The effect of letrozole on liver function and some biochemical parameters in rats

Abstract

Letrozole (LTZ), is an aromatase inhibitor, that has been widely used in a variety of diseases such as polycystic ovary syndrome, endometriosis, and breast cancer. LTZ is received via the oral route and metabolized in the liver. Therefore, LTZ may have toxic effects like other drugs metabolized in the liver. Based on this, our study aimed to investigate the effect of LTZ on liver function and biochemical parameters. For this purpose, 16 Wistar albino female rats were divided into two groups (n=8): Control and LTZ respectively. The rats in the letrozole group were administered with 2 mL/kg LTZ by oral gavage once a day for 21 days. The Control group received the vehicle once a day for 21 days. Blood samples were collected on the 22nd day of the experiment. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), lactate dehydrogenase (LDH), albumin (ALB), alkaline phosphatase (ALP), direct bilirubin and total bilirubin were measured. Biochemical analysis indicated that ALT, AST, LDH, ALP, and total bilirubin levels were significantly higher in the LTZ administrated group compared to the Control. ALB levels decreased in the LTZ group. In conclusion, it was determined that LTZ has toxic and detrimental effects on the liver. We suggested that long-term LTZ administrated patients should be under control against liver damage and may have liver supporting adjuvant therapies for robust liver functions.

Keywords

• Letrazole
• hepatotoxicity
• liver function tests
• albümin

References

1. Akşi̇t, H., Akşi̇t, D., Bi̇ldi̇k, A., Kara, H., Yavuz, Ö., & Seyrek, K., (2015). Effects of N-acetyl cysteine on glutathione metabolism and lipid peroxidation in experimental liver intoxication. Ankara Üniversitesi Veteriner Fakültesi Dergisi (62). https://doi.org/10.1501/Vetfak_0000002649
2. Aydin, M., Oktar, S., Özkan, O. V., Alçin, E., Öztürk, O. H., & Nacar, A. (2011). Letrozole induces hepatotoxicity without causing oxidative stress: the protective effect of melatonin. Gynecological Endocrinology: The Official Journal of the International Society of Gynecological Endocrinology, 27(4), 209–215. https://doi.org/10.3109/09513590.2010.488769
3. Barnhart, K. T., Gosman, G., Ashby, R., & Sammel, M. (2003). The medical management of ectopic pregnancy: A meta-analysis comparing “single dose” and “multidose” regimens. Obstetrics and Gynecology, 101(4), 778–784. https://doi.org/10.1016/S0029-7844(02)03158-7
4. Bhatnagar, A. S. (2007). The discovery and mechanism of action of letrozole. Breast Cancer Research and Treatment, 105 (1), 7–17. https://doi.org/10.1007/S10549-007-9696-3
5. Brennan, P. N., Dillon, J. F., & Tapper, E. B. (2022). Gamma-Glutamyl Transferase (γ-GT) – an old dog with new tricks? Liver International, 42(1), 9–15. https://doi.org/10.1111/LIV.15099
6. Bulun, S. E., & Simpson, E. R. (1994). Regulation of aromatase expression in human tissues. Breast Cancer Research and Treatment, 30(1), 19–29. https://doi.org/10.1007/BF00682738
7. Carvalho, J. R., & Machado, M. V. (2018). New insights about albumin and liver disease. Annals of Hepatology, 17(4), 547–560. https://doi.org/10.5604/01.3001.0012.0916
8. Chaudhary, A., & Chauhan, V. (2015). Lactate dehydrogenase as an indicator of liver diseases. Journal of Advanced Medical and Dental Sciences Research, 3(5), S20-S22.

9. Čustović, N., Selimović, A. H., Saray, A., Prohić, D., Cerić, T., Đuran, A., Redžepagi, J., Sprečkić, S., Mehmedbašić, S. Ato, & Sivac, N. (2019). P-011. Letrozole-induced hepatitis in a 42-year-old woman with invasive ductal breast cancer. The Turkish Journal of Gastroenterology, 30(supp1), S30. https://doi.org/10.5152/TJG.2019.17
10. Deveci, H. A., Nur, G., Aksu-Kılıçle, P. (2021). Effect of subacut malathion application on oxidative stress biomarkers. Journal of Advances in VetBio Science and Techniques, 6(3), 193-201. https://doi.org/10. 31797/vetbio.917112
11. Eren, M., Saltık-Temizel, İ. N., & Koçak, N. (2007). Drug-induced hepatotoxicity. Additive Journal of Pediatrics 29: 274-283.
12. Ersoy, O. (2012). Evaluation of liver enzyme elevation. Ankara Medical Journal, 12(3), 129-135.
13. Faloppi, L., Bianconi, M., Memeo, R., Casadei Gardini, A., Giampieri, R., Bittoni, A., Andrikou, K., Del Prete, M., Cascinu, S., & Scartozzi, M. (2016). Lactate dehydrogenase in hepatocellular carcinoma: something old, something new. BioMed Research International, 2016. https://doi.org/10.1155/2016/7 196280
14. Fernandez, N. J., & Kidney, B. A. (2007). Alkaline phosphatase: beyond the liver. Veterinary Clinical Pathology, 36(3), 223–233. https://doi.org/ 10.1111/J.1939-165X.2007.TB00216.X
15. Gharia, B., Seegobin, K., Maharaj, S., Marji, N., Deutch, A., & Zuberi, L. (2017). Letrozole-induced hepatitis with autoimmune features: a rare adverse drug reaction with a review of the relevant literature. Oxford Medical Case Reports, 2017(11), 226–228. https://doi.org/10.1093/OMCR/OMX074
16. Green, R. M., & Flamm, S. (2002). AGA technical review on the evaluation of liver chemistry tests. Gastroenterology, 123(4), 1367–1384. https://doi.org/ 10.1053/GAST.2002.36061
17. Guerra Ruiz, A. R., Crespo, J., López Martínez, R. M., Iruzubieta, P., Casals Mercadal, G., Lalana Garcés, M., Lavin, B., & Morales Ruiz, M. (2021). Measurement and clinical usefulness of bilirubin in liver disease. Advances in Laboratory Medicine, 2(3), 352–361. https://doi.org/10.1515/ALMED-2021-0047
18. Işık, S. A., Seyman, D., Zerdali, E., Ayan, S., Kakaliçoğlu, D., Ayaz, T., Ünlü, E. C., Çetinkaya, R. A., Yenilmez, E., Görenek, L., & Köse, Ş. (2020). Evaluation of 170 followed-up cases treated for hydatid disease: a multicentre study. Turkish Journal of Parasitology, 44(4), 197–202. https://doi.org/ 10.4274/TPD.GALENOS.2020.6737
19. Jin, S. J., Jung, J. A., Cho, S. H., Kim, U. J., Choe, S., Ghim, J. L., Noh, Y. H., Park, H. J., Kim, J. C., Lim, H. S., & Bae, K. S. (2012). The pharmacokinetics of letrozole: Association with key body mass metrics. International Journal of Clinical Pharmacology and Therapeutics, 50(8), 557–565. https://doi.org/ 10.5414/CP201709
20. Kafali, H., Iriadam, M., Ozardali, I., & Demir, N. (2004). Letrozole-induced polycystic ovaries in the rat: a new model for cystic ovarian disease. Archives of Medical Research, 35(2), 103–108. https://doi.org/ 10.1016/J.ARCMED.2003.10.005
21. Karapehlivan, M., Başer, Ömer F., Dolanbay, T., & Alwazeer, D. (2023). Effects of hydrogen-enriched water on lipid profile and some biochemical markers: Effects of hydrogen-enriched water on lipid profile. Rats, 1(2), 47–50. https://doi.org/10.5281/zenodo. 10444706
22. Kharb, R., Haider, K., Neha, K., & Yar, M. S. (2020). Aromatase inhibitors: Role in postmenopausal breast cancer. Archiv Der Pharmazie, 353(8), 2000081. https://doi.org/10.1002/ARDP.202000081
23. Kıncı, M. F., Şehirli Kıncı, Ö., & Karakaş Paskal, E. (2021). Intrahepatic cholestasis of pregnancy. Muğla Sıtkı Koçman University Medical Journal, 8(2), 158-162. https://doi.org/10.47572/muskutd.716205
24. Kuru, M., Akyüz, E., Makav, M. (2022). Some metabolic profile markers in goats. Turkish Journal of Veterinary Internal Medicine, 1(2), 32-39. https://doi.org/10.5281/zenodo.7486065
25. Kutlubay, R., Oğuz, E., Turgut, G., & Kocamaz, E. (2009). Toxicity of ethanol on liver and kidney and protective effect of L-NAME. SDU Medical Faculty Journal, 15(4), 11-17. https://doi.org/10.17343/ SDUTFD.14900
26. Limdi, J. K., & Hyde, G. M. (2003). Evaluation of abnormal liver function tests. Postgraduate Medical Journal, 79(932), 307. https://doi.org/ 10.1136/PMJ.79.932.307
27. Makav, M., Kuru, M., Aras, Ş. Y., Sarı, E. K., Bulut, M., & Alwazeer, D. (2023). The effect of hydrogen-rich water on letrozole-induced polycystic ovary syndrome in rats. Reproductive BioMedicine Online, 47(6), 103332. https://doi.org/10.1016/J.RBMO. 2023.103332
28. Moy, B., Neven, P., Lebrun, F., Bellet, M., Xu, B., Sarosiek, T., Chow, L., Goss, P., Zacharchuk, C., Leip, E., Turnbull, K., Bardy‐Bouxin, N., Duvillié, L., & Láng, I. (2014). bosutinib in combination with the aromatase inhibitor letrozole: a phase ii trial in postmenopausal women evaluating first‐line endocrine therapy in locally advanced or metastatic hormone receptor‐positive/HER2‐negative breast cancer. The Oncologist, 19(4), 348–349. https://doi.org/10.1634/ THEONCOLOGIST.2014-0021
29. Mukherjee, A. G., Wanjari, U. R., Nagarajan, D., Vibhaa, K K, Anagha, V., Joshua Paul, P., Tharani Priya, T., Chakraborty, R., Renu, K., Dey, A., Vellingiri, B., & Gopalakrishnan, A. V. (2022). Letrozole: Pharmacology, toxicity, and potential therapeutic effects. Life Sciences, 310. https://doi.org/10.1016/J.LFS.2022.121074
30. Perez, E. A., Serene, M., Durling, F. C., & Weilbaecher, K. (2006). Aromatase inhibitors and bone loss. Oncology, 20(9), 1029.
31. Ratre, P., Mishra, K., Dubey, A., Vyas, A., Jain, A., & Thareja, S. (2020). Aromatase inhibitors for the treatment of breast cancer: A journey from the scratch. Anti-Cancer Agents in Medicinal Chemistry, 20(17), 1994–2004. https://doi.org/10.2174 /1871520620666200627204105
32. Requena, A., Herrero, J., Landeras, J., Navarro, E., Neyro, J. L., Salvador, C., Tur, R., Callejo, J., Checa, M. A., Farré, M., Espinós, J. J., Fábregues, F., & Graña-Barcia, M. (2008). Use of letrozole in assisted reproduction: a systematic review and meta-analysis. Human Reproduction Update, 14(6), 571–582. https://doi.org/10.1093/HUMUPD/DMN033
33. Sharma, S., Ghosh, S., Singh, S., Chakravarty, A., Ganesh, A., Rajani, S., & Chakravarty, B. N. (2014). Congenital malformations among babies born following letrozole or clomiphene for infertility treatment. Plos One, 9(10), e108219. https://doi.org/10.1371/JOURNAL.PONE.0108219
34. Sun, L., Zha, J., Spear, P. A., & Wang, Z. (2007). Toxicity of the aromatase inhibitor letrozole to Japanese medaka (Oryzias latipes) eggs, larvae, and breeding adults. Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology, 145(4), 533–541. https://doi.org/10.1016/J. CBPC.2007.01.017
35. Taniguchi, F., Kaponis, A., Izawa, M., Kiyama, T., Deura, I., Ito, M., Iwabe, T., Adonakis, G., Terakawa, N., & Harada, T. (2011). Apoptosis and endometriosis. Frontiers in Bioscience - Elite, 3 E(2), 648–662. https://doi.org/10.2741/E277/PDF
36. Wang, K., Wang, W., Zhang, X. Y., Jiang, A. Q., Yang, Y. S., & Zhu, H. L. (2021). Fluorescent probes for the detection of alkaline phosphatase in biological systems: Recent advances and prospects. TrAC Trends in Analytical Chemistry, 136, 116189. https://doi.org/10.1016/J.TRAC.2021.116189
37. Wit, J. M., Hero, M., & Nunez, S. B. (2012). Aromatase inhibitors in pediatrics. Nature Reviews Endocrinology, 8(3), 135–147. https://doi.org/10. 1038/nrendo.2011.161
38. Yılmaz, M., Gürses (2020). Evaluation of aspirin-induced hepatotoxicity in the treatment of acute rheumatic fever. Pamukkale Medical Journal, 13(2), 268-274. https://doi.org/10.31362/PATD.657971
39. Yuechong, L., Zixi, D., Yingjiao, W., Tao, X., Qiang, S., & Songjie, S. (2023). A real-world study of the effects of endocrine therapy on liver function in breast cancer. Zhonghua Wai Ke Za Zhi Chinese Journal of Surgery, 61(2), 107–113. https://doi.org/10.3760/CMA.J. CN112139-20220925-0040