Study of Phenytoin Effect on the genes involved in glucose and lipid metabolism expression in liver: A mouse model study

Fatemeh Samimi, Ali Mohammad Ahadi, Nafiseh Boroomand, Farzaneh Mohammadzadeh Rostami

Abstract


Phenytoin as an anti-seizure medication, is useful for the prevention of tonic-clonic seizures and focal seizures. In this study we focused on the probable effects of Phenytoin drug on gene expression profile of liver related to lipid metabolism balance in mouse as a model. In this study, a group including 7 male mice of BALB/c were treated with phenytoin 3–5 mg/kg/day orally and a group including 7 male mice of BALB/c were took standard food. Liver tissue samples were isolated. Total RNA was extracted and cDNA was synthesized. Expression of Akt1, Leptin, Adipoq and GLUT4 genes was measured using Real-time RT-PCR method. Results showed an increase about 15 and 3 fold changes in Akt1 and Adipoq gene expression respectively in treatment group compare to control mice. Also, we detected decreasing in Leptin and GLUT4 genes expression in the mice treated with phenytoin drug. Several studies indicated that phenytoin can promote hyperglycemia in human and animal. We proposed here that this effects may resulted from an interference between the phenytoin drug and gene expression profile in liver. Decreasing of leptin level here may be a result of glucose level elevation in blood that can induce a satiety situation result in decrease of leptin production. It may that Akt1 gene expression is increased to compensate the low level of GLUT4 protein. We concluded that phenytoin is a relatively high-risk antiepileptic drug for obesity and metabolic syndrome, but more studies are needed.


Keywords


Phenytoin; Akt1; Leptin; Adipoq; GLUT4

References


Webster RK, Rubin GJ. Influencing Side-Effects to Medicinal Treatments: A Systematic Review of Brief Psychological Interventions. Front Psychiatry. 2018; 9:775.

Temkin NR, Dikmen SS, Wilensky AJ, Keihm J, Chabal S, Winn HR. A randomized, double-blind study of phenytoin for the prevention of post-traumatic seizures. N Engl J Med. 1990; 323(8):497-502.

Molnár P, Erdö SL. Vinpocetine is as potent as phenytoin to block voltage-gated Na+ channels in rat cortical neurons. Eur J Pharmacol. 1995; 273(3):303-6.

Yang M, Kozminski DJ, Wold LA, Modak R, Calhoun JD, Isom LL, et al. Therapeutic potential for phenytoin: targeting Na(v)1.5 sodium channels to reduce migration and invasion in metastatic breast cancer. Breast Cancer Res Treat. 2012; 134(2):603-15.

Scheinfeld N. Phenytoin in cutaneous medicine: its uses, mechanisms and side effects. Dermatol Online J. 2003; 9(3):6.

Ekaidem IS, Usoh IF, Uboh FE. Phenytoin induced changes in glucose and lipid metabolism is related to increased urate synthesis. J Adv Med Med Res. 2016; 16(7):1-10.

Ritchie HE, Oakes D, Farrell E, Ababneh D, Howe A. Fetal hypoxia and hyperglycemia in the formation of phenytoin-induced cleft lip and maxillary hypoplasia. Epilepsia Open. 2019; 4(3):443-51.

Nair SS, Harikrishnan S, Sarma PS, Thomas SV. Metabolic syndrome in young adults with epilepsy. Seizure. 2016; 37:61-4.

Leibiger B, Moede T, Uhles S, Barker CJ, Creveaux M, Domin J, et al. Insulin-feedback via PI3K-C2alpha activated PKBalpha/Akt1 is required for glucose-stimulated insulin secretion. Faseb j. 2010; 24(6):1824-37.

Ivy JL. Muscle insulin resistance amended with exercise training: role of GLUT4 expression. Med Sci Sports Exerc. 2004; 36(7):1207-11.

Thong FS, Bilan PJ, Klip A. The Rab GTPase-activating protein AS160 integrates Akt, protein kinase C, and AMP-activated protein kinase signals regulating GLUT4 traffic. Diabetes. 2007; 56(2):414-23.

Whiteman EL, Cho H, Birnbaum MJ. Role of Akt/protein kinase B in metabolism. Trends Endocrinol Metab. 2002; 13(10):444-51.

Perry RJ, Wang Y, Cline GW, Rabin-Court A, Song JD, Dufour S, et al. Leptin Mediates a Glucose-Fatty Acid Cycle to Maintain Glucose Homeostasis in Starvation. Cell. 2018; 172(1-2):234-48.e17.

Vega GL, Grundy SM. Metabolic risk susceptibility in men is partially related to adiponectin/leptin ratio. J Obes. 2013; 2013:409679.

German JP, Wisse BE, Thaler JP, Oh IS, Sarruf DA, Ogimoto K, et al. Leptin deficiency causes insulin resistance induced by uncontrolled diabetes. Diabetes. 2010; 59(7):1626-34.

Buettner C, Muse ED, Cheng A, Chen L, Scherer T, Pocai A, et al. Leptin controls adipose tissue lipogenesis via central, STAT3-independent mechanisms. Nat Med. 2008; 14(6):667-75.

Liu Q, Yuan B, Lo KA, Patterson HC, Sun Y, Lodish HF. Adiponectin regulates expression of hepatic genes critical for glucose and lipid metabolism. Proc Natl Acad Sci U S A. 2012; 109(36):14568-73.

Stern JH, Rutkowski JM, Scherer PE. Adiponectin, Leptin, and Fatty Acids in the Maintenance of Metabolic Homeostasis through Adipose Tissue Crosstalk. Cell Metab. 2016; 23(5):770-84.

Kim JY, van de Wall E, Laplante M, Azzara A, Trujillo ME, Hofmann SM, et al. Obesity-associated improvements in metabolic profile through expansion of adipose tissue. J Clin Invest. 2007; 117(9):2621-37.

Nair AB, Jacob S. A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm. 2016; 7(2):27-31.

Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001; 25(4):402-8.

Carter BL, Small RE, Mandel MD, Starkman MT. Phenytoin-induced hyperglycemia. Am J Hosp Pharm. 1981; 38(10):1508-12.

Manto M, Preiser JC, Vincent JL. Hypoglycemia associated with phenytoin intoxication. J Toxicol Clin Toxicol. 1996; 34(2):205-8.

Metin Aksu N, Yazgan Aksoy D, Akkaş M, Çinar N, Uçar F, Yildiz OB, et al. Adiponectin levels decrease independently of body mass index and diabetes type after the normalization of hyperglycemia. Turk J Med Sci. 2020; 50(2):312-5.

Chai F, Wang Y, Zhou Y, Liu Y, Geng D, Liu J. Adiponectin downregulates hyperglycemia and reduces pancreatic islet apoptosis after roux-en-y gastric bypass surgery. Obes Surg. 2011; 21(6):768-73.

López-Jaramillo P, Gómez-Arbeláez D, López-López J, López-López C, Martínez-Ortega J, Gómez-Rodríguez A, et al. The role of leptin/adiponectin ratio in metabolic syndrome and diabetes. Horm Mol Biol Clin Investig. 2014; 18(1):37-45.

Uludag IF, Kulu U, Sener U, Kose S, Zorlu Y. The effect of carbamazepine treatment on serum leptin levels. Epilepsy Res. 2009; 86(1):48-53.

Yu ZW, Burén J, Enerbäck S, Nilsson E, Samuelsson L, Eriksson JW. Insulin can enhance GLUT4 gene expression in 3T3-F442A cells and this effect is mimicked by vanadate but counteracted by cAMP and high glucose--potential implications for insulin resistance. Biochim Biophys Acta. 2001; 1535(2):174-85.

Kato M, Suwa A, Shimokawa T. Glucose catabolic gene mRNA levels in skeletal muscle exhibit non-coordinate expression in hyperglycemic mice. Horm Metab Res. 2004; 36(8):513-8.

Dimitrakoudis D, Vranic M, Klip A. Effects of hyperglycemia on glucose transporters of the muscle: use of the renal glucose reabsorption inhibitor phlorizin to control glycemia. J Am Soc Nephrol. 1992; 3(5):1078-91.

Hay N. Akt isoforms and glucose homeostasis - the leptin connection. Trends Endocrinol Metab. 2011; 22(2):66-73.

Hou N, Mai Y, Qiu X, Yuan W, Li Y, Luo C, et al. Carvacrol Attenuates Diabetic Cardiomyopathy by Modulating the PI3K/AKT/GLUT4 Pathway in Diabetic Mice. Front Pharmacol. 2019; 10:998.

Rowland AF, Fazakerley DJ, James DE. Mapping insulin/GLUT4 circuitry. Traffic. 2011; 12(6):672-81.




DOI: https://doi.org/10.52547/JCBioR.2.2.62

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