Dichloroacetate is a Novel Safe Treatment for Beta-ketothiolase Deficiency: Towards Better Therapeutic Outcomes (An Original Article)

Salah Mohamed El Sayed^{1, 2,} , Elsayed Abdelkreem³, Moutasem Salih Aboonq⁴, Sultan S. Al Thagfan⁵, Yaser M. Alahmadi⁵, Osama Alhadramy⁶, Hussam Baghdadi¹, Mohammed Hassan³, Faten M. Omran⁷, Hytham Mahmoud Abdel-Latif⁷, Wafaa Abdel-ziz⁷, Azza Mahmoud Ahmed Abouelella⁷, Amr El-Dardear⁸, Mohamed Abdel-haleem⁹, Elhussainy MA Elhussainy¹⁰, Hassan El-Alaf¹¹ and Manal Mohamed Helmy Nabo¹²

¹Department of Clinical Biochemistry and Molecular Medicine, Taibah Faculty of Medicine, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia

²Department of Medical Biochemistry, Sohag Faculty of Medicine, Sohag University, Egypt

³Department of Pediatrics, Faculty of Medicine, Sohag University, Sohag, Egypt

⁴Department of Medical Physiology, Taibah Faculty of Medicine, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia

⁵Department of Clinical and Hospital Pharmacy, College of pharmacy, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia.

⁶Division of Cardiology, Department of Medicine, Taibah College of Medicine, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia

⁷Department of Medical Pharmacology, Sohag Faculty of Medicine, Sohag University, Egypt

⁸Department of Pediatrics, Taibah Faculty of Medicine, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia

⁹Department of Ear, Nose and Throat, Taibah Faculty of Medicine, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia

¹⁰0Department of Medical Physiology, Kafr Elshekh Faculty of Medicine, Kafr Elshekh University, Egypt

¹¹1Department of Medical Physiology, Sohag Faculty of Medicine, Sohag University, Egypt

¹²2Department of Pediatrics, Division of Pediatric Cardiology, Sohag Teaching Hospital, Sohag, Egypt

Cite this paper:
Salah Mohamed El Sayed, Elsayed Abdelkreem, Moutasem Salih Aboonq, Sultan S. Al Thagfan, Yaser M. Alahmadi, Osama Alhadramy, Hussam Baghdadi, Mohammed Hassan, Faten M. Omran, Hytham Mahmoud Abdel-Latif, Wafaa Abdel-ziz, Azza Mahmoud Ahmed Abouelella, Amr El-Dardear, Mohamed Abdel-haleem, Elhussainy MA Elhussainy, Hassan El-Alaf and Manal Mohamed Helmy Nabo. Dichloroacetate is a Novel Safe Treatment for Beta-ketothiolase Deficiency: Towards Better Therapeutic Outcomes (An Original Article). International Journal of Clinical and Experimental Neurology. 2020; 8(1):4-8. doi: 10.12691/ijcen-8-1-2

Abstract

Beta-ketothiolase deficiency (BKTD) is an inborn error of ketone bodies and isoleucine metabolism. Patients with BKTD manifest during late infancy and early childhood with recurrent episodes of ketoacidosis (accumulated acetoacetate and β-hydroxybutyrate) that may be refractory to treatment and life-threatening. BKTD is exaggerated by fasting, starvation and catabolic conditions. Dichloroacetate (DCA) is a safe effective treatment for both lactic acidosis and non-Hodgkin’s lymphoma. DCA is non-toxic and non-carcinogenic at therapeutic doses. DCA toxic doses are hundred times (12- gram/l) more than the therapeutic doses. In experimental models of ketosis, DCA reduces ketonemia and ketonuria while significantly lowering blood glucose. Importantly, DCA was reported to divert pyruvate (amino group acceptor to form alanine in transamination reactions to regenerate α-ketoglutarate from glutamate) to oxidative pathways to form acetyl CoA that is oxidized in Krebs cycle. That inhibits first step of isoleucine catabolism (transamination step) and consequently blocks formation of acetoacetate and β-hydroxybutyrate. That alleviates ketone bodies-induced refractory metabolic acidosis. On biochemical and pharmacological bases, we suggest DCA as a novel evidence-based adjuvant and life-saving treatment for BKTD. Moreover, DCA-induced inhibition of ketone bodies uptake will be alleviated by insulin effects. Causes of refractory metabolic acidosis in BKTD are increased levels of ketone bodies (due to increased isoleucine catabolism, increased ketone bodies formation and decreased ketone bodies utilization). DCA relieves most of these. Biochemically, DCA and ketone bodies (acetoacetate and β-hydroxybutyrate) are structural analogs derived from acetic acid. In neonatology, DCA improved neonatal septicaemia-induced refractory metabolic acidosis that did not respond to conventional sodium bicarbonate. In conclusion, DCA is strongly suggested to treat BKTD.

Keywords:
Dichloroacetate beta-ketothiolase deficiency antimetabolite pharmacological antagonist ketone bodies acidosis isoleucine

This work is licensed under a Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

References:

[1]	Fukao T, Sasai H, Aoyama Y, Otsuka H, Ago Y, Matsumoto H, Abdelkreem E. Recent advances in understanding beta-ketothiolase (mitochondrial acetoacetyl-CoA thiolase, T2) deficiency. J Hum Genet. 2019 Feb; 64(2): 99-111.
[2]	Vakili R, Hashemian S. A Novel Mutation of Beta-ketothiolase Deficiency: The First Report from Iran and Review of Literature. Iran J Child Neurol. 2018 Summer; 12(3): 113-121.
[3]	Adeva-Andany MM, López-Maside L, Donapetry-García C, Fernández-Fernández C, Sixto-Leal C. Enzymes involved in branched-chain amino acid metabolism in humans. Amino Acids. 2017 Jun; 49(6): 1005-1028.
[4]	Reddy N, Calloni SF, Vernon HJ, Boltshauser E, Huisman TAGM, Soares BP. Neuroimaging Findings of Organic Acidemias and Aminoacidopathies. Radiographics. 2018 May-Jun; 38(3): 912-931.
[5]	Snell K, Duff DA. Branched-chain amino acid metabolism and alanine formation in rat diaphragm muscle in vitro. Effects of dichloroacetate. Biochem J. 1984 Nov 1; 223(3): 831-5.
[6]	Ward RA, Wathen RL, Harding GB, Thompson LC. Comparative metabolic effects of acetate and dichloroacetate infusion in the anesthetized dog. Metabolism. 1985 Jul; 34(7): 680-7.
[7]	El Sayed SM, Baghdadi H, Ahmed NS, Almaramhy HH, Mahmoud AA, El-Sawy SA, Ayat M, Elshazley M, Abdel-Aziz W, Abdel-Latif HM, Ibrahim W, Aboonq MS. Dichloroacetate is an antimetabolite that antagonizes acetate and deprives cancer cells from its benefits: A novel evidence-based medical hypothesis. Med Hypotheses. 2019 Jan; 122: 206-209.
[8]	Ayat M. Dichloroacetate is Promising for Treating Hematological Malignancy through Inhibiting Ketone Bodies Oxidation: towards Better Understanding of Its Anticancer Mechanisms. American Journal of Cancer Prevention. 2018, 6(1), 5-8.
[9]	McAllister A, Allison SP, Randle PJ. Effects of dichloroacetate on the metabolism of glucose, pyruvate, acetate, 3-hydroxybutyrate and palmitate in rat diaphragm and heart muscle in vitro and on extraction of glucose, lactate, pyruvate and free fatty acids by dog heart in vivo. Biochem J. 1973 Aug; 134(4): 1067-81.
[10]	Stacpoole PW, Greene YJ. Dichloroacetate. Diabetes Care. 1992 Jun; 15(6):785-91.
[11]	Pardridge WM, Duducgian-Vartavarian L, Casanello-Ertl D. Effects of dichloroacetate on the lactate/pyruvate ratio and on aspartate and leucine metabolism in cultured rat skeletal muscle cells. Biochem Pharmacol. 1983 Jan 1; 32(1): 97-100.
[12]	Backshear PJ, Holloway PA, Alberti KG. Metabolic interactions of dichloroacetate and insulin in experimental diabetic ketoacidosis. Biochem J. 1975 Feb; 146(2): 447-56.
[13]	Blackshear PJ, Holloway PA, Alberti KG. The metabolic effects of sodium dichloroacetate in the starved rat. Biochem J. 1974 Aug; 142(2): 279-86.
[14]	Graf H, Leach W, Arieff A I. Effects of dichloroacetate in the treatment of hypoxic lactic acidosis in dogs. J Clin Invest. 1985 Sep; 76(3): 919-923.
[15]	Gin-Shaw SL, Barsan WG, Eymer V, Hedges J. Effects of dichloroacetate following canine asphyxial arrest. Ann Emerg Med. 1988 May; 17(5): 473-7.
[16]	James MO, Jahn SC, Zhong G, Smeltz MG, Hu Z, Stacpoole PW. Therapeutic applications of dichloroacetate and the role of glutathione transferase zeta-1. Pharmacol Ther. 2017 Feb; 170: 166-180.