Toxicological evaluation of subchronic use of pioglitazone in mice

Document Type: Original Article


1 Department of Forensic Medicine and Clinical Toxicology, College of Medicine, Taif University, Suez Canal University, Taif, KSA

2 Department of Pathology, College of Medicine, Taif University, Taif, KSA

3 Department of Molecular Biology, GEBRI, University of Sadat City, Egypt

4 Department of Anatomy, College of Medicine, Taif University, Al-Azhar University, Taif, KSA


Objective(s): Pioglitazone (Actos) is one of the most controversial recent oral antidiabetic drugs. It was originally authorized in the European Union in 2000, and approved as an oral monotherapy for overweight second type of diabetic patients in 2002. It belongs to the thiazolidinedione group which some of its members have been withdrawn from the market due to the hepatotoxicity or cardiotoxicity effects.This studyinvestigates sub-chronic use of pioglitazone induced toxicity in mice by the assessment of renal and liver function tests, cardiac enzymes, and some hematological indices with histological changes of liver, kidney, heart, and bladder.
Materials and Methods: 120 albino mice were divided into four groups; 30 in each. The first group (control) received water, second (diabetic) group received alloxan only, while the third and the fourth groups received alloxan with 200 and 400 mg/kg/day of pioglitazone, respectively for 90 days.
Results: Prolonged use of pioglitazone induced significant abnormalities of hepatic, renal, and cardiac biomarkers and some hematological indices associated with histopathological changes in the liver, kidney, heart, and bladder that increased based on administered dose.
Conclusion: Subchronic use of pioglitazone leads to hepatic, renal, cardiac, hematological, and bladder affection depending on the applied dose.


1. World Health Organization “WHO”. Global Health Estimates: Deaths by Cause, Age, Sex and Country, 2000-2012. Geneva: 2014.

2. Mizrachi E, Bernel-Mizrachi C. Diabetes mellitus and related disorders. In: Cooper DH, Krainik AJ, Lubner SJ, Reno HEL, editors. Washington manual of medical therapeutics. 32nd ed. Philadelphia, PA: Wolters Kluwer/Lippincott Williums and Wilkins; 2007.p. 600-623.

3. Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 2006; 355:2297-2307.

4. Nolte MS. Pancreatic hormones and antidiabetic drugs. In: Katzung BG, Masters SB, Trevor AJ, editors. Basic and clinical pharmacology. 11th ed. New Delhi: Tata McGraw Hill Education Private Limited; 2009.p. 727-751.

5. Schernthaner G, Matthews DR, Charbonnel B, Hanefeld M, Brunetti P. Quartet Study Group. Efficacy and safety of pioglitazone versus metformin in patients with type 2 diabetes mellitus: a doubleblind, randomized trial. J Clin Endocrinol Metab 2004; 89:6068-6076.

6. Saha SK, Das SC, Abdullah AE, Sarker M, Uddin MA, Chowdhury AK, et al. Biochemical alterations and liver toxicity analysis with pioglitazone in healthy subjects. Drug Chem Toxicol 2012; 36:149-154.

7. Brunton LL, Lazo JS, Parker KL. Goodman and Gilman's the Pharmacological Basis of Therapeutics, 11th ed. United States of America: McGraw Medical Publishing Division; 2006.p.1613-1645.

8. Patel C, Wyne KL, McGuire DK. Thiazolidine-diones, peripheral oedema and congestive heart failure: what is the evidence? Diabetes Vasc Dis Res 2005; 2:61-66.

9. Shukla R, Karla S. Pioglitazone: Indian perspec-tive. Indian J Endocrinol Metab 2011; 15:294-297.

10. Tolman KG, Chandramouli J. Hepatotoxicity of the thiazolidinediones. Clin Liver Dis 2003; 7:369-79.

11. Saha SK, Chowdhury AK, Bachar SC, Das SC, Kuddus RH, Uddin MA. Comparative in vitro- in vivo correlation analysis with pioglitazone tablets. Asian Pac J Trop Dis 2013; 3:487-491.

12. Schernthaner G, Currie C, Schernthaner GH. Do we still need pioglitazone for the treatment of Type 2 Diabetes? Diabetes Care 2013; 36:155-161.

13. Lenzen S. The mechanisms of alloxan and streptozotocin-induced diabetes,” Diabetologia 2008; 2:216-226.

14. Chinnam P, Mohsin M, Shafee LM.  Evaluation of acute toxicity of pioglitazone in mice. Toxicol Int 2012; 19:250- 254.

15. Ankur R, Shahjad A. Alloxan induced diabetes: mechanisms and effects. Int J Res Pharm Biomed Sci 2012; 3:819-823.

16. Alexander RH, Griffith JM. Clinical/Nutritional Biochemistry. Basic Biochemical Methods. 2nd ed. Wiley-Liss, New York: John Wiley & Sons; 1992.

17. McKenzie M. Clinical Laboratory Hematology. 2nd ed. Prentice Hall; 2010.p. 411- 422.

18. Wu AH, Apple FS, Valdes RJ. National academy of clinical Biochemistry Standards of Laboratory Practice: recommendations for use of cardiac markers in coronary artery diseases. Clin Chem 1999; 45:1104-1121.

19. Bancroft JD, Gamble M. Theory and Practice Histological Techniques, 5th ed., Churchill Living-stone. New York: Edinburgh and London: 2002.p. 173-175.

20. Chojkier M. Troglitazone and liver injury: in search of answers. Hepatology 2005; 41:237-246.

21. Nathan DM. Rosiglitazone and cardiotoxicity- weighing the evidence. N Engl J Med 2007; 357:64- 66.

22. Chase MP, Yarze JC. Pioglitazone-associated fulminant hepatic failure. Am J Gastroenterol 2002; 97: 502-503.

23. Farley-Hills E, Sivasankar R, Martin M. Fatal liver failure associated with pioglitazone. BMJ 2004; 329:429.

24. Pessayre D, Mansouri A, Haouzi D, Fromenty B. Hepatotoxicity due to mitochondrial dysfunction. Cell Biol Toxicol 1999; 15:367-373.

25. Elgawly H, Tawfik MK, Rashwan MF, Baruzaig AS. The effect of pioglitazone on the liver of strepto-zotocin-induced diabetic albino wistar rats. Eur Rev Med Pharm Sci 2009; 13:443-451.

26. Budde K, Neumayer HH, Fritsche L, Sulowicz W, Stompor T, Eckland D. The pharmacokinetics of pioglitazone in patients with impaired renal function. Br J Clin Pharmacol 2003; 55:368-374.

27. Yang H, Kim WS, Kim DH, Kang JS. Histopatho-logical Evaluation of Heart Toxicity of a Novel Selective PPAR-γ Agonists CKD-501 in db/db Mice. Biomol Ther 2013; 21:84-88.

28. Lincoff AM, Wolski K, Nicholls SJ, Nissen SE.  Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA 2007; 298:1180-1188.

29. Jeremias A, Gibson CM. Narrative review: alter-native causes for elevated cardiac troponin levels when acute coronary syndromes are excluded. ANN Intern Med 2005; 142:786-791.

30. O, Brien PJ. Cardiac troponin is the most effective translational safety biomarker for myocardial infarction in cardiotoxicity. Toxicology 2008; 245:206-218.

31. Lin KD, Lee MY, Feng CC, Chen BK, Yu ML, Shin SJ. 

Residual effect of reductions in red blood cell count and haematocrit and haemoglobin levels after 10-month withdrawal of pioglitazone in patients with Type 2 diabetes. Diabet Med 2014; 31:1341-1349.

32. Berria R, Glass L, Mahankali A, Miyazaki Y, Monroy A, De Filippis E, et al. Reduction in hematocrit and hemoglobin following pioglitazone treatment is not hemodilutional in Type II diabetes mellitus. Clin Pharmacol Ther 2007; 82:275-281.

33. Cheng L, Cheville JC, Neumann RM, Bostwick DG. Natural history of urothelial dysplasia of the bladder. Am J Surg Pathol 1999; 23:443-447.

34.  Piccinni C, Motola D, Marchesini G, Poluzzi E. Assessing the association of pioglitazone use and bladder cancer through drug adverse event reporting. Diabetes Care 2011; 34:1369-1371.

35. Berger J, Moller DE. The mechanisms of action of PPARs. Annu Rev Med 2002; 53:409-435.

36. Varley CL, Southgate J. Effects of PPAR agonists on proliferation and differentiation in human urothelium. Exp Toxicol Pathol 2008; 60:435-441.

37. Lee MY, Hsiao PJ, Yang YH, Lin KD, Shin SJ. The Association of Pioglitazone and Urinary Tract Disease in Type 2 Diabetic Taiwanese: Bladder Cancer and Chronic Kidney Disease. PLoS One 20149; 1:e85479.