Molecular and Cellular Biochemistry

, Volume 386, Issue 1–2, pp 27–34 | Cite as

Therapeutic exploration of betulinic acid in chemically induced hypothyroidism

  • Muhammad Afzal
  • Imran KazmiEmail author
  • Susmita Semwal
  • Fahad A. Al-Abbasi
  • Firoz AnwarEmail author


Hypothyroidism is a chronic condition characterized by abnormally low thyroid hormone production. The decreased serum level (>5.1 mIU/l) of thyroid-stimulating hormone (TSH) in blood indicates hypothyroidism. The study was an attempt to access the effect of betulinic acid on chemically induced hypothyroidism in female albino rats. Betulinic acid is a naturally occurring pentacyclic triterpenoid, which has antiretroviral, antimalarial, and anti-inflammatory properties, as well as anticancer potential, by inhibiting topoisomerase. Hypothyroidism was induced in female albino rats using propylthiouracil (PTU) at a dose of 60 μg/kg body weight orally for 1 month. Induction of hypothyroidism was confirmed by increased TSH level. At the end of second month, blood was collected, centrifuged and serum was analyzed for TSH, T3, and T4 level and protocol was terminated by killing of animals. The animals exposed to PTU were treated with pure standard drug thyroxine at a dose of 10 μg/kg of body weight by oral route and the test drug betulinic acid 20 mg/kg by oral route through force feeding in their respective groups. Treatment was carried out for a period of 2 months. Group with PTU-induced hypothyroidism showed an elevation in serum TSH and reduction level, which was restored by the betulinic acid in treated female albino rats. Betulinic acid also reduced the damage caused in the thyroid tissues by PTU, thus minimizing the symptoms of hypothyroidism. Histopathological examinations of the thyroid tissue showed changes in the thyrocytes of PTU-treated group while thyroxine group showed normal thyroid follicles cell architecture and the group treated with betulinic acid also showed marked improvement in the follicles integrity which shows that betulinic acid has some protective activity. This study shows that the betulinic acid has thyroid-enhancing potential by lowering down the TSH levels and reducing the damage caused in the thyroid tissues, thus minimizing the symptoms of hypothyroidism when used anaphylactically in rats.


Betulinic acid Hypothyroidism Propylthiouracil Thyroxine Thyroid-stimulating hormone 


  1. 1.
    Almandoz JP, Gharib H (2012) Hypothyroidism: etiology, diagnosis and management. Med Clin North Am 96:203–221PubMedCrossRefGoogle Scholar
  2. 2.
    Ahmed OM, El-Gareib AW, El-bakry AM, El-Tawab SMA, Ahmed RG (2008) Thyroid hormones states and brain development interactions. Int J Dev Neurosci 26:147–209PubMedCrossRefGoogle Scholar
  3. 3.
    Schlenker EH (2012) Effects of hypothyroidism on the respiratory system and control of breathing human studies and animal models. Respir Physiol Neurobiol 181:123–131PubMedCrossRefGoogle Scholar
  4. 4.
    Koromilas C, Liapi C, Schulpis KH, Kalafatakis K, Zarros A, Tsakiris S (2010) Structural and functional alterations in the hippocampus due to hypothyroidism. Metab Brain Dis 25:339–354PubMedCrossRefGoogle Scholar
  5. 5.
    Ahmed OM, Abd El-Tawab SM, Ahmed RG (2010) Effects of experimentally induced maternal hypothyroidism and neurotransmitters and adenosinergic system interactions. Int J Dev Neurosci 28:437–454PubMedCrossRefGoogle Scholar
  6. 6.
    Wang Y, Zhong J, Wei W, Gong J, Dong J, Yu F, Wang Y, Chen J (2011) Developmental iodine deficiency and hypothyroidism impair neural development, upregulate caveolin-1, and downregulate synaptophysin in rat hippocampus. Biol Trace Elem Res 144:1039–1049PubMedCrossRefGoogle Scholar
  7. 7.
    Rugge B, Balshem H, Sehgal R, Relevo R, Gorman P, Helfand M (2011) Screening and treatment of subclinical hypothyroidism or hyperthyroidism. Rockville (MD): Agency for Healthcare Research and Quality (US). Report No.: 11(12)-EHC033-EFGoogle Scholar
  8. 8.
    Kansagra S, McCudden C, Willis M (2010) The challenges and complexities of thyroid hormone replacement. Labmedicine 41:229–348Google Scholar
  9. 9.
    Saini V, Yadav A, Arora M, Arora S, Singh R, Bhattacharjee J (2012) Correlation of creatinine with TSH levels in overt hypothyroidism-A requirement for monitoring of renal function in hypothyroid patients. Clin Biochem 45:212–214PubMedCrossRefGoogle Scholar
  10. 10.
    Mitrou P, Raptis SA, Dimitriadis G (2011) Thyroid disease in older people. Maturitas 70:5–9PubMedCrossRefGoogle Scholar
  11. 11.
    Ogbera A, Kuku S, Dada O (2012) The metabolic syndrome in thyroid disease: a report from Nigeria. Indian J Endocrinol Metab 16:417–422PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Schlenker EH (2012) Effects of hypothyroidism on the respiratory system and control of breathing: human studies and animal models. Respir Physiol Neurobiol 181:123–131PubMedCrossRefGoogle Scholar
  13. 13.
    Adrees M, Gibney J, El-Saeity N, Boran G (2009) Effects of 18 months of L-T4 replacement in women with subclinical hypothyroidism. Clin Endocrinol 71:298–303CrossRefGoogle Scholar
  14. 14.
    Santos SO, Loureiro SM, Alves IG, Jesus CS, Santos PR, Santos MR, Dias DP, Santana-Filho VJ, Badauê-Passos D Jr (2012) Experimental gestational hypothyroidism evokes hypertension in adult offspring rats. Auton Neurosci 170:36–41PubMedCrossRefGoogle Scholar
  15. 15.
    Stagnaro-Green A (2011) Overt hyperthyroidism and hypothyroidism during pregnancy. Clin Obstet Gynecol 54:478–487PubMedCrossRefGoogle Scholar
  16. 16.
    Gartner R (2009) Thyroid diseases in pregnancy. Curr Opin Obstet Gynecol 21:501–507PubMedCrossRefGoogle Scholar
  17. 17.
    Ige SF, Akhigbe RE, Akinsemola OO (2011) Intrauterine programming and postnatal hypertension. Res J Obstet Gynecol 4:01–27CrossRefGoogle Scholar
  18. 18.
    Fowden AL, Forhead AJ (2009) Endocrine regulation of feto-placental growth. Horm Res 72:257–265PubMedCrossRefGoogle Scholar
  19. 19.
    Chattergoon NN, Giraud GD, Louey S, Stork P, Fowden AL, Thornburg KL (2012) Thyroid hormone drives fetal cardiomyocyte maturation. FASEB J 26:397–408PubMedCrossRefGoogle Scholar
  20. 20.
    Chowdhury AR, Mandal S, Mittra B, Sharma S, Mukhopadhyay S, Majumder HK (2008) Betulinic acid, a potent inhibitor of eukaryotic topoisomerase I: identification of the inhibitory step, the major functional group responsible and development of more potent derivatives. Med Sci Monit 8(7):BR254–BR265Google Scholar
  21. 21.
    Yogeeswari P, Sriram D (2005) Betulinic acid and its derivatives: a review on their biological properties. Curr Med Chem 12:657–666PubMedCrossRefGoogle Scholar
  22. 22.
    Einzhammer DA, Xu ZQ (2004) Betulinic acid: a promising anticancer candidate. IDrugs 4:359–373Google Scholar
  23. 23.
    Domínguez-Carmona DB, Escalante-Erosa F, García-Sosa K, Ruiz-Pinell G, Gutierrez-Yapu D, Chan-Bacab MJ, Giménez-Turba A, Peña-Rodríguez LM (2010) Antiprotozoal activity of betulinic acid derivatives. Phytomedicine 17(5):379–382PubMedCrossRefGoogle Scholar
  24. 24.
    Liu WK, Ho JC, Cheung FW, Liu BP, Ye WC, Che CT (2004) Apoptotic activity of betulinic acid derivatives on murine melanoma B16 cell line. Eur J Pharmacol 498(1–3):71–78PubMedCrossRefGoogle Scholar
  25. 25.
    Alakurtti S, Makela T, Koskimies S, Yli-Kauhaluoma J (2006) Pharmacological properties of the ubiquitous natural product betulin. Eur J Pharm Sci 29:1–13PubMedCrossRefGoogle Scholar
  26. 26.
    Takada Y, Aggarwal BB (2003) Betulinic acid suppresses carcinogen-induced NF kappa B activation through inhibition of I kappa B alpha kinase and p65 phosphorylation: abrogation of cyclooxygenase-2 and matrix metalloprotease-9. J Immunol 171:3278–3286PubMedGoogle Scholar
  27. 27.
    Salvati S, Attorri L, Campeggi LM (1994) Effect of propylthiouracil-induced hypothyroidism on cerebral cortex of young and aged rats: lipid composition of synaptosomes, muscarinic receptor sites, and acetylcholinesterase activity. Neurochem Res 19:1181–1186PubMedCrossRefGoogle Scholar
  28. 28.
    Cano-Europa E, Blas-Valdivia V, Franco-Colin M, Gallardo-Casas CA, Ortiz-Butrón R (2011) Methimazole-induced hypothyroidism causes cellular damage in the spleen, heart, liver, lung and kidney. Acta Histochem 113:1–5PubMedCrossRefGoogle Scholar
  29. 29.
    Wan Y, Wu YL, Lian LH, Xie WX, Li X, Ouyang BQ, Bai T, Li Q, Yang N, Nan JX (2012) The anti-fibrotic effect of betulinic acid is mediated through the inhibition of NF-κB nuclear protein translocation. Chem Biol Interact 195:215–223PubMedCrossRefGoogle Scholar
  30. 30.
    Tousson E, Beltagy DM, El-Gerbed M, Gazia MA, Mohamed A (2012) The ameliorating role of folic acid in rat hippocampus after propylthiouracil-induced hypothyroidism. Biomed Aging Pathol 2:104–110CrossRefGoogle Scholar
  31. 31.
    Cooper DS (2000) Treatment of thyrotoxicosis. In: Bravermann LE, Utiger RD (eds) Werner & Ingbar’s, The Thyroid. A fundamental and clinical text, 8th edn. Lippincott Williams & Wilkins, Philadelphia, pp 691–715Google Scholar
  32. 32.
    Taurog A (1976) The mechanism of action of thioureylene antithyroid drugs. Endocrinology 98:1031–1046PubMedCrossRefGoogle Scholar
  33. 33.
    Salminen A, Lehtonen M, Suuronen T, Kaarniranta K, Huuskonen J (2008) Terpenoids: natural inhibitors of NF-kappa B signaling with anti-inflammatory and anticancer potential. Cell Mol Life Sci 65:2979–2999PubMedCrossRefGoogle Scholar
  34. 34.
    Ness GC, Lopez D, Chambers CM, Newsome WP, Cornelius P, Long CA, Harwood HJ Jr (1998) Effects of L-triiodothyronine and the thyromimetic L-94901 on serum lipoprotein levels and hepatic low-density lipoprotein receptor, 3-hydroxy-3-methylglutaryl coenzyme A reductase, and apo A-I gene expression. Biochem Pharmacol 56:121–129PubMedCrossRefGoogle Scholar
  35. 35.
    Ness GC, Lopez D (1995) Transcriptional regulation of rat hepatic low-density lipoprotein receptor and cholesterol 7 alpha hydroxylase by thyroid hormone. Arch Biochem Biophys 323:404–408PubMedCrossRefGoogle Scholar
  36. 36.
    Taylor AH, Stephan ZF, Steele RE, Wong NC (1997) Beneficial effects of a novel thyromimetic on lipoprotein metabolism. Mol Pharmacol 52:542–547PubMedGoogle Scholar
  37. 37.
    Malik R, Hodgson H (2002) The relationship between the thyroid gland and the liver. QJM 95(9):559–569PubMedCrossRefGoogle Scholar
  38. 38.
    Yi JE, Obminska-Mrukowicz B, Yuan LY, Yuan H (2010) Immunomodulatory effects of betulinic acid from the bark of white birch on mice. J Vet Sci 11:305–313PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Lluberas-Acosta G, Schumacher HRJ (1996) Markedly elevated erythrocyte sedimentation rates: consideration of clinical implications in a hospital population. Br J Clin Pract 50:138–142PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Siddhartha Institute of PharmacyDehradunIndia
  2. 2.Department of Biochemistry, Faculty of SciencesKing Abdulaziz UniversityJeddahKingdom of Saudi Arabia

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