Ukr.Biochem.J. 2013; Volume 85, Issue 2, Mar-Apr, pp. 59-67


Mechanism of hepatoprotective action of methionine and composition “Metovitan” against a background of antituberculosis drugs administration to rats

S. I. Anisimova1, G. V. Donchenko2, Yu. M. Parkhomenko2, V. M. Kovalenko1

1SI Institute of Pharmacology and Toxicology, National Academy of Medical Sciences of Ukraine, Kyiv;
2Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv;

Oral administration of antituberculosis drugs to rats for 60 days in doses that are equivalent to clinical ones, causes changes in mRNA levels expression of liver cytochrome P-450 isoforms CYP3A2, CYP2C23, CYP2E1 and pro- and antioxidant state. Experimental composition “Metovitan” given with anti-TB drugs provided a correction of these abnormalities, that is evidenced by modulation of the level of CYP3A2, CYP2C23, CYP2E1 gene expression and antioxidant activity, inhibition of lipid peroxidation. “Metovitan” normalizes the enzymatic activity and content of total billirubin in the blood serum, shows high hepatoprotective properties, exceeding the efficiency of methionine.

Keywords: , , , , , , ,


  1. Moskalenko VF, Petrenko VI, Protsyuk RG, Donets DG. Tuberculosis is actual problem in Ukraine. Tuberculosis, Lung diseases, HIV infection. 2010;(1(01)):8-17.
  2. Saukkonen JJ, Cohn DL, Jasmer RM, Schenker S, Jereb JA, Nolan CM, Peloquin CA, Gordin FM, Nunes D, Strader DB, Bernardo J, Venkataramanan R, Sterling TR; ATS (American Thoracic Society) Hepatotoxicity of Antituberculosis Therapy Subcommittee. An official ATS statement: hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med. 2006 Oct 15;174(8):935-52. Review. PubMed
  3. Mishin VYu, Chukanov VI, Grigorev YuG. Side effects of anti-TB drugs at standard and individual chemotherapy regimens. M.: Kompyuterburg, 2004.  208 p.
  4. Bibi Z. Role of cytochrome P450 in drug interactions. Nutr Metab (Lond). 2008 Oct 18;5:27. PubMed, PubMedCentral, CrossRef
  5. Nishimura Y, Kurata N, Sakurai E, Yasuhara H. Inhibitory effect of antituberculosis drugs on human cytochrome P450-mediated activities. J Pharmacol Sci. 2004 Nov;96(3):293-300. PubMed, CrossRef
  6. Shimada T, Yamazaki H, Mimura M, Inui Y, Guengerich FP. Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther. 1994 Jul;270(1):414-23. PubMed
  7. Strachunskiy LS, Kozlov SN. Antimicrobial Therapy: A Guide for Physicians (E-resource). M. Borges, 2002.  431 p. Regime of access: http://
  8. Guidance for Industry and Reviewers Estimating the Safe Starting Dose in Clinical Trials for Therapeutics in Adult Healthy Volunteers U.S. Department of Health and Human Services, FDA, CDER and CBER [Electronic resource]. Regime of access:
  9. Anisimova SI, Kovalenko VМ, Shayakhmetova GM, Bondarenko LB, Matvienko AV. Influences of antitubercular medicines on some isoforms of cytochrome P-450 mRNA levels expression in rats liver. Pharmacol Drug Toxicol. 2012;(3(28)):26-31. Ukrainian.
  10. Kamath SA, Kummerow FA, Narayan KA. A simple procedure for the isolation of rat liver microsomes. FEBS Lett. 1971 Sep 15;17(1):90-92. PubMed, CrossRef
  11. Omura T, Sato R. The carbon monoxide-binding pigment of liver microsomes. I. Evidence for its hemoprotein nature. J Biol Chem. 1964 Jul;239:2370-8. PubMed
  12. Current Protocols in Toxicology. Ed. by M. Maines, John Wiley & Sons, Inc., 2005. P. 2758.
  13. Sedlak J, Lindsay RH. Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman’s reagent. Anal Biochem. 1968 Oct 24;25(1):192-205. PubMed, CrossRef
  14. Modern Methods in Biochemistry / Ed. by V. N. Orehovich. M.: Medicina, 1977. P. 66-68.
  15. Koroliuk MA, Ivanova LI, Maiorova IG, Tokarev VE. A method of determining catalase activity. Lab Delo. 1988;(1):16-9. Russian. PubMed
  16. Patent No. 2144674 Russian Federation, G01N33/52, G01N33/68. The Mode of Determination of Antioxidant Activity of Superoxide Dismutase and Chemical Substances / Sirota T.V. Publ. 20.01.00. (E-resourse). Regime of access:
  17. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265-75. PubMed
  18. Simon VA. Cytochrome P450 and drug interactions. Russ. J. Gastroenterol. Hepatol. Coloproctol. 2002;(6(12)):25-30.
  19. Yue J, Peng RX, Yang J, Kong R, Liu J. CYP2E1 mediated isoniazid-induced hepatotoxicity in rats. Acta Pharmacol Sin. 2004 May;25(5):699-704.  PubMed
  20. Zhang ZH, Tang JH, Zhan ZL, Zhang XL, Wu HH, Hou YN. Cellular toxicity of isoniazid together with rifampicin and the metabolites of isoniazid on QSG-7701 hepatocytes. Asian Pac J Trop Med. 2012 Apr;5(4):306-9. PubMed, CrossRef
  21. Tostmann A, Boeree MJ, Peters WH, Roelofs HM, Aarnoutse RE, van der Ven AJ, Dekhuijzen PN. Isoniazid and its toxic metabolite hydrazine induce in vitro pyrazinamide toxicity. Int J Antimicrob Agents. 2008 Jun;31(6):577-80. PubMed, CrossRef
  22. Leclercq IA, Farrell GC, Field J, Bell DR, Gonzalez FJ, Robertson GR. CYP2E1 and CYP4A as microsomal catalysts of lipid peroxides in murine nonalcoholic steatohepatitis. J Clin Invest. 2000 Apr;105(8):1067-75. PubMed. PubMedCentral, CrossRef
  23. Pöschl G, Seitz HK. Alcohol and cancer. Alcohol Alcohol. 2004 May-Jun;39(3):155-65. PubMed, CrossRef
  24. Torres L, Avila MA, Carretero MV, Latasa MU, Caballería J, López-Rodas G, Boukaba A, Lu SC, Franco L, Mato JM. Liver-specific methionine adenosyltransferase MAT1A gene expression is associated with a specific pattern of promoter methylation and histone acetylation: implications for MAT1A silencing during transformation. FASEB J. 2000 Jan;14(1):95-102. PubMed
  25. Thum T, Borlak J. Testosterone, cytochrome P450, and cardiac hypertrophy. FASEB J. 2002 Oct;16(12):1537-49. PubMed, CrossRef
  26. Simpson AE. The cytochrome P450 4 (CYP4) family. Gen Pharmacol. 1997 Mar;28(3):351-9. Review. PubMed, CrossRef
  27. Capdevila JH, Falck JR, Harris RC. Cytochrome P450 and arachidonic acid bioactivation. Molecular and functional properties of the arachidonate monooxygenase. J Lipid Res. 2000 Feb;41(2):163-81. Review. PubMed
  28. Fulton D, Mahboubi K, McGiff JC, Quilley J. Cytochrome P450-dependent effects of bradykinin in the rat heart. Br J Pharmacol. 1995 Jan;114(1):99-102. PubMed, PubMedCentral, CrossRef
  29. Omdahl JL, Bobrovnikova EA, Choe S, Dwivedi PP, May BK. Overview of regulatory cytochrome P450 enzymes of the vitamin D pathway. Steroids. 2001 Mar-May;66(3-5):381-9. Review. PubMed, CrossRef
  30. Kumar S, Davydov DR, Halpert JR. Role of cytochrome B5 in modulating peroxide-supported cyp3a4 activity: evidence for a conformational transition and cytochrome P450 heterogeneity. Drug Metab Dispos. 2005 Aug;33(8):1131-6. PubMed, CrossRef
  31. Patten CJ, Koch P. Baculovirus expression of human P450 2E1 and cytochrome b5: spectral and catalytic properties and effect of b5 on the stoichiometry of P450 2E1-catalyzed reactions. Arch Biochem Biophys. 1995 Mar 10;317(2):504-13. PubMed, CrossRef
  32. Cooper MT, Porter TD. Cytochrome b(5) coexpression increases the CYP2E1-dependent mutagenicity of dialkylnitrosamines in methyltransferase-deficient strains of Salmonella typhimurium. Mutat Res. 2001 Dec 12;484(1-2):61-8. PubMed, CrossRef
  33. Porubsky PR, Meneely KM, Scott EE. Structures of human cytochrome P-450 2E1. Insights into the binding of inhibitors and both small molecular weight and fatty acid substrates. J Biol Chem. 2008 Nov 28;283(48):33698-707. PubMed, PubMedCentral, CrossRef
  34. Liakhovich VV, Vavilin VA, Zenkov NK, Menshikova EB. Reactive oxygen species during monooxygenase reactions.  Bull Siber Dep RAMS. 2005;118(4):7-12.
  35. Leclercq IA, Farrell GC, Field J, Bell DR, Gonzalez FJ, Robertson GR. CYP2E1 and CYP4A as microsomal catalysts of lipid peroxides in murine nonalcoholic steatohepatitis. J Clin Invest. 2000 Apr;105(8):1067-75. PubMed, PubMedCentral, CrossRef
  36. Gridnev OIe. Lipid peroxidation and liver. Contemporary Gastroenterology. 2005;(5(25)):80-83.
  37. Pentyuk AA, Kachula SA, Gerich EF. Cytochrome P4502E1. Polymorphism, physiological function, regulation, and role in pathology. Ukr Biokhim Zhurn. 2004 Sep-Oct;76(5):16-28. Ukrainian. PubMed
  38. Cederbaum AI. Hepatoprotective effects of S-adenosyl-L-methionine against alcohol- and cytochrome P450 2E1-induced liver injury. World J Gastroenterol. 2010 Mar 21;16(11):1366-76. Review. PubMed, PubMedCentral, CrossRef
  39. Pilat TL, Ivanov AA. Biologically active food supplements (theory, production, application). M.: Avvallon, 2002. 710 p.
  40. Marí M, Cederbaum AI. Induction of catalase, alpha, and microsomal glutathione S-transferase in CYP2E1 overexpressing HepG2 cells and protection against short-term oxidative stress. Hepatology. 2001 Mar;33(3):652-61. PubMed, CrossRef
  41. Marí M, Wu D, Nieto N, Cederbaum AI. CYP2E1-dependent toxicity and up-regulation of antioxidant genes. J Biomed Sci. 2001 Jan-Feb;8(1):52-8. PubMed, CrossRef
  42. Marí M, Cederbaum AI. CYP2E1 overexpression in HepG2 cells induces glutathione synthesis by transcriptional activation of gamma-glutamylcysteine synthetase. J Biol Chem. 2000 May 19;275(20):15563-71. PubMed, CrossRef
  43. Korzhov VI, Zhadan VN, Korzhov MV. The role of glutathione system in the processes of detoxication and antioxidant protection (review of literature). Zhurn Nats Akad Med Nauk Ukrainy. 2007;13(1):3-19.
  44. Pérez MJ, Cederbaum AI. Metallothionein 2A induction by zinc protects HEPG2 cells against CYP2E1-dependent toxicity. Free Radic Biol Med. 2003 Feb 15;34(4):443-55. PubMed, CrossRef

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