In Silico Approach For Detection Of The Effect Of UGT1A1 Polymorphisms On Telmisartan Response

Abstract

Hypertension is a cardiovascular disease that manifests itself with a continuous increase in systemic arterial blood pressure and can lead to serious complications over time. It is estimated that 37% of hypertensive patients receive treatment and one-third of them are under control. Telmisartan is an angiotensin receptor blocker used in the treatment of hypertension. Uridine 5'-diphospho-glucuronyltransferase 1 (UGT1A1) gene encodes the Uridine 5'-diphospho-glucuronyltransferase (UGT) enzyme and metabolizes the telmisartan. Single nucleotide polymorphisms cause amino acid, protein structure, and function to change. These changes affect the drug response and therapy. Polymorphisms of the UGT1A1 gene (rs4148323, rs28934877) cause telmisartan resistance. In this study, the SWISS-MODEL database and Chimera 1.15 ver. Programs were used to create homology models. The HOPE database was used to calculate the damage of mutation on protein structure and show the mutation effects on protein. The HDock server was used to demonstrate interactions between telmisartan and wild-type protein and, mutant type protein. It was detected that the mutant residue of UGT1A1 (rs4148323) is located in an important domain for protein activity. Mutation might disturb the protein function. rs28934877 was detected that this mutation is probably damaging to the protein. These mutations cause the loss of interactions and affect the drug response. By docking analysis, Telmisartan drug interactions were shown between wild and mutant types protein Possible drug conformation is designed for the effective treatment of patients carrying the common mutation.

Keywords

• homology modeling
• docking
• telmisartan
• in silico
• single nucleotide polymorphism

References

1. Bosma PJ, Van Der Meer IM, Bakker CT, Hofman A, Paul-Abrahamse M, Witteman JC (2003) UGT1A1*28 Allele and coronary heart disease: The Rotterdam study. Clin. Chem. 49(7): 1180–1181
2. Di YM, Chan E, Wei MQ, Liu JP, & Zhou SF (2009) Prediction of deleterious non-synonymous single-nucleotide polymorphisms of human uridine diphosphate glucuronosyltransferase genes. AAPS Journal, 11(3): 469–480
3. Ding C, Yang Z, Wang S, Sun F, & Zhan S (2018) The associations of metabolic syndrome with incident hypertension, type 2 diabetes mellitus and chronic kidney disease: a cohort study. Endocrine, 60(2): 282–291
4. Dutton GJ (1980) Developmental aspects of drug conjugation, with special reference to glucuronidation. Annu Rev Pharmacol Toxicol 18:17–35
5. Ebner T, Schänzle G, Weber W, Sent U, & Elliott J (2013) In vitro glucuronidation of the angiotensin II receptor antagonist telmisartan in the cat: A comparison with other species. J. Vet. Pharmacol. Ther., 36(2): 154–160
6. Huang L, Yang L, Huang J, Tan H, Liu S, Kun- Guo C, Pei Q (2019) Effects of UGT1A1 Polymorphism, Gender and Triglyceride on the Pharmacokinetics of Telmisartan in Chinese Patients with Hypertension: A Population Pharmacokinetic Analysis. Eur J Drug Metab Pharmacokinet, 44(6): 797–806
7. Huang X, Bo Chen F, Dai W, Song L, Tu J, Xu J Zhao S (2018) Prevalence and risk factors associated with hypertension in the Chinese Qiang population. Clin. Exp. Hypertens., 40(5): 427–433
8. Kılıç M (2016) Uzunçakmak T. Hipertansiyon Hakkındaki Eğitimin Hipertansiyon Kontrolüne Etkisi. Bozok Tıp Dergisi 1(1): 13-9

9. Martinez-Quinones P, McCarthy CG, Watts SW, Klee NS, Komic A, Calmasini FB, Wenceslau CF (2018, September 11). Hypertension induced morphological and physiological changes in cells of the arterial wall. American Journal of Hypertension. Oxford University Press.
10. Maruo Y, Nishizawa K, Sato H, Sawa H, & Shimada M (2000) Prolonged unconjugated hyperbilirubinemia associated with breast milk and mutations of the bilirubin uridine diphosphate- glucuronosyltransferase gene. Pediatrics 106(5)
11. Papathanasiou G, Zerva E, Zacharis I, Papandreou M, Papageorgiou E, Tzima C, Evangelou A (2015) Association of High Blood Pressure with Body Mass Index, Smoking and Physical Activity in Healthy Young Adults. Open Cardiovasc. Med. J., 9(1): 5–17
12. Pei Q, Yang L, Tan HY, Liu SK, Liu Y, Huang L, Yang GP (2017) Effects of genetic variants in UGT1A1, SLCO1B3, ABCB1, ABCC2, ABCG2, ORM1 on PK/PD of telmisartan in Chinese patients with mild to moderate essential hypertension. Int J Clin Pharmacol Ther., 55(8): 659–665
13. Ritter JK, Chen F, Sheen YY, Tran HM, Kimura S, Yeatman MT, Owens IS (1992) A novel complex locus UGT1 encodes human bilirubin, phenol and other UDP-glucuronosyltransferase isozymes with identical carboxyl termini. J Biol Chem 267: 3257–3261
14. Schwertner HA, Vítek L (2008) Gilbert syndrome, UGT1A1*28 allele, and cardiovascular disease risk: Possible protective effects and therapeutic applications of bilirubin. Atherosclerosis. Elsevier Ireland Ltd.
15. Sharpe M, Jarvis B, & Goa KL (2001) Telmisartan: A review of its use in hypertension. Drugs. Adis International Ltd.
16. Shin HJ, Kim JE, Lim SJ, Seo JE, Kim MH, Hoon OK, Shin JG (2015) Effect of UGT1A1 and UGT1A3 polymorphisms on Pharmacokinetics of Telmisartan in Korean. Clinical Therapeutics 37(8):87
17. WHO (2015) http://www.who.int/ Accessed: 14.08.2022.
18. WHO (2015) https://www.who.int/gho/ncd/risk_factors/blood_p ressure_prevalence_text/en/ Accessed: 14.08.2022 .
19. Yan Y, Zhang D, Zhou P, Li B, & Huang SY (2017) HDOCK: A web server for protein-protein and protein-DNA/RNA docking based on a hybrid strategy. Nucleic Acids Res. Spec. Publ., 45:365-373.
20. Zhang X, Ao G, Wang Y, Yan W, Wang M, Chen E, Yang, J (2012) Genetic variants and haplotypes of the UGT1A9, 1A7 and 1A1 genes in Chinese Han. Genet. Mol. Biol., 35(2): 428-434 .
21. Zhuo ZL, Xian HP, Long Y, Liu C, Sun YY, Ma YT, Zhao XT (2018) Association between cyp2c19 and abcb1 polymorphisms and clopidogrel resistance in clopidogrel-treated chinese patients. Anatol. J. Cardiol., 19(2): 123–129.