winn LM. Valproic acid increases formation of reactive oxygen species and induces apoptosis in postimplantation embryos: A role for oxidative stress in valproic acid-induced neural tube defects. Mol Pharmacol 2011; 80(6):979-87
59. Thurston JH, Hauhart RE. Reversal of the adverse chronic effects of the unsaturated derivative of valproic acid-2-n-propyl-4-pentenoic acid on ketogenesis and liver Coenzyme A metabolism by a single injection of pantothenate, carnitine, and acetylcysteine in developing mice. Pediatr Res 1993;33(1):72-6
60. Garst JE. Carnitine and its esters as potential biomarkers of environmentaltoxicological exposure to nongenotoxictumorigens. In: Blancato J, Brown RN, Dary CC, Saleh MA, editors. Biomarkers for agrochemicals and toxic substances, ACS Symposium Series. American Chemical Society; Washington, DC, USA: 1996
61. Nagai G, Ono S, Yasui-Furukori N, et al. Formulations of valproate alter valproate metabolism: A single oral dose kinetic study. Ther Drug Monit 2009;31(5):592-6