Volume 27, Issue 2 (July 2023)                   Physiol Pharmacol 2023, 27(2): 150-160 | Back to browse issues page


XML Print


Download citation:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:

Olaitan Abdulkareem A, Olusegun Abe E, Adefoluke Ala A, Aderemi Olatunji L. Letrozole ameliorates fructose-induced hyperlipidaemia and uric acid accumulation in male Wistar rats. Physiol Pharmacol 2023; 27 (2) :150-160
URL: http://ppj.phypha.ir/article-1-1874-en.html
Abstract:   (891 Views)

Introduction: High fructose consumption is commonly associated with increased risk of cardiovascular disease (CVD). However, cardiovascular effects of aromatase inhibitors remain unresolved, although they are effective in the treatment of breast cancer. Thus, this study investigated the effect of letrozole on CVD indicators in Wistar rats exposed to high fructose intake.
Methods: Twenty male rats were randomly placed in four groups (n=5/group): control (distilled water), fructose (10% fructose in drinking water), letrozole (1mg/kg) and fructose+ letrozole. After 21-day exposure, fasting blood glucose was taken and the rats were sacrificed, while blood and heart were collected and prepared for biochemical analyses.
Results: Our data showed that 10% fructose induced hyperglycaemia and lipid peroxidation. It reduced serum high-density lipoprotein cholesterol, elevated serum total cholesterol (TC), triglycerides and free fatty acid but did not alter serum low-density lipoprotein cholesterol significantly, when compared with the control. Furthermore, high fructose-intake increased serum or cardiac adenosine deaminase (ADA), xanthine oxidase and uric acid. Our findings revealed that letrozole, when taken with 10% fructose, attenuated all the observed fructose-induced alterations. However, when administered alone, letrozole elevated serum TC as well as cardiac malondialdehyde and ADA.
Conclusion: This study showed that high fructose-intake promoted the risk of CVDs in rats, while administration of letrozole attenuated fructose effects. Hence, letrozole may serve as a potential adjuvant therapy for attenuating CVD risk. However, further pre-clinical and clinical findings are necessary to thoroughly investigate the cardiometabolic effects of letrozole.

Full-Text [PDF 897 kb]   (249 Downloads)    

References
1. Abdel-Qadir H, Amir E, Fischer HD, Fu L, Austin PC, Harvey PJ, et al. The risk of myocardial infarction with aromatase inhibitors relative to tamoxifen in post-menopausal women with early stage breast cancer. Eur J Cancer 2016; 68: 11-21. [DOI:10.1016/j.ejca.2016.08.022]
2. Abdulkareem AO, Olafimihan TF, Akinbobola OO, Busari SA, Olatunji LA. Effect of untreated pharmaceutical plant effluent on cardiac Na+-K+- ATPase and Ca2+-Mg2+-ATPase activities in mice (Mus Musculus). Toxicol Rep 2019; 6: 439-43. [DOI:10.1016/j.toxrep.2019.05.002]
3. Benjamin EJ, Virani SS, Callaway CW, Chamberlain AM, Chang AR, Cheng S, et al. Heart disease and stroke statistics-2018 update: a report from the American Heart Association. Circulation 2018; 137: e67-492. [DOI:10.1161/CIR.0000000000000573]
4. Bickel C, Rupprecht HJ, Blankenberg S, Rippin G, Hafner G, Daunhauer A, et al. Serum uric acid as an independent predictor of mortality in patients with angiographically proven coronary artery disease. Am J Cardiol 2002; 89: 12-7. [DOI:10.1016/S0002-9149(01)02155-5]
5. Blondeaux E, Musio D, Bruzzi P, Lambertini M, Gazzola V, Poggio F, et al. Treatment with aromatase inhibitors and markers of cardiovascular disease. Breast Cancer Res Treat 2016; 160:261-7. [DOI:10.1007/s10549-016-3985-7]
6. Boutas I, Pergialiotis V, Salakos N, Agrogiannis G, Konstantopoulos P, Korou L, et al. The impact of Anastrazole and Letrozole on the metabolic profile in an experimental animal model. Sci Rep 2015; 5: 17493. [DOI:10.1038/srep17493]
7. Bundred NJ. The effects of aromatase inhibitors on lipids and thrombosis. Br J Cancer 2005; 93: S23-S7. [DOI:10.1038/sj.bjc.6602692]
8. Buzdar A, Howell A, Cuzick J, Wale C, Distler W, Hoctin-Boes G, et al. Comprehensive side- effect profile of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: long-term safety analysis of the ATAC trial. Lancet Oncol 2006; 7: 633-43. [DOI:10.1016/S1470-2045(06)70767-7]
9. Delarue J, Magnan C. Free fatty acids and insulin resistance. Curr Opin Clin Nutr Metab Care 2007; 10: 142-8.
10. Dornas WC, de Lima WG, Pedrosa ML, Silva ME. Health Implications of high-fructose intake and current research. Adv Nutr 2015; 6:729-37. [DOI:10.3945/an.114.008144]
11. Early Breast Cancer Trialists’ Collaborative Group. Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet 2015; 386: 1341-52. [DOI:10.1016/S0140-6736(15)61074-1]
12. Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y, et al. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest 2017; 114: 1752-1761. [DOI:10.1172/JCI21625]
13. Geisler J, Haynes B, Anker G, Dowsett M, Lønning PE. Influence of letrozole and anastrozole on total body aromatization and plasma estrogen levels in postmenopausal breast cancer patients evaluated in a randomized, cross-over study. J Clin Oncol 2002; 20: 751-7. [DOI:10.1200/JCO.2002.20.3.751]
14. Hasan AS, Luo L, Baba S, Li TS. Estrogen is required for maintaining the quality of cardiac stem cells. PLoS One 2021; 16: e0245166. [DOI:10.1371/journal.pone.0245166]
15. Hedayatnia M, Asadi Z, Zare-Feyzabadi R, Yaghooti-Khorasani M, Ghazizadeh H, Ghaffarian- Zirak R, et al. Dyslipidemia and cardiovascular disease risk among the MASHAD study population. Lipids Health Dis 2020; 19: 42. [DOI:10.1186/s12944-020-01204-y]
16. Hozumi Y, Suemasu K, Takei H, Aihara T, Takehara M, Saito T, et al. The effect of exemestane, anastrozole, and tamoxifen on lipid profiles in Japanese postmenopausal early breast cancer patients: final results of National Surgical Adjuvant Study BC 04, the TEAM Japan sub-study. Ann Oncol 2011; 22: 1777-82. [DOI:10.1093/annonc/mdq707]
17. Jin M, Yang F, Yang I, Yin Y, Luo JJ, Wang H, et al. Uric acid, hyperuricemia and vascular diseases. Front Biosci (Landmark Ed) 2012; 17: 656-69. [DOI:10.2741/3950]
18. Kamaraju S, Shi Y, Smith E, Nattinger AB, Laud P, Neuner J. Are aromatase inhibitors associated with higher myocardial infarction risk in breast cancer patients? A Medicare population- based study. Clin Cardiol 2019; 42: 93-100. [DOI:10.1002/clc.23114]
19. Khitan Z, Kim DH. Fructose: A Key Factor in the development of metabolic syndrome and hypertension. J Nutr Metab 2013; 2013: 682673. [DOI:10.1155/2013/682673]
20. Khosrow-Khavar F, Filion KB, Bouganim N, Suissa S, Azoulay L. Aromatase inhibitors and the risk of cardiovascular outcomes in women with breast cancer. Circulation 2020; 141: 549-59. [DOI:10.1161/CIRCULATIONAHA.119.044750]
21. Klop B, Elte JWF, Cabezas MC. Dyslipidemia in obesity: mechanisms and potential targets. Nutrients 2013; 5: 1218-40. [DOI:10.3390/nu5041218]
22. Lê KA, Faeh D, Stettler R, Ith M, Kreis R, Vermathen P, et al. A 4-wk high-fructose diet alters lipid metabolism without affecting insulin sensitivity or ectopic lipids in healthy humans. Am J Clin Nutr 2006; 84: 1374-9. [DOI:10.1093/ajcn/84.6.1374]
23. Le Y, Zhou X, Zheng J, Yu F, Tang Y, Yang Z, et al. Anti-hyperuricemic effects of astaxanthin by regulating xanthine oxidase, adenosine deaminase and urate transporters in rats. Mar Drugs 2020; 18: 610. [DOI:10.3390/md18120610]
24. Malik VS, Hu FB. Fructose and Cardiometabolic Health: What the Evidence From Sugar-Sweetened Beverages Tells Us. J Am Coll Cardiol 2015; 66(14):1615-1624. [DOI:10.1016/j.jacc.2015.08.025]
25. Olaniyi KS, Olatunji LA. Oral ethinylestradiol-levonorgestrel attenuates cardiac glycogen and triglyceride accumulation in high fructose female rats by suppressing pyruvate dehydrogenase kinase-4. Naunyn-Schmiedeberg’s Arch Pharmacol 2019; 392: 89-101. [DOI:10.1007/s00210-018-1568-3]
26. Park JE, Yeom Z, Park KT, Han EH, Yu HJ, Kang H et al. Hypouricemic effect of ethanol extract of Aster glehni leaves in potassium oxonate-induced hyperuricemic rats. Clin Nutr Res 2018b; 7: 126–135. [DOI:10.7762/cnr.2018.7.2.126]
27. Park JH, Ku HJ, Kim JK, Park J, Lee JH. Amelioration of high fructose induced cardiac hypertrophy by naringin. Sci Rep 2018a; 8: 9464. [DOI:10.1038/s41598-018-27788-1]
28. Peng TC, Wang CC, Kao TW, Chan JY, Yang YH, Chang YW, et al. Relationship between hyperuricemia and lipid profiles in US adults. Biomed Res Int 2015; 2015: 127596. [DOI:10.1155/2015/127596]
29. Ramos VW, Batistaa LO, Albuquerque KT. Effects of fructose consumption on food intake and biochemical and body parameters in Wistar rats. Rev Port Cardiol 2017; 36: 937-41. [DOI:10.1016/j.repc.2017.04.003]
30. Roth GA, Abate D, Abate KH, Abay SM, Abbafati C, Abbasi N, et al. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980- 2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 2018; 392: 1736-88. [DOI:10.1016/S0140-6736(18)32203-7]
31. Rutledge AC, Adeli K. Fructose and the metabolic syndrome: pathophysiology and molecular mechanisms. Nutr Rev 2007; 65: S13-23. [DOI:10.1111/j.1753-4887.2007.tb00322.x]
32. Sievenpiper JL, de Souza RJ, Kendall CW, Jenkins DJ. Is fructose a story of mice but not men? J Am Diet Assoc 2011; 111: 219-22. [DOI:10.1016/j.jada.2010.12.001]
33. Skarra DV, Hernández-Carretero A, Rivera AJ, Anvar AR, Thackray VG. Hyperandrogenemia induced by letrozole treatment of pubertal female mice results in hyperinsulinemia prior to weight gain and insulin resistance. Endocrinology 2017; 158: 2988-3003. [DOI:10.1210/en.2016-1898]
34. Stanhope KL, Schwarz JM, Keim NL, Griffen SC, Bremer AA, Graham JL, et al. Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans. J Clin Invest 2009; 119: 1322-34. [DOI:10.1172/JCI37385]
35. Teff KL, Elliott SS, Tschöp M, Kieffer TJ, Rader D, Heiman M, et al. Dietary fructose reduces circulating insulin and leptin, attenuates postprandial suppression of ghrelin, and increases triglycerides in women. J Clin Endocrinol Metab 2004; 89: 2963-72. [DOI:10.1210/jc.2003-031855]
36. Tappy L, Lê KA. Metabolic effects of fructose and the worldwide increase in obesity. Physiol Rev 2010; 90: 23-46. [DOI:10.1152/physrev.00019.2009]
37. Vega GL, Barlow CE, Grundy SM, Leonard D, DeFina LF. Triglyceride-to-high-density- lipoprotein-cholesterol ratio is an index of heart disease mortality and of incidence of type 2 diabetes mellitus in men. J Investig Med 2014; 62: 345-9. [DOI:10.2310/JIM.0000000000000044]
38. Wasan KM, Goss PE, Pritchard PH, Shepherd L, Palmer MJ, Liu S, et al. The influence of letrozole on serum lipid concentrations in postmenopausal women with primary breast cancer who have completed 5 years of adjuvant tamoxifen (NCIC CTG MA.17L). Ann Oncol 2005; 16: 707-15. [DOI:10.1093/annonc/mdi158]
39. Xu J, Dun J, Yang J, Zhang J, Lin Q, Huang M, et al. Letrozole rat model mimics human polycystic ovarian syndrome and changes in insulin signal pathways. Med Sci Monit 2020; 26: e923073-1-13. [DOI:10.12659/MSM.923073]
40. Yang Q, Zhang Z, Gregg EW, Flanders WD, Merritt R, Hu FB. Added sugar intake and cardiovascular diseases mortality among US adults. JAMA Intern Med 2014; 174: 516- 24. [DOI:10.1001/jamainternmed.2013.13563]
41. Yoo SY, Ahn H, Park YK. High dietary fructose intake on cardiovascular disease related parameters in growing rats. Nutrients 2017; 9: 11. [DOI:10.3390/nu9010011]
42. Zhao J, He X, Yang N, Sun L, Li G. Study of drug metabolism by xanthine oxidase. Int J Mol Sci 2012; 13: 4873-9. [DOI:10.3390/ijms13044873]

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.