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Advances in Environmental Biology, 7(14) December 2013, Pages: 4768-4772 AENSI Journals Advances in Environmental Biology Journal home page: http://www.aensiweb.com/aeb.html Investigating Effect of Raloxifene on the Factors of Blood Urea Nitrogen, Uric Acid and Creatinine in Female Rats 1,2 6 Ebadi Zahra, 1,3Kargar Jahromi Hossein, 4Ghorishi Fakhrossadat, 4Zahedi Ali, 5Khodaparast Zahra, Azhdari Sara, 6Farzam Mohammad 1 Jahrom University of Medical Sciences, Jahrom, Iran. Developmental Biology, Islamic Azad University, Jahrom, Fars, Iran. Young Researchers Club Elite, Jahrom Branch, Islamic Azad University, Jahrom, Iran. 4 The Departmant General of Bandar Abbas Province Education. 5 Department of Biology, Islamic Azad University, Arsanjan, Fars, Iran. 6 Department of Anatomy and Embryology, International Branch, Shiraz University, Shiraz, Iran. 2 3 ARTICLE INFO Article history: Received 15 November Received in revised form 14 January 2014 Accepted 20 January 2014 Available online 20 February 2014 Key words: Raloxifene Blood urea nitrogen Uric acid Creatinine, Rat. ABSTRACT Introduction: Raloxifene is from SERM drugs groups (selective estrogen receptor modulators). These drugs in some tissues have similar effects of estrogen (agonist) and prevent the effects of estrogen in other tissues (antagonistic). In this study, the effects of raloxifene on the factors of blood urea nitrogen, uric acid and creatinine in rats were measured. Methods: 40 female Wistar rats were divided randomly into 5 groups. The first group (control group) did not receive any medication. The second group (sham group) only distilled water injected. Experimental group 1 received raloxifene 5 mg/kg daily, experimental group 2 received raloxifene 10 mg/kg, and experimental group 3 received raloxifene 20 mg/kg that all was based on body weight and were received intraperitoneally. At the end of 30 days, the rats were bled and concentration of blood serum of urea nitrogen, uric acid and creatinine were measured. Data were analyzed using SPSS software version 18. Results: The results show that the concentration of creatinine in experimental groups 1, 2 and 3 showed a significant increase compared to the control group. Concentrations of Blood urea nitrogen and uric acid have no significant change compared to control group. Conclusion: We may conclude that raloxifene in low rates, causes changes in concentration of Renal factors. © 2013 AENSI Publisher All rights reserved. To Cite This Article: Ebadi Zahra, Kargar Jahromi Hossein, Ghorishi Fakhrossadat, Zahedi Ali, Khodaparast Zahra, Azhdari Sara, Farzam Mohammad., Investigating effect of raloxifene on the factors of blood urea nitrogen, uric acid and creatinine in female rats. Adv. Environ. Biol., 7(14), 4768-4772, 2013 INTRODUCTION Brand name of Raloxifene drug is EVISTA [1]. Because this drug, only is effective on sex hormone of females, it is prescribed only for women. Raloxifene is as tablet and consumes one tablet per day and it is taken orally [2]. This medication is used to treat osteoporosis [3]. Raloxifene is as estrogen receptor of selective nonsteroidal regulator and it has recently been set up to help improve common diseases in postmenopausal women. Raloxifene is to be from SERM drug groups (selective estrogen receptor modulators). These drugs in some tissues have similar effects of estrogen (agonist) and prevent the effects of estrogen in other tissues (antagonistic) [4 and 5]. Raloxifene is prescribed for the treatment of hormone-responsive cancers and in this tissue as an antagonist, prevents the activation of estrogen receptor of androgen. Estrogenic and anti-estrogenic effects of raloxifene are entirely clear on the organization and regulation of the nervous system in controlling reproductive function. Since 2007, stated that raloxifene is useful for reducing the risk of breast cancer in postmenopausal women who are facing breast cancer. Raloxifene hydrochloride, a pale yellow solid which is slightly soluble in water [4,5]. In fact, we can say that raloxifene has an estrogen replacement therapy for those who are at risk for osteoporosis [6]. Raloxifene, reduces bone resorption, and on target tissues act as an antagonist [7]. Raloxifene metabolizes by the liver, but in the people with nufruity syndrome who are at high risk for blood clots in the veins of the heart, it is better not to use Raloxifene [9,8]. On the other hand, the effect of raloxifene as modulators of the selective estrogen receptor, has been investigated to prevent functional and histological changes in the kidneys of rats with type 2 diabetes. The results of this study suggest that raloxifene significantly, reduces Mzanzhyal cell proliferation and fibronectin accumulation in the kidneys of diabetic rats Corresponding Author: Ebadi Zahra, Islamic Azad University of Jahrom Branch, Jahrom, Iran. Tel: +989372777533; E-mail: ebadizahra96@ yahoo.com 4769 Ebadi Zahra et al, 2013 Advances in Environmental Biology, 7(14) December 2013, Pages: 4768-4772 [10,11]. Also, it is reported that Raloxifene reduces Collagen synthesis of renal Mzanzhyal cell and noting that the raloxifene for treatment of kidney diseases can be useful [12]. The present study examined the effect of raloxifene drug on renal parameters changes. Method: All work ethic with laboratory animals has been complied. 40 adult female Wistar rats, weighing 200 ± 5% grand age of 100 - 110 days were obtained from the Jerome research center. Rats were placed in the animals house of Jahrom Islamic Azad university for 21 days in laboratory conditions include temperature of 21 ± 2 ° C , 12 hours light and 12 hours dark. Rats were used standard foods (pellet). Also, water from special glass bottles were given to them. Cages were disinfected with 70% alcohol 3 times a week. The lethal dose of the drug was 40 mg. Accordingly, doses of minimum, average and maximum were determined. In this case, maximum dose was half of Lethal dose, average dose was half of maximum dose, and minimum dose was half of average dose. Raloxifene drug is soluble in water. In this study, distilled water was used as solvent. All solutions were prepared fresh each morning . The rats were divided into 5 groups of 8 as follows : Control group (A) : They did not receive any medical, and nutrition, and all conditions were similar to other groups. Sham group (B) : Based on body weight of rats, they received distilled water. Experimental group 1 (C1) : Amount of drug was based on their weight, they received 30 mg raloxifene tablet dissolved in 1 ml of distilled water. Experimental group 2 (C2) : Amount of drug was based on their weight, they received 60 mg raloxifene tablet dissolved in 1 ml of distilled water. Experimental group 3 (C3) : Amount of drug was based on their weight, they received 120 mg raloxifene tablet dissolved in 1 ml of distilled water. After the end of the 21 day period, rats of all groups after weighing were anesthetized with ether, and blood samples were collected from their heart by 5 cc syringe, and after separation blood serum, concentration of factors of blood urea nitrogen (BUN), uric acid (UA), and creatinine (Cr) in the laboratory of Jahrom medical university were measured. For comparison between treatments One-way ANOVA followed by t-test and Duncan test was used that was for multiple comparisons between groups. Significance level (P<0/05) was used. Data analysis and statistical testing were performed using SPSS software, version 18. Results: The results showed that concentration of blood urea nitrogen in the groups receiving raloxifene drug, did not show significant change compared to control group (table 1). Table 1: Changes about blood urea nitrogen in different groups The results show that changes in uric acid in experimental groups have no significant changes compared to control groups. 4770 Ebadi Zahra et al, 2013 Advances in Environmental Biology, 7(14) December 2013, Pages: 4768-4772 Table 2: Changes about blood urea nitrogen in different groups Concentration of creatinine in experimental groups 1, 2 and 3 have no significant increase compared to control group. Table 3: Changes about blood urea nitrogen in different groups Discussions: The urinary system is one of the major body systems that are more routine protocols for testing to determine the amount of toxicity. The kidneys play a major role in filtration, metabolism and excretion of xenobiotics or metabolic products. Chemicals or other active metabolic forms may transfer from plasma to renal tubules and to multiply the concentration level that can be found in other tissues. In addition, the kidneys receive approximately 25% of cardiac output that it increases the distribution of chemicals to the kidneys and Measurement of blood urea nitrogen and creatinine are valid tests for kidney functions [13]. In researching conducted in the past stated that the symptoms of kidney failure and damage to the tubules of the kidney can be as follows : 1. Increase of creatinine clearance, increase of BUN and uric acid serum. 2. Increase of tissue damage in pathology studies and other cases can be cited [14]. In the present study the changes in blood urea nitrogen and uric acid is not statistically significant But what is certain is that the groups that had received a higher dose of the drug, increase in blood urea nitrogen and uric acid concentration is observed which can not be ignored. Studies indicate that raloxifene causes morphometric changes in the kidney [15]. Studies show that Raloxifene acts as Selective Estrogen Receptor. In fact function of alpha and beta receptors of estrogen influence on kidney cells. And by this way, causing an increase in cell sizes [16,17]. Some studies suggest that raloxifene, binds to alpha and beta receptors of estrogen. Alpha receptor is in Glomerular and near and far 4771 Ebadi Zahra et al, 2013 Advances in Environmental Biology, 7(14) December 2013, Pages: 4768-4772 complex tubular [16,17]. Estrogen increase, reduces calcium absorption in near and far complex tubular, so, the transfer or absorption of sodium increases. Estrogen also, transfer of sodium chloride and activation of sodium potassium ATP pump, increase in near and far complex tubular that this lead to enlargement of near and far complex tubular cells. Since raloxifene acts as an estrogen, this lead to enlargement of kidney cells [16, 17]. In the present study this effect occurs as changes in the concentrations of blood urea nitrogen and creatinine and uric acid and What is certain is that increase of these factors in blood serum indicate damage to kidney tissue. In the present study, changes about uric acid and blood urea nitrogen is not significant But creatinine in a dose dependent manner, has a significant increase compared to control group that indicate damage to kidney tissue. Probably the causes that factors of blood urea nitrogen and uric acid have not significant changes is due to dose and time duration of drug and type of laboratory animal. Previously expressed that Raloxifene by inhibiting AP1 activity prevents stimulation of TGF-B1 and expression of fibronectin. In fact, raloxifene inhibits fibronectin expression through AP-1 mechanism that prevents the proliferation of Mzanzhyal cells [18]. It may be that this effects occur as changes in renal tissue and so change in secretions of factors in blood urea nitrogen, creatinine, uric acid. Conclusion: The results show that with doses used in the study, changes in blood urea nitrogen and uric acid is not significant, but changes related to creatinine are significant that indicate negative effect of drug. Probably, drug with effect on alpha and beta receptors and change in kidney tissue causes changes of kidney morphometric and changes in secretion of kidney factors. It is recommended that, in future, the effects of high doses of raloxifene on all changes of kidney factors be examined. REFERENCES [1] Eli, L.E., 1998. Formulary Pack (for health professionals). [2] Lawrence, R.B. and L.C. Hartmann, 2003. Selective estrogen- receptor modulators mechanism of action and application to clinical practice. N Engl J Med., 347: 618-29. [3] Jones, C.D., M.G. Jevnikar, A.J. Pike, M.K. Peters, L.J. Black and A.R. Thompson, 1982. Antiestrogens 2 Structure- activity studies in a series of 3- aroyl- 2- arylbenzo [b]thiophene derivatives leading to [6hydroxy- 2- (4-hydroxyphenyl)benzo[b] thien- 3- yl][4- [2- (1- piperidinyl)ethoxy] phenyl]methanone hydrochloride(LY156758), a remarkable effective estrogen antagonist with only minimal intrinsic estrogenicity. J Med Chem., 27: 1057-66. [4] Vogel, V., C. Joseph and W. Lawrence, 2006. Effects of tamoxifen and raloxifene on the risk of developing invasive breast cancer and other disease outcomes. The Journal of the American Medical Association. 295 (23): 2727 2741. [5] Bryant, H.U., 1999. An estrogen receptor basis for raloxifene action in bone. J Steroid Biochem Mol Biol 1999 / 69 (1- 6) / 37- 44., Hannon R, et al, 1998. Response of biochemical markers of bone turn over to hormone replacement therapy: impact of biological variability. J. Bone Miner. Res., 13(7): 1124-1133. [6] Delmas, P.D., N.H. Bjarnason and B.H. Mitlak, 1997. 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Journal of the Biology, 7(3): 9-1. [16] Kuiper, G.G., E. Enmark, H.M. Pelto, S. Nilsson and J.A. Gustafsson, 1996. Cloning a novel estrogen receptor expressed in rat prostate and ovary. PNAS. 93: 5925-5930. [17] Enmark, E., H.M. Pelto, K. Gradien, S. Lagercrantz, J. Lagercrantz, M. Nokdenskjold and J.A. Gustafsson, 1998. Human estrogen receptor beta- gene structure, chromosomal localization, and expression pattern. Journal of Clinical Endocrinology and Metabolism., 89: 42584265. [18] Peach, K., B.P. Web, G. Kuiper, S. Nilsson, J.A. Gustafsson, P.J. Kushner and T.S. Scanlan, 1997. Differential ligand activation of estrogen receptors ER and ER at AP1 sites. Science, 277: 1508-1510.