First-line antituberculosis drugs disrupt endocrine balance and induce ovarian and uterine oxidative stress in rats
-
Olayinka A. Adebayo
Abstract
Background:
The first-line antituberculosis (anti-TB) drugs, isoniazid (INH), rifampicin (RIF), ethambutol (EMB), and pyrazinamide (PZA), are effective in the treatment of pulmonary tuberculosis. However, the toxicity of these drugs in the clinical setting limits their use. Here, we evaluated the effects of anti-TB drugs on the reproductive system in female rats.
Methods:
Thirty-five female Wistar rats were assigned into five groups of seven animals each. The control group received normal saline, whereas others received INH (5 mg/kg), RIF (10 mg/kg), EMB (15 mg/kg), and PZA (15 mg/kg) through gavage thrice a week for 8 consecutive weeks.
Results:
Administration of anti-TB drugs significantly (p<0.05) reduced uterine and ovarian weight, as well as the relative weight of the uterus when compared with controls. In addition, anti-TB drugs increased the activities of alanine aminotransferase as well as the level of total bilirubin. Treatment with INH, RIF, and PZA significantly (p<0.05) reduced the levels of follicle-stimulating and luteinizing hormones, estrogen, and prolactin. The INH, RIF, EMB, and PZA caused significant (p<0.05) increases in uterine malondialdehyde (MDA) levels by 281%, 214%, 273% and 190%, respectively, whereas INH and EMB increased the ovarian malondialdehyde by 111% and 129%, respectively. These drugs significantly (p<0.05) decreased the activities of ovarian glutathione-S-transferase and uterine glutathione peroxidase, superoxide dismutase, and catalase. Histology revealed the erosion of uterine mucosa, debris in the lumen of the uterus, congestion, and underdeveloped follicles in ovaries.
Conclusions:
The first-line anti-TB drugs elicited reproductive toxicity in the uterus and ovaries of rats through mechanisms that involved oxidative stress.
Acknowledgments
The authors acknowledge with thanks the technical Staff of the Department of Biochemistry, University of Ibadan, Nigeria for their support.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
References
1. Madhavi M, Samudruam P, Hemanth A, Lalitha V. Effect of antioxidant vitamins C and E supplementation its plasma levels and on lipid profile in pulmonary tuberculosis patients. Am J Infect Dis 2009;5:263–72.10.3844/ajidsp.2009.263.272Suche in Google Scholar
2. World Health Organization. Reproductive health strategy to accelerate progress towards the attainment of international development goals and targets. http://whqlibdoc.who.int/hq/2004/WHO_RHR_04.8.pdf. 2004.Suche in Google Scholar
3. Adekambi T, Ibegbu CC, Kalokhe AS, Yu T, Ray SM, Rengarajan J. Distinct effector memory CD4+ T cell signatures in latent Mycobacterium tuberculosis infection, BCG vaccination and clinically resolved tuberculosis. PLoS One 2012;7:e36046.10.1371/journal.pone.0036046Suche in Google Scholar
4. World Health Organization. Global tuberculosis report: Epidemiology. Geneva: World Health Organization, WHO/HTM/TB/2015.22, 2015.Suche in Google Scholar
5. De Backer AI, Mortele KJ, Keulenear BL, Parizel PM. Tuberculosis: epidemiology, manifestation, and the value of medical imaging in diagnosis. JBR-BTR 2006;89:143–50.Suche in Google Scholar
6. Bhadauria S, Singh G, Sinha N, Srivastava S. Isoniazid induces oxidative stress, mitochondrial dysfunction and apoptosis in Hep G2 cells. Cell Mol Biol (Noisy-le-grand) 2007;53:102–14.Suche in Google Scholar
7. Imam MK, Anwer M, Iqbal S, Alam K, Khayyam U, Sharma M. Tuberculosis: brief overview and its shifting paradigm for management in India. Int J Pharmacol 2010;6:755–83.10.3923/ijp.2010.755.783Suche in Google Scholar
8. 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 pyrazinaminde. Interdiscip Toxicol 2012;5:9–14.10.2478/v10102-012-0002-9Suche in Google Scholar
9. Kehinde A, Adefisan A, Adebayo O, Adaramoye O. Biflavonoid fraction from Garcinia kola seed ameliorates hormonal imbalance and testicular oxidative damage by anti-tuberculosis drugs in Wistar rats. J Basic Clin Physiol Pharmacol 2016;27:393–401.10.1515/jbcpp-2015-0063Suche in Google Scholar
10. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem 1951;193:265–75.10.1016/S0021-9258(19)52451-6Suche in Google Scholar
11. McCord JM, Fridovich I. Superoxide dismutase, an enzymatic function for erythrocuperin. J Biol Chem 1969;244:6049–55.10.1016/S0021-9258(18)63504-5Suche in Google Scholar
12. Aebi HE. Catalase. In: Bergmeyer HU, editor. Methods of enzymatic analysis. Weinhem: Verlag Chemie, 1983;273–86.10.1016/B978-0-12-091302-2.50032-3Suche in Google Scholar
13. Habig WH, Pabst MJ, Jakoby WB. Glutathione-S-transferases. The first enzymatic step in mercapturic acid formation. J Biol Chem 1974;249:7130–9.10.1016/S0021-9258(19)42083-8Suche in Google Scholar
14. Rotruck JT, Pope AL, Ganther HE, Swanson AB, Hafeman DG, Hoekstra WG. Selenium: biochemical role as a component of glutathione peroxidase. Science 1973;179:588–90.10.1126/science.179.4073.588Suche in Google Scholar PubMed
15. Moron MS, Depierre JW, Mannervick B. Levels of glutathione, glutathione reductase and glutathione-s-transferase activities in rat lung and liver. Biochim Biophys Acta 1979;582:67–78.10.1016/0304-4165(79)90289-7Suche in Google Scholar
16. Buege JA, Aust SD. Microsomal lipid peroxidation. Method Enzymol 1978;52:302–10.10.1016/S0076-6879(78)52032-6Suche in Google Scholar
17. Tietz NW. Clinical guide to laboratory tests, 3rd ed. Philadelphia, PA: W.B. Saunders Company, 1995:215–23.Suche in Google Scholar
18. Uotila M, Ruoslahti E, Engvali EJ. Two-site sandwich enzyme immunoassay with monoclonal antibodies to human alpha-fetoprotein. J Immunol Methods 1981;42:11–5.10.1016/0022-1759(81)90219-2Suche in Google Scholar
19. Mohun AF, Cook LJ. Simple method for measuring serum level of glutamate-oxaloacetate and glutamate-pyruvate transaminases in laboratories. J Clin Pathol 1957;10:394–9.10.1136/jcp.10.4.394Suche in Google Scholar PubMed PubMed Central
20. Reitman S, Frankel S. A colorimetric method for the determination of serum level of glutamate-oxaloacetate and pyruvate transaminases. Am J Clin Pathol 1957;28:56–63.10.1093/ajcp/28.1.56Suche in Google Scholar PubMed
21. Jaffe M. Ueber den Neiderschlag, welchen Pikrinsäure im normalen harn Erzeught und über eine neue Reaction des Kreatinins. Z Physiol Chem 1886;10:391–400.10.1515/bchm1.1886.10.5.391Suche in Google Scholar
22. Rutkowski RB, Debaare L. An ultra-micro colorimetric method for determination of total and direct serum bilirubin. Clin Chem 1966;12:432–8.10.1093/clinchem/12.7.432Suche in Google Scholar
23. Tony IO, Odunayo OO, Victor A. A retrospective study on incidence of pulmonary tuberculosis and human immunodeficiency virus co-infection among patients attending National Tuberculosis and Leprosy Control Programme, Owo centre. The Pan Afr Med J 2015;20:345.10.11604/pamj.2015.20.345.5643Suche in Google Scholar
24. Tasduq SA, Peerzada K, Koul S, Bhat R, Johri RK. Biochemical manifestations of anti-tuberculosis drugs induced hepatotoxicity and the effect of silymarin. Hepatol Res 2005;31:132–5.10.1016/j.hepres.2005.01.005Suche in Google Scholar PubMed
25. Rana SV, Attri S, Vaiphei K, Pal R, Attri A, Singh K. Role of N-acetylcysteine in rifampicin-induced hepatic injury of young rats. World Gastroenterol 2006;12:287–91.10.3748/wjg.v12.i2.287Suche in Google Scholar PubMed PubMed Central
26. Victorrajmohan C, Pradep K, Karthikeyan S. Influence of silymarin administration on hepatic glutathione-conjugating enzyme system in rats treated with antitubercular drugs. Drugs R D 2005;6:395–400.10.2165/00126839-200506060-00007Suche in Google Scholar PubMed
27. Pal R, Vaiphei K, Sikander A, Singh K, Rana SV. Effects of garlic on isoniazid and rifampicin-induced hepatic injury in rats. World Gastroenterol 2006;12:636–9.10.3748/wjg.v12.i4.636Suche in Google Scholar PubMed PubMed Central
28. Santhosh S, Sini TK, Anandan R, Mathew PT. Hepatoprotective activity of chitosan against Isoniazid and Rifampicin-induced toxicity in experimental rats. Eur J Pharmacol 2007;572:69–73.10.1016/j.ejphar.2007.05.059Suche in Google Scholar PubMed
29. Mehmet UC, Adullah A, Hales T, Sefer V, Adalet A, Yavuz Y, et al. Toxic effect of isoniazid and rifampicin on rat brain tissue: the preventive role of caffeic acid phenylester. Int J Pharmacol 2012;8:555–60.10.3923/ijp.2012.555.560Suche in Google Scholar
30. Abolaji AO, Adedara IA, Abajingin AO, Fatunmibi OJ, Ladipo EO, Farombi EO. Evidence of oxidative damage and reproductive dysfunction accompanying 4-vinylcyclohexene diepoxide exposure in female Wistar rats. Reprod Toxicol 2016;66:10–9.10.1016/j.reprotox.2016.09.009Suche in Google Scholar PubMed
31. Yoshida M, Ishigaki K, Nagai T, Chikyu M, Pursel VG. Glutathione concentration during maturation and after fertilization in pig oocytes: relevance to the ability of oocytes to form male pronucleus. Biol Reprod 1993;49:89–94.10.1095/biolreprod49.1.89Suche in Google Scholar PubMed
32. Devasagayam TP, Sivabalan R, Tarachand U. Lipid peroxidation in the rat uterus during deciduoma-induced cell differentiation. Biochem Int 1990;21:27–33.Suche in Google Scholar
33. Laloraya M, Kumar GP, Laloraya MM. Changes in the superoxide radical and superoxide dismutase levels in the uterus of Rattus norvegicus during the estrous cycle and a possible role for superoxide radical in uterine oedema and cell proliferation at proestrus. Biochem Cell Biol 1991;69:313–6.10.1139/o91-048Suche in Google Scholar PubMed
34. Farombi EO, Adedara IA, Ebokaiwe AP, Teberen R, Ehwerhemuepha T. Nigerian bonny light crude oil disrupts antioxidant systems in the testis and sperm of rats. Arch Environ Contam Toxicol 2010;59:166–74.10.1007/s00244-009-9443-3Suche in Google Scholar PubMed
35. Appiah I, Milovanovic S, Radojicic R, Nikolic-Kokic A, Orescanin-Dusic Z, Slavic M, et al. Hydrogen peroxide affects contractile activity and antioxidant enzymes in rat uterus. Br J Pharmacol 2009;158:1932–41.10.1111/j.1476-5381.2009.00490.xSuche in Google Scholar PubMed PubMed Central
36. Eminzade F, Uras F, Izzettin V. Silymarin protects liver against toxic effects of anti-tuberculosis drugs in experimental rats. Nutr Metab 2008;5:18.10.1186/1743-7075-5-18Suche in Google Scholar PubMed PubMed Central
37. Marzouk M, Hassaneen S, Hussein H, Sammaan A. Ameliorative effect of Mecapure against rimactazid-induced hepatotoxicity in rats. Aus J Basic Appl Sci 2009;3:2350–4.Suche in Google Scholar
38. Adaramoye OA, Kehinde AO, Adefisan A, Adeyemi O, Oyinlola I, Akanni OO. Ameliorative effects of kolaviron, a biflavonoid fraction from Garcinia kola seed, on hepato-renal toxicity of anti-tuberculosis drugs in Wistar rats. Tokai J Exp Clin Med 2016;41:14–21.Suche in Google Scholar
39. Murthy GD, Byron D, Shoemaker D, Visweswaraiah H, Pasquale D. The utility of rifampicin in diagnosing Gilbert’s syndrome. Am J Gastroenterol 2001;96:1150–4.10.1111/j.1572-0241.2001.03693.xSuche in Google Scholar PubMed
40. Keating AF, Hoyer PB. Mechanisms of reproductive toxicity. In: Nassar AF, Hollenberg PF, Scatina J, editors. Drug metabolism in phamaceuticals: concepts and applications. New Jersey, USA: John Wiley & Sons Publication, 2009:697–734.10.1002/9780470439265.ch24Suche in Google Scholar
41. Raju GA, Chavan R, Deenadayal M, Gunasheela D, Gutgutia R, Haripriya G, et al. Luteinizing hormone and follicle stimulating hormone synergy: a review of role in controlled ovarian hyper-stimulation. J Hum Reprod Sci 2013;6:227–34.10.4103/0974-1208.126285Suche in Google Scholar PubMed PubMed Central
42. Gonçalves PB, Portela VM, Ferreira R, Gasperin BG. Role of angiotensin II on follicle development and ovulation. Anim Reprod 2010;7:140–5.Suche in Google Scholar
43. Jana K, Jana S, Samanta PK. Effects of chronic exposure to sodium arsenite on hypothalamo-pituitary-testicular activities in adult rats: possible an estrogenic mode of action. Rep Biol Endocrinol 2006;4:1–13.10.1186/1477-7827-4-9Suche in Google Scholar PubMed PubMed Central
©2018 Walter de Gruyter GmbH, Berlin/Boston
Artikel in diesem Heft
- Frontmatter
- Minireview
- Acorus calamus: a bio-reserve of medicinal values
- Behavior and Neuroprotection
- Electrodermal response to auditory stimuli in relation to menopausal transition period
- Reproduction
- First-line antituberculosis drugs disrupt endocrine balance and induce ovarian and uterine oxidative stress in rats
- Launaea taraxacifolia (Willd.) Amin ex C. Jeffrey inhibits oxidative damage and econucleotidase followed by increased cellular ATP in testicular cells of rats exposed to metropolitan polluted river water
- Cardiovascular Function
- Ameliorative effect of Azadirachta indica on sodium fluoride-induced hypertension through improvement of antioxidant defence system and upregulation of extracellular signal regulated kinase 1/2 signaling
- Regulation of hypoxia inducible factor/prolyl hydroxylase binding domain proteins 1 by PPARα and high salt diet
- Oxidative Stress
- Amla (Emblica officinalis) improves hepatic and renal oxidative stress and the inflammatory response in hypothyroid female wistar rats fed with a high-fat diet
- Metabolism
- Cocos nucifera water improves metabolic functions in offspring of high fat diet fed Wistar rats
- Prevalence of dry eye disease and its association with dyslipidemia
- Phytotherapy
- An isobolographic analysis of the anti-nociceptive effect of geraniin in combination with morphine or diclofenac
- Antidiarrheal and antimicrobial activities of the ethanol extract from the Icacina senegalensis root bark
- Chromatographic fingerprint analysis, antioxidant properties, and inhibition of cholinergic enzymes (acetylcholinesterase and butyrylcholinesterase) of phenolic extracts from Irvingia gabonensis (Aubry-Lecomte ex O’Rorke) Baill bark
- Corrigendum
- Corrigendum to: Possible modulation of PPAR-γ cascade against depression caused by neuropathic pain in rats
Artikel in diesem Heft
- Frontmatter
- Minireview
- Acorus calamus: a bio-reserve of medicinal values
- Behavior and Neuroprotection
- Electrodermal response to auditory stimuli in relation to menopausal transition period
- Reproduction
- First-line antituberculosis drugs disrupt endocrine balance and induce ovarian and uterine oxidative stress in rats
- Launaea taraxacifolia (Willd.) Amin ex C. Jeffrey inhibits oxidative damage and econucleotidase followed by increased cellular ATP in testicular cells of rats exposed to metropolitan polluted river water
- Cardiovascular Function
- Ameliorative effect of Azadirachta indica on sodium fluoride-induced hypertension through improvement of antioxidant defence system and upregulation of extracellular signal regulated kinase 1/2 signaling
- Regulation of hypoxia inducible factor/prolyl hydroxylase binding domain proteins 1 by PPARα and high salt diet
- Oxidative Stress
- Amla (Emblica officinalis) improves hepatic and renal oxidative stress and the inflammatory response in hypothyroid female wistar rats fed with a high-fat diet
- Metabolism
- Cocos nucifera water improves metabolic functions in offspring of high fat diet fed Wistar rats
- Prevalence of dry eye disease and its association with dyslipidemia
- Phytotherapy
- An isobolographic analysis of the anti-nociceptive effect of geraniin in combination with morphine or diclofenac
- Antidiarrheal and antimicrobial activities of the ethanol extract from the Icacina senegalensis root bark
- Chromatographic fingerprint analysis, antioxidant properties, and inhibition of cholinergic enzymes (acetylcholinesterase and butyrylcholinesterase) of phenolic extracts from Irvingia gabonensis (Aubry-Lecomte ex O’Rorke) Baill bark
- Corrigendum
- Corrigendum to: Possible modulation of PPAR-γ cascade against depression caused by neuropathic pain in rats
