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Najafi S, Moshtaghie A A, Hassanzadeh F, Nayeri H, Jafari E. Synthesis of New Atorvastatin Derivatives and Assessing Their Effect on Liver and Kidney Serum Parameters, Function, and Histology in Rabbits. Qom Univ Med Sci J 2023; 17 : 2866.1
URL: http://journal.muq.ac.ir/article-1-3716-en.html
URL: http://journal.muq.ac.ir/article-1-3716-en.html
1- Department of Biochemistry, Faculty of Basic Sciences, Falavarjan Branch, Islamic Azad University, Isfahan, Iran.
2- Department of Biochemistry, Faculty of Basic Sciences, Falavarjan Branch, Islamic Azad University, Isfahan, Iran. ,moshtaghie@pharm.mui.ac.ir
3- Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.
4- Department of Medicinal Chemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, I.R. Iran
2- Department of Biochemistry, Faculty of Basic Sciences, Falavarjan Branch, Islamic Azad University, Isfahan, Iran. ,
3- Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.
4- Department of Medicinal Chemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, I.R. Iran
Abstract: (476 Views)
Background and Objectives: Cardiovascular diseases are the main cause of death worldwide. High cholesterol level is a risk factor for coronary artery disease. Cholesterol production is regulated by the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Statins, as the inhibitors of HMG-CoA reductase, are often used as cholesterol-lowering drugs to prevent cardiovascular diseases. This study aims to synthesize novel derivatives of atorvastatin and investigate their effect on liver and kidney serum parameters, function, and histology.
Methods: Atorvastatin derivatives named S1, S2, and S3 were synthesized by acylation of the benzene ring of atorvastatin. The effect of compound S3 on serum parameters related to liver and kidney function was evaluated in rabbits with a high-fat diet-induced hypercholesterolemia. SPSS software, version 20 was used to analyze the data using statistical tests.
Results: The compound S3 increased high-density lipoprotein cholesterol and reduced total cholesterol, low-density lipoprotein, and triglyceride compared to the standard drug atorvastatin during 30 days of treatment (P<0.05). The liver enzymes were used to evaluate the toxicity of compound S3. In addition, the S3 compound significantly reduced the amount of urea, creatinine, and uric acid compared to the hyperlipidemic group. Histological study results showed that the compound S3 reduces tissue damage in hypercholesterolemic rabbits.
Conclusion: The S3 compound of atorvastatin can be considered as a cholesterol-lowering agent. This indicates that phenyl rings with higher electron density attached to propargyl show better inhibitory effects against ?? The S3 can be an effective drug for preventing atherosclerosis. However, more research is needed to clarify its exact mechanism.
Methods: Atorvastatin derivatives named S1, S2, and S3 were synthesized by acylation of the benzene ring of atorvastatin. The effect of compound S3 on serum parameters related to liver and kidney function was evaluated in rabbits with a high-fat diet-induced hypercholesterolemia. SPSS software, version 20 was used to analyze the data using statistical tests.
Results: The compound S3 increased high-density lipoprotein cholesterol and reduced total cholesterol, low-density lipoprotein, and triglyceride compared to the standard drug atorvastatin during 30 days of treatment (P<0.05). The liver enzymes were used to evaluate the toxicity of compound S3. In addition, the S3 compound significantly reduced the amount of urea, creatinine, and uric acid compared to the hyperlipidemic group. Histological study results showed that the compound S3 reduces tissue damage in hypercholesterolemic rabbits.
Conclusion: The S3 compound of atorvastatin can be considered as a cholesterol-lowering agent. This indicates that phenyl rings with higher electron density attached to propargyl show better inhibitory effects against ?? The S3 can be an effective drug for preventing atherosclerosis. However, more research is needed to clarify its exact mechanism.
Article number: 2866.1
Type of Study: Original Article |
Subject:
بیوشیمی بالینی-عمومی
Received: 2023/04/14 | Accepted: 2023/06/6 | Published: 2023/08/1
Received: 2023/04/14 | Accepted: 2023/06/6 | Published: 2023/08/1
References
1. Han JB, Shu QH, Zhang YF, Yi YX. Predictive value of inflammation biomarkers in patients with portal vein thrombosis. J Clin Transl Hepatol. 2021; 9(3):384-91. [DOI:10.1038/s41366-018-0020-6] [PMID] [PMCID] [DOI:10.1038/s41366-018-0020-6]
2. Alarcon G, Roco J, Medina M, Medina A, Peral M, Jerez S. High fat diet-induced metabolically obese and normal weight rabbit model shows early vascular dysfunction: Mechanisms involved. Int J Obes. 2018; 42(9):1535-43. [DOI:10.1038/s41366-018-0020-6] [PMID] [DOI:10.1038/s41366-018-0020-6]
3. Bonaterra GA, Bender K, Wilhelm B, Schwarzbach H, Metz S, Kelber O, et al. Effect of cholesterol re-supplementation and atorvastatin on plaque composition in the thoracic aorta of New Zealand white rabbits. BMC Cardiovasc Disord. 2020; 20(1):420. [DOI:10.1186/s12872-020-01703-x] [PMID] [DOI:10.1186/s12872-020-01703-x]
4. Dong J, Yang S, Zhuang Q, Sun J, Wei P, Zhao X, et al. The associations of lipid profiles with cardiovascular diseases and death in a 10-year prospective cohort study. Front Cardiovasc Med. 2021; 8:745539. [DOI:10.3389/fcvm.2021.745539] [PMID] [DOI:10.3389/fcvm.2021.745539]
5. Gesto DS, Pereira CMS, Cerqueira NMFS, Sousa SF. An atomic-level perspective of HMG-CoA-reductase: The target enzyme to treat hypercholesterolemia. Molecules. 2020; 25(17):3891. [DOI:10.3390/molecules25173891] [PMID] [DOI:10.3390/molecules25173891]
6. Komukai K, Kubo T, Kitabata H, Matsuo Y, Ozaki Y, Takarada S, et al. Effect of atorvastatin therapy on fibrous cap thickness in coronary atherosclerotic plaque as assessed by optical coherence tomography: The EASY-FIT study. J Am Coll Cardiol. 2014; 64(21):2207-17. [DOI:10.1016/j.jacc.2014.08.045] [PMID] [DOI:10.1016/j.jacc.2014.08.045]
7. Schonewille M, de Boer JF, Mele L, Wolters H, Bloks VW, Wolters JC, et al. Statins increase hepatic cholesterol synthesis and stimulate fecal cholesterol elimination in mice. J Lipid Res. 2016; 57(8):1455-64. [DOI:10.1194/jlr.M067488] [PMID] [DOI:10.1194/jlr.M067488]
8. Bobulescu IA. Renal lipid metabolism and lipotoxicity. Curr Opin Nephrol Hypertens. 2010; 19(4):393-402. [DOI:10.1097/MNH.0b013e32833aa4ac] [PMID] [DOI:10.1097/MNH.0b013e32833aa4ac]
9. Heravi MM, Zadsirjan V, Saedi P, Momeni T. Applications of friedel-crafts reactions in total synthesis of natural products. RSC Adv. 2018; 8(70):40061-3. [DOI:10.1039/C8RA07325B] [PMID] [DOI:10.1039/C8RA07325B]
10. Vernon H, Wehrle CJ, Sampson K. Alia V, Kasi A. Anatomy, abdomen and pelvis: Liver. Treasure Island: StatPearls Publishing; 2022. [Link]
11. Vogel AI, Furniss BS, Smith PW, Tatchell AR. Vogel's textbook of practical organic chemistry, including qualitative organic analysis. Wilmington: Longman; 1986. [Link]
12. Lu M, Lu Q, Zhang Y, Tian G. ApoB/apoA1 is an effective predictor of coronary heart disease risk in overweight and obesity. J Biomed Res. 2011; 25(4):266-73. [DOI:10.1016/S1674-8301(11)60036-5] [PMID] [DOI:10.1016/S1674-8301(11)60036-5]
13. Kaneva AM, Potolitsyna NN, Bojko ER, Odland JØ. The apolipoprotein B/apolipoprotein A-I ratio as a potential marker of plasma atherogenicity. Dis Markers. 2015; 2015:591454.[DOI:10.1155/2015/591454] [PMID] [DOI:10.1155/2015/591454]
14. Marston NA, Giugliano RP, Melloni GEM, Park JG, Morrill V, Blazing MA, et al. Association of apolipoprotein B-containing lipoproteins and risk of myocardial infarction in individuals with and without atherosclerosis: Distinguishing between particle concentration, type, and content. JAMA Cardiol. 2022; 7(3):250-6. [DOI:10.1001/jamacardio.2021.5083] [PMID] [DOI:10.1001/jamacardio.2021.5083]
15. Zhan X, Chen Y, Yan C, Liu S, Deng L, Yang Y, et al. Apolipoprotein B/apolipoprotein A1 ratio and mortality among incident peritoneal dialysis patients. Lipids Health Dis. 2018; 17(1):117. [DOI:10.1186/s12944-018-0771-z] [PMID] [DOI:10.1186/s12944-018-0771-z]
16. Giannini EG, Testa R, Savarino V. Liver enzyme alteration: A guide for clinicians. CMAJ. 2005; 172(3):367-79. [DOI:10.1503/cmaj.1040752] [PMID] [DOI:10.1503/cmaj.1040752]
17. Jeong WI, Jeong DH, Do SH, Kim YK, Park HY, Kwon OD, et al. Mild hepatic fibrosis in cholesterol and sodium cholate diet-fed rats. J Vet Med Sci. 2005; 67(3):235-42. [DOI:10.1292/jvms.67.235] [PMID] [DOI:10.1292/jvms.67.235]
18. Basaranoglu M, Neuschwander-Tetri BA. Nonalcoholic fatty liver disease: Clinical features and pathogenesis. Gastroenterol Hepatol. 2006; 2(4):282-91. [PMID] [PMCID]
19. Abo-Zalam HB, El-Denshary ES, Abdelsalam RM, Khalil IA, Khattab MM, Hamzawy MA. Therapeutic advancement of simvastatin-loaded solid lipid nanoparticles (SV-SLNs) in treatment of hyperlipidemia and attenuating hepatotoxicity, myopathy and apoptosis: Comprehensive study. Biomed Pharmacother. 2021; 139:111494. [DOI:10.1016/j.biopha.2021.111494] [PMID] [DOI:10.1016/j.biopha.2021.111494]
20. Gao M, Ma Y, Liu D. High-fat diet-induced adiposity, adipose inflammation, hepatic steatosis and hyperinsulinemia in outbred CD-1 mice. Plos One. 2015; 10(3):e0119784. [DOI:10.1371/journal.pone.0119784] [PMID] [DOI:10.1371/journal.pone.0119784]
21. Joles JA, Kunter U, Janssen U, Kriz W, Rabelink TJ, Koomans HA, et al. Early mechanisms of renal injury in hypercholesterolemic or hypertriglyceridemic rats. J Am Soc Nephrol. 2000; 11(4):669-83. [DOI:10.1681/ASN.V114669] [PMID] [DOI:10.1681/ASN.V114669]
22. Samuelsson O, Mulec H, Knight-Gibson C, Attman PO, Kron B, Larsson R, et al. Lipoprotein abnormalities are associated with increased rate of progression of human chronic renal insufficiency. Nephrol Dial Transplant. 1997; 12(9):1908-15. [DOI:10.1093/ndt/12.9.1908] [PMID] [DOI:10.1093/ndt/12.9.1908]
23. Li C, Lim SW, Choi BS, Lee SH, Cha JH, Kim IS, et al. Inhibitory effect of pravastatin on transforming growth factor beta1-inducible gene h3 expression in a rat model of chronic cyclosporine nephropathy. Am J Nephrol. 2005; 25(6):611-20. [DOI:10.1159/000089905] [PMID] [DOI:10.1159/000089905]
24. Li C, Yang CW, Park JH, Lim SW, Sun BK, Jung JY, et al. Pravastatin treatment attenuates interstitial inflammation and fibrosis in a rat model of chronic cyclosporine-induced nephropathy. Am J Physiol Renal Physiol. 2004; 286(1):F46-57. [DOI:10.1152/ajprenal.00428.2002] [PMID] [DOI:10.1152/ajprenal.00428.2002]
25. Sun BK, Li C, Lim SW, Choi BS, Lee SH, Kim IS, et al. Blockade of angiotensin II with losartan attenuates transforming growth factor-beta1 inducible gene-h3 (betaig-h3) expression in a model of chronic cyclosporine nephrotoxicity. Nephron Exp Nephrol. 2005; 99(1):e9-16. [DOI:10.1159/000081793] [PMID] [DOI:10.1159/000081793]
26. Declèves AE, Zolkipli Z, Satriano J, Wang L, Nakayama T, Rogac M, et al. Regulation of lipid accumulation by AMP-activated kinase [corrected] in high fat diet-induced kidney injury. Kidney Int. 2014; 85(3):611-23. [DOI:10.1038/ki.2013.462] [PMID] [DOI:10.1038/ki.2013.462]
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