COMPARATIVE INVESTIGATION OF ANTI-TUBERCULOSIS DRUGS EFFECTS ON TESTICULAR CYP2Е1 EXPRESSION AND MALE REPRODUCTIVE PARAMETERS UNDER SEPARATE AND COMBINED ADMINISTRATION IN MALE RATS

G. Shayakhmetova
SI "Institute of Pharmacology and Toxicology NAMS of Ukraine" Kiev, Ukraine

Abstract


Comparative study of anti-tuberculosis drugs anti-androgenic effects and effects on testicular CYP2Е1 has been performed. Testicular CYP2E1 mRNA and protein expression, serum total testosterone level, fertility and spermatogenesis parameters in male rats under simultaneous and separate administration of ethambutol, isoniazid, rifampin and pyrazinamide have been investigated. Analysis of the obtained data has proved the prominent role of ethambutol and isoniazid in gonadal toxicity of antituberculosis drugs combination. Activation of CYP2Е1-dependent metabolizing systems in testicular steroidogenic cells could stipulate at least a part of ethambutol, isoniazid and anti-tuberculosis drugs combination negative effects on testosterone level and spermatogenesis processes. Mechanisms of spermatogenesis alteration by rifampin and pyrazinamide need to be explored more extensively, but in the light of our observations they do not depend from testicular CYP2E1.

Keywords


anti-androgenic effects, anti-tuberculosis drugs, protein expression, ethambutol, isoniazid

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References


Santic Z, Galic K. Epidemiology of Tuberculosis During the Period 1703–2011: Honoring the World Tuberculosis Day. Mater Sociomed. 2013 Dec;25(4):291-4.

Palomino JC, Martin A. Tuberculosis clinical trial update and the current anti-tuberculosis drug portfolio. Curr Med Chem. 2013;20(30):3785-96.

Shayakhmetova GM, Bondarenko LB, Kovalenko VM. Damage of testicular cell macromolecules and reproductive capacity of male rats following co-administration of ethambutol, rifampicin, isoniazid and pyrazinamide. Interdiscip Toxicol. 2012 Mar;5(1):9-14.

Shayakhmetova GM, Bondarenko LB, Matvienko AV, Kovalenko VM. Effect of antituberculosis drugs combination on isoforms P-450 mRNA

level in rats testes and state of their spermatogenic epithelium. Odessa Medical Journal. 2012; 4: 11-14 [In Russian].

Murono EP, Fisher-Simpson V. Microsomal ethanol oxidizing system in purified rat Leydig cells. Biochim Biophys Acta. 1987 Apr 3;918(2):136-40.

Jiang Y, Kuo CL, Pernecky SJ, Piper WN. The detection of cytochrome P450 2E1 and its catalytic activity in rat testis. Biochem Biophys Res Commun. 1998 May 29;246(3):578-83.

Forkert PG, Lash LH, Nadeau V, Tardif R, Simmonds A. Metabolism and toxicity of trichloroethylene in epididymis and testis. Toxicol Appl Pharmacol. 2002 Aug 1;182(3):244-54.

Lieber CS. Cytochrome P-4502E1: Its Physiological and Pathological Role. Physiol Rev. 1997 Apr;77(2):517-44.

Jochi JM. Tuberculosis chemotherapy in the 21st century: Back to the basics. Lung India. 2011; 28: 193–200.

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. Available from:

Male reproductive toxicology (Chapter 16). In: Maines MD (Ed.), Current Protocols in Toxicology. New York: John Wiley & Sons Inc.; 2005.

Chitra KC, Rao KR, Mathur PP. Effect of bisphenol A and coadministration of bisphenol A and vitamin C on epididymis of adult rats: A histological and biochemical study. Asian J Androl. 2003 Sep;5(3):203-8.

Shrivastava V, Pekar M, Grosser E, Im J, Vigodner M. SUMO proteins are involved in the stress response during spermatogenesis and are localized to DNA double-strand breaks in germ cells. Reproduction. 2010 Jun;139(6):999-1010.

de Kretser DM, Loveland KL, Meinhardt A, Simorangkir D, Wreford N. Spermatogenesis. Hum Reprod. 1998; 13:1-8.

Lanning LL, Creasy DM, Chapin RE, Mann PC, Barlow NJ, Regan KS, Goodman DG. Recommended Approaches for the Evaluation of Testicular and Epididymal Toxicity. Toxicol Pathol. 2002 Jul-Aug;30(4):507-20.

Teerds KJ, Huhtaniemi IT. Morphological and functional maturation of Leydig cells: from rodent models to primates. Hum Reprod Update. 2015 May-Jun;21(3):310-28.

Cederbaum AI. CYP2E1-biochemical and toxicological aspects and role in alcohol-induced liver injury. Mt Sinai J Med. 2006 Jul;73(4):657-72.

Tsai SC, Lu CC, Lin CS, Wang PS. Antisteroidogenic actions of hydrogen peroxide on rat Leydig cells. J Cell Biochem. 2003 Dec 15;90(6):1276-86.

Lee SY, Gong EY, Hong CY, Kim KH, Han JS, Ryu JC, Chae HZ, Yun CH, Lee K. ROS inhibit the expression of testicular steroidogenic enzyme genes via the suppression of Nur77 transactivation. Free Radic Biol Med. 2009 Dec 1;47(11):1591-600.

Sharpe RM. Environmental/lifestyle effects on spermatogenesis. Philos Trans R Soc Lond B Biol Sci. 2010 May 27;365(1546):1697-712.


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