Skip to main content
SpringerLink
Log in

The Effect of Streptozotocin and Alloxan on the mRNA Expression of Rat Hepatic Transporters In Vivo

  • Research Article
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

The effect of streptozotocin (STZ) and alloxan (ALX) on the hepatic messenger RNA (mRNA) expression of four transporters (Mrp2, Mdr1, Oct1, and Oatp1) was studied in the present work. After the healthy male Wistar rats were individually treated by a single intraperitoneal injection of ALX monohydrate (150 mg/kg) or STZ (50 mg/kg), the hepatic mRNA expression levels of Mrp2, Mdr1, Oct1, and Oatp1 were detected by real-time quantitative PCR. The results indicated that the mRNA expression levels of the Mrp2, Mdr1, Oct1, and Oatp1 in ALX-induced diabetic rats, as well as the hepatic mRNA expression of Mdr1 and Oatp1 in STZ-induced diabetic rats, were significantly decreased as compared with the control. The inhibition of ALX and STZ on hepatic transporter expression suggested that alterations of drug transporters under diabetic condition can be responsible for reduced drug clearance.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Szkudelski T. The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas. Physiol Res. 2001;50:536–46.

    Google Scholar 

  2. Elsner M, Guldbakke B, Tiedge M, Munday R, Lenzen S. Relative importance of transport and alkylation for pancreatic beta-cell toxicity of streptozotocin. Diabetologia. 2000;43:1528–33.

    Article  CAS  PubMed  Google Scholar 

  3. Elsner M, Tiedge M, Lenzen S. Mechanism underlying resistance of human pancreatic beta cells against toxicity of streptozotocin and alloxan. Diabetologia. 2003;46:1713–4.

    Article  CAS  PubMed  Google Scholar 

  4. Mizuno N, Niwa T, Yotsumoto Y, Sugiyama Y. Impact of drug transporter studies on drug discovery and development. Pharmacol Rev. 2003;55:425–61.

    Article  CAS  PubMed  Google Scholar 

  5. Rahi M, Heikkinen T, Hakkola J, Hakala K, Wallerman O, Wadelius M, et al. Influence of adenosine triphosphate and ABCB1(MDR1) genotype on the P-glycoprotein-dependent transfer of saquinavir in the dually perfused human placenta. Hum Exp Toxicol. 2008;27:65–71.

    Article  CAS  PubMed  Google Scholar 

  6. Borst P, Evers R, Kool M, Wijnholds J. A family of drug transporters: the multidrug resistance-associated proteins. J Natl Cancer I. 2000;92:1295–302.

    Article  CAS  Google Scholar 

  7. Sun H, Frassetto L, Benet LZ. Effects of renal failure on drug transport and metabolism. Pharmacol Therapeut. 2006;109:1–11.

    Article  CAS  Google Scholar 

  8. Holzer B, Stieger B, Folkers G, Meier PJ, Fattinger K. Differential regulation of basolateral and canalicular transporter expression in rat liver in chronic renal failure. Clin Pharmacol Ther. 2005;77:34.

    Article  Google Scholar 

  9. Laouari D, Yang R, Veau C, Blanke I, Friedlander G. Two apical multidrug transporters, P-gp and MRP2, are differently altered in chronic renal failure. Am J Physiol Renal Physiol. 2001;280:636–45.

    Google Scholar 

  10. Grover B, Buckley D, Buckley AR, Cacini W. Reduced expression of organic cation transporters rOCT1 and rOCT2 in experimental diabetes. J Pharmacol Exp Ther. 2004;308:949–56.

    Article  CAS  PubMed  Google Scholar 

  11. Eliza J, Daisy P, Ignacimuthu S, Duraipandiyan V. Antidiabetic and antilipidemic effect of eremanthin from Costus speciosus (Koen.) Sm. in STZ-induced diabetic rats. Chem-Biol Interact. 2009;182:67–72.

    Article  CAS  PubMed  Google Scholar 

  12. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2−△△CT method. Methods. 2001;25:402–8.

    Article  CAS  PubMed  Google Scholar 

  13. Kim YC, Lee AK, Lee JH, Lee I, Lee DC, Kim SH, et al. Pharmacokinetics of theophylline in diabetes mellitus rats: induction of CYP1A2 and CYP2E1 on 1, 3-dimethyluric acid formation. Eur J Pharm Sci. 2005;26:114–23.

    Article  CAS  PubMed  Google Scholar 

  14. Kim YC, Oh EY, Kim SH, Lee MG. Pharmacokinetics of diclofenac in rat model of diabetes mellitus induced by alloxan or steptozotocin. Biopharm Drug Dispos. 2006;27:85–92.

    Article  CAS  PubMed  Google Scholar 

  15. Hasegawa Y, Kishimoto S, Shibatani N, Inotsume N, Takeuchi Y, Fukushima S. The disposition of pravastatin in a rat model of streptozotocin-induced diabetes and organic anion transporting polypeptide 2 and multidrug resistance-associated protein 2 expression in the liver. Biol Pharm Bull. 2010;33:153–6.

    Article  CAS  PubMed  Google Scholar 

  16. van Waarde WM, Verkade HJ, Wolters H, Havinga R, Baller J, Bloks V, et al. Differential effects of streptozotocin-induced diabetes on expression of hepatic ABC-transporters in rats. Gastroenterology. 2002;122:1842–52.

    Article  PubMed  Google Scholar 

  17. Salil G, Nevin KG, Rajamohan T. Arginine rich coconut kernel protein modulates diabetes in alloxan treated rats. Chem-Biol Interact. 2011;189:107–11.

    Article  CAS  PubMed  Google Scholar 

  18. Kullak-Ublick GA, Stieger B, Meier PJ. Enterohepatic bile salt transporters in normal physiology and liver disease. Gastroenterology. 2004;126:322–42.

    Article  CAS  PubMed  Google Scholar 

  19. Trauner M, Boyer JL. Bile salt transporters: molecular characterization, function, and regulation. Physiol Rev. 2003;83:633–71.

    Article  CAS  PubMed  Google Scholar 

  20. Stahl S, Davies MR, Cook DI, Graham MJ. Nuclear hormone receptor-dependent regulation of hepatic transporters and their role in the adaptive response in cholestasis. Xenobiotica. 2008;38:725–77.

    Article  CAS  PubMed  Google Scholar 

  21. Villanueva GR, Herreros M, Perez-Barriocanal F, Bolanos JP, Bravo P, Marin JJ. Enhancement of bile acid-induced biliary lipid secretion by streptozotocin in rats: role of insulin deficiency. J Lab Clin Med. 1990;115:441–8.

    CAS  PubMed  Google Scholar 

  22. Icarte MA, Pizarro M, Accatino L. Adaptive regulation of hepatic bile salt transport: effects of alloxan diabetes in the rat. Hepatology. 1991;14:671–8.

    CAS  PubMed  Google Scholar 

  23. Kruh GD, Belinsky MG. The MRP family of drug efflux pumps. Oncogene. 2003;22:7537–52.

    Article  CAS  PubMed  Google Scholar 

  24. Ellis LC, Hawksworth GM, Weaver RJ. ATP-dependent transport of statins by human and rat MRP2/Mrp2. Toxicol Appl Pharmacol. 2013;269:187–94.

    Article  CAS  PubMed  Google Scholar 

  25. Maeng HJ, Yoo HJ, Kim IW, Sonq IS, Chung SJ, Shim CK. P-glycoprotein–mediated transport of berberine across Caco-2 cell monolayers. J Pharm Sci. 2002;91:2614–21.

    Article  CAS  PubMed  Google Scholar 

  26. The International Transporter Consortium. Membrane transporters in drug development. Nat Rev Drug Discov. 2010;9:215–36.

    Article  PubMed Central  Google Scholar 

  27. Sogame Y, Kitamura A, Yabuki M, Komuro S. A comparison of uptake of metformin and phenformin mediated by hOCT1 in human hepatocytes. Biopharm Drug Dispos. 2009;30:476–84.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the ChenGuang Project of youth science-technology in Wuhan, No. 201150431135.

Author information

Authors and Affiliations

  1. Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, Hubei Collaborative Innovation Center for Green Transformation of Bio-resources, Hubei University, Wuhan, 430062, China

    Ting Zhai, Junjun Wang, Lijuan Sun & Yong Chen

Authors
  1. Ting Zhai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Junjun Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lijuan Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yong Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yong Chen.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhai, T., Wang, J., Sun, L. et al. The Effect of Streptozotocin and Alloxan on the mRNA Expression of Rat Hepatic Transporters In Vivo . AAPS PharmSciTech 16, 767–770 (2015). https://doi.org/10.1208/s12249-014-0262-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12249-014-0262-0

KEY WORDS

Search

Navigation