J Appl Biomed 14:25-34, 2016 | DOI: 10.1016/j.jab.2015.08.001

Atorvastatin up-regulates the expression and activity of renal Cytochrome P450 3A2 in diabetic rats

Hassan Malekinejada,b,*, Shahin Alizadeh-Fanaloub, Rahim Hobbenaghic, Shirin Rokhsartalb-Azarb
a Department of Pharmacology and Toxicology, Faculty of Pharmacy, Urmia University of Medical Sciences, Urmia, Iran
b Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Urmia University, Iran
c Department of Pathology, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran

Effects of atorvastatin on the expression of Cytochrome P450 3A2 and its enzymatic activity in the kidney of diabetic rats were investigated. Diabetes was induced by injection of streptozotocine (50 mg/kg, b.w., i.p.) in male Wistar rats. The animals were assigned into four groups including control (C), non-treated diabetic (D), atorvastatin-treated diabetic (AD) and atorvastatin-treated non-diabetic (A) groups. Metabolism of testosterone was examined in the presence of renal microsomes. The expression of CYP 3A2 at mRNA level was examined by means of PCR technique. The atorvastatin administration resulted in a remarkable improvement of diabetes-induced nephropathy and oxidative stress. Enzyme kinetics analyses showed that both diabetic groups produced significantly (P < 0.05) more 6β-hydroxytestosterone (Vmax for D = 34.7 ± 1.3 and for AD = 45.1 ± 2.3 pM/min/mg) than that of the control group (Vmax = 21.6 ± 1.5 pM/min/mg). Both diabetes and atorvastatin administration resulted in a significant up regulation of CYP 3A2 mRNA level in the kidney. Our data suggest that due to profound influence of diabetes and atorvastatin on renal metabolism of CYP 3A2 substrate and up-regulation of this gene, there should be adjusted dose regimen for medications which are classified as CYP 3A2 substrates.

Keywords: Atorvastatin; Diabetes; Cytochrome P450 3A2; Renal metabolism; Testosterone

Received: April 2, 2015; Revised: July 17, 2015; Accepted: August 10, 2015; Published: February 1, 2016  Show citation

ACS AIP APA ASA Harvard Chicago Chicago Notes IEEE ISO690 MLA NLM Turabian Vancouver
Malekinejad H, Alizadeh-Fanalou S, Hobbenaghi R, Rokhsartalb-Azar S. Atorvastatin up-regulates the expression and activity of renal Cytochrome P450 3A2 in diabetic rats. J Appl Biomed. 2016;14(1):25-34. doi: 10.1016/j.jab.2015.08.001.
Share...
Download citation
  • BibTeX (.bib)
  • Bookends (.ris)
  • EasyBib (.ris)
  • EndNote (.enw)
  • EndNote 8 (.xml)
  • ISI WoS (.isi)
  • Medlars (.medlars)
  • Mendeley (.ris)
  • MODS (.xml)
  • Papers (.ris)
  • RefWorks (.txt)
  • RefManager (.ris)
  • RIS (.ris)
  • MS Word (.xml)
  • Zotero (.ris)
    • Open full article

    References

    1. Aoki, T., Kaneko, S., Tanimoto, M., Gohda, T., Hagiwara, S., Murakoshi, M., et al., 2012. Identification of quantitative trait loci for diabetic nephropathy in KK-Ay/Ta mice. J. Nephrol. 25, 127-136. Go to original source... Go to PubMed...
    2. Bertrand-Thiebault, C., Masson, C., Siest, G., Batt, A.M., VisvikisSiest, S., 2007. Effect of HMGCoA reductase inhibitors on cytochrome P450 expression in endothelial cell line. J. Cardiovasc. Pharmacol. 49, 306-315. Go to original source... Go to PubMed...
    3. Chen, T.L., Hen, S.H., Tai, T.Y., Chao, C.C., Park, S.S., Guengerich, F.P., et al., 1996. Induction and suppression of renal and hepatic cytochrome P450-dependent monooxygenases by acute and chronic streptozotocin diabetes in hamsters. Arch. Toxicol. 70, 202-208. Go to original source... Go to PubMed...
    4. Christ, M., Bauersachs, J., Liebetrau, C., Heck, M., Günther, A., Wehling, M., 2002. Glucose increases endothelial-dependent superoxide formation in coronary arteries by NADPH oxidase activation: attenuation by the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor atorvastatin. Diabetes 51, 2648-2652. Go to original source... Go to PubMed...
    5. Dellamea, B.S., Leitão, C.B., Friedman, R., Canani, L.H., 2014. Nitric oxide system and diabetic nephropathy. Diabetol. Metab. Syndr. 6, 17, http://dx.doi.org/10.1186/1758-5996-6-17. Go to original source... Go to PubMed...
    6. Dong, B., Qatanani, M., Moore, D.D., 2009. CAR mediates the induction of drug metabolism in mouse models of type 1 diabetes. Hepatology 50, 622-629. Go to original source... Go to PubMed...
    7. Eid, A.A., Gorin, Y., Fagg, B.M., Maalouf, R., Barnes, J.L., Block, K., et al., 2009. Mechanisms of podocyte injury in diabetes role of cytochrome P450 and NADPH oxidases. Diabetes 58, 1201- 1211. Go to original source... Go to PubMed...
    8. Goodman, H.M., 2003. Basic Medical Endocrinology, 3rd ed. Academic Press, 165-182. Go to original source...
    9. Giacco, F., Brownlee, M., 2010. Oxidative stress and diabetic complications. Circ. Res. 107, 1058-1070. Go to original source... Go to PubMed...
    10. Gibson, G.G., Plant, N.J., Swales, K.E., Ayerton, A., El-Sankary, W., 2002. Receptor-dependent transcriptional activation of cytochrome P450 3A genes: induction mechanisms, species, differences and individual variation in man. Xenobiotica 32, 165-206. Go to original source... Go to PubMed...
    11. Green, L.C., Wagner, A.D., Glogowski, J., Skipper, P.L., Wishnok, J. S., Tannenbaum, S.R., 1982. Analysis of nitrate, nitrite, and [15N] nitrate in biological fluids. Anal. Biochem. 126, 131-138. Go to original source... Go to PubMed...
    12. Hoffart, E., Ghebreghiorghis, L., Nussler, A.K., Thasler, W.E., Weiss, T.S., Schwab, M., et al., 2012. Effects of atorvastatin metabolites on induction of drug-metabolizing enzymes and membrane transporters through human pregnane X receptor. Br. J. Pharmacol. 165, 1595-1608. Go to original source... Go to PubMed...
    13. Hu, J.J., Lee, M.J., Vapiwala, M., Reuhl, K., Thomas, P.E., Yang, C. S., 1993. Sex-related differences in mouse renal metabolism and toxicity of acetaminophen. Toxicol. Appl. Pharmacol. 122, 16-26. Go to original source... Go to PubMed...
    14. Hu, Z., Wang, H., Lee, I.H., Du, J., Mitch, W.E., 2009. Endogenous glucocorticoids and impaired insulin signaling are both required to stimulate muscle wasting under pathophysiological conditions in mice. J. Clin. Invest. 119, 3059-3069. Go to original source... Go to PubMed...
    15. Kocarek, T.A., Dahn, M.S., Cai, H., Strom, S.C., Mercer-Haines, N. A., 2002. Regulation of CYP2B6 and CYP3A expression by hydroxymethylglutaryl coenzyme A inhibitors in primary cultured human hepatocytes. Drug Metab. Dispos. 30, 1400-1405. Go to original source... Go to PubMed...
    16. Lau, Y.Y., Okochi, H., Huang, Y., Benet, L.Z., 2006. Pharmacokinetics of Atorvastatin and its hydroxyl metabolites in rats and the effects of concomitant rifampicin single doses: relevance of first-pass effect from hepatic uptake transporters, and intestinal and hepatic metabolism. Drug Metab. Dispos. 34, 1175-1181. Go to original source... Go to PubMed...
    17. Li, N., Fu, J., Koonen, D.P., Kuivenhoven, J.A., Snieder, H., Hofker, M.H., et al., 2013. Are hypertriglyceridemia and low HDL causal factors in the development of insulin resistance? Atherosclorosis 233, 130-138. Go to original source... Go to PubMed...
    18. Lohr, J.W., Willsky, G.R., Acara, M.A., 1998. Renal drug metabolism. Pharmacol. Rev. 50, 107-141. Go to PubMed...
    19. Lowry, O.H., Rosebrough, N.J., Farr, A.L., Randall, R.J., 1951. Protein measurement with the Folin phenol reagent. J. Biol. Chem. 193, 265-275. Go to original source...
    20. Malekinejad, H., Rokhsartalab-Azar, Sh., Hassani-Dizaj, S., Alizadeh-Fanalou, Sh., Rezabakhsh, A., Amniattalab, A., 2014. Effects of silymarin on the pharmacokinetics of atorvastatin in diabetic rats. Eur. J. Drug Metab. Pharmacokinet. 39, 311-320. Go to original source... Go to PubMed...
    21. Malekinejad, H., Maas-Bakker, R.F., Fink-Gremmels, J., 2005. Bioactivation of zearalenone by porcine hepatic biotransformation. Vet. Res. 36, 799-810. Go to original source... Go to PubMed...
    22. Malekinejad, H., Rezabakhsh, A., Rahmani, F., Hobbeneghi, R., 2012. Silymarin regulates the cytochrome P450 3A2 and glutathione peroxides in the liver of streptozotocin-induced diabetic rats. Phytomedicine 19, 583-590. Go to original source... Go to PubMed...
    23. Niehaus Jr., W.G., Samuelsson, B., 1968. Formation of malonaldehyde from phospholipid arachidonate during microsomal lipid peroxidation. Eur. J. Biochem. 6, 126-130. Go to original source... Go to PubMed...
    24. Paolini, M., Pozzetti, L., Mesirca, R., Sapone, A., Cantelli-Forti, G., 1996. Testosterone hydroxylase in evaluating induction and suppression of murine CYP isoenzymes by fenarimol. Arch. Toxicol. 70, 451-456. Go to original source... Go to PubMed...
    25. Parada, B., Reis, F., Pinto, A., 2012. Chemopreventive efficacy of atorvastatin against nitrosamine-induced rat bladder cancer: antioxidant, anti-proliferative and anti-inflammatory properties. Int. J. Mol. Sci. 13, 8482-8499. Go to original source... Go to PubMed...
    26. Poon, K., Pang, S., 1995. Benzoic acid glycine conjugation in the isolated perfused rat kidney. Drug Metab. Dispos. 23, 255-260. Go to PubMed...
    27. Ranjbar, A., Khorami, S., Safarabadi, M., Shahmoradi, A., Malekirad, A.A., Vakilian, K., et al., 2006. Antioxidant activity of Iranian Echium amoenum fisch & C.A. Mey flower decoction in humans: a cross-sectional before/after clinical trial. Evid. Based Complement Altern. Med. 3, 469-473. Go to original source... Go to PubMed...
    28. Sarnak, M.J., Levey, A.S., Schoolwerth, A.C., Coresh, J., Culleton, B., Hamm, L.L., et al., 2003. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Circulation 108, 2154-2169. Go to original source... Go to PubMed...
    29. Shibata, M., Hariya, T., Hatao, M., Ashikaga, T., Ichikawa, H., 1999. Quantitative polymerase chain reaction using an external control mRNA for determination of gene expression in a heterogeneous cell population. Toxicol. Sci. 49, 290-296. Go to original source... Go to PubMed...
    30. Shibata, S., Nagase, M., Fujita, T., 2006. Fluvastatin ameliorates podocyte injury in proteinuric rats via modulation of excessive Rho signaling. J. Am. Soc. Nephrol. 17, 754-764. Go to original source... Go to PubMed...
    31. Soucek, D., Gut, I., 1992. Cytochrome P-450 in rats: structures, functions, properties and relevant human forms. Xenobiotica 22, 83-103. Go to original source... Go to PubMed...
    32. Srinivasan, A., Menon, V.P., 2003. Protection of pancreatic b-cell by the potential antioxidant bis-ohydroxycinnamoyl methane, analogue of natural curcuminoid in experimental diabetes. J. Pharm. Pharm. Sci. 6, 327-333. Go to PubMed...
    33. Stanton, R.C., 2011. Oxidative stress and diabetic kidney disease. Curr. Diab. Rep. 11, 330-336. Go to original source... Go to PubMed...
    34. Takemoto, M., Ishikawa, T., Onishi, S., Okabe, E., Ishibashi, R., He, P., et al., 2013. Atorvastatin ameliorates podocyte injury in patients with type 2 diabetes complicated with dyslipidemia. Diabetes Res. Clin. Pract. 100, e26-e29. Go to original source... Go to PubMed...
    35. Tesch, G.H., Lim, A.K.H., 2011. Recent insights into diabetic renal injury from the db/db mouse model of type 2 diabetic nephropathy. Am. J. Physiol. 300, F301-F310. Go to original source... Go to PubMed...
    36. Tonelli, M., Muntner, P., Lloyd, A., Manns, B.J., Klarenbach, S., Pannu, N., et al., 2012. Risk of coronary events in people with chronic kidney disease compared with those with diabetes: a population-level cohort study. Lancet 380, 807-814. Go to original source... Go to PubMed...
    37. Vecchione, C., Gentile, M.T., Aretini, A., Marino, G., Poulet, R., Maffei, A., et al., 2007. A novel mechanism of action for statins against diabetes-induced oxidative stress. Diabetologia 50, 874-880. Go to original source... Go to PubMed...
    38. Wang, X., Hu, Z., Hu, J., Du, J., Mitch, W.E., 2006. Insulin resistance accelerates muscle protein degradation: activation of the Ubiquitin-proteasome pathway by defects in muscle cell signaling. Endocrinology 147, 4160-4168. Go to original source... Go to PubMed...
    39. Wauthier, V., Verbeeck, R.K., Calderon, B.P., 2006. Decreased CYP3A2 expression and activity in senescent male Wistar rats: is there a role for HNF4a? Exp. Gerontol. 41, 846-854. Go to original source... Go to PubMed...
    40. Willrich, M.A.V., Rodrigues, A.C., Cerda, A., 2013. Effects of atorvastatin on CYP3A4 and CYP3A5 mRNA expression in mononuclear cells and CYP3A activity in hypercholeresterolemic patients. Clin. Chim. Acta 421, 157-163. Go to original source... Go to PubMed...
    41. Zelmanovitz, T., Gerchman, F., Balthazar, A.P.S., Thomazelli, F. C., Matos, J.D., Canani, L.H., 2009. Diabetic nephropathy. Diabetol. Metab. Syndr. 1, 10, http://dx.doi.org/10.1186/17585996-1-10. Go to original source... Go to PubMed...

    Return to the content