Evaluation of changes in cytochrome P450 2C19 activity in type 2 diabetic rats before and after treatment, by using isolated perfused liver model

Document Type: Original Article

Authors

Biopharmaceutics and Pharmacokinetic Division, Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

10.22038/ijbms.2020.40836.9642

Abstract

Objective(s): Alteration in drug metabolism is very likely in diabetes mellitus. This study assessed changes in CYP2C19 enzymatic activity in the liver using omeprazole as a probe in the animal model of type II diabetes (T2DM) before and after treatment with metformin and cinnamon.
Materials and Methods: Twenty-eight male Wistar rats were randomly divided into seven groups. Fourteen days after induction of type 2 diabetic mellitus (T2DM), rats in the test group received metformin, cinnamon, and metformin plus cinnamon daily for 14 days. On day 28, rats were subjected to liver perfusion by Krebs-Henseleit buffer containing omeprazole as a CYP2C19 probe. Perfusate samples were analyzed by HPLC-UV to evaluate the activity of CYP2C19.
Results: Mean metabolic ratio of omeprazole was changed from 0.091±0.005 in the control group to 0.054±0.005 in the untreated-diabetic rats. This average was increased inordinately to 0.218±0.036 in the treated rats with metformin. Interestingly, the administration of cinnamon in combination with metformin in diabetic rats caused the enzyme activity to return to (0.085±0.002) approximately the observed levels in the control group (0.091±0.005).
Conclusion: Results showed that despite the suppression of the CYP2C19 enzyme activity in T2DM rats, metformin treatment could increase the enzyme activity. Simultaneous application of cinnamon and metformin can modulate the function of CYP2C19 to the observed level in the control group and make it more predictable to treat diabetes mellitus and fate of drugs that are metabolized by this enzyme.

Keywords


1. Cederbaum AI. Molecular mechanisms of the microsomal mixed function oxidases and biological and pathological implications. Redox Biol 2015; 4:60-73.
2. Sychev DA, Ashraf GM, Svistunov AA, Maksimov ML, Tarasov VV, Chubarev VN, et al. The cytochrome P450 isoenzyme and some new opportunities for the prediction of negative drug interaction in vivo. Drug Des Devel Ther 2018; 12:1147-1156.
3. Desta Z, Zhao X, Shin JG, Flockhart DA. Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin Pharmacokinet 2002; 41:913-958.
4. Lee SJ. Clinical application of CYP2C19 pharmacogenetics toward more personalized medicine. Front Genet 2012; 3:318.
5. Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther 2013; 138:103-141.
6. Zhou SF, Liu JP, Chowbay B. Polymorphism of human cytochrome P450 enzymes and its clinical impact. Drug Metab Rev 2009; 41:89-295.
7. Ortiz de Montellano PR. Cytochrome P450-activated prodrugs. Future Med Chem 2013; 5:213-228.
8. Hashemizadeh Z, Malek-Hosseini SA, Badiee P. Prevalence of CYP2C19 genetic polymorphism among normal people and patients with hepatic diseases. Int J Organ Transplant Med 2018; 9:27-33.
9. Pinto N, Dolan ME. Clinically relevant genetic variations in drug metabolizing enzymes. Curr Drug Metab 2011; 12:487-497.
10. Nebert DW, Wikvall K, Miller WL. Human cytochromes P450 in health and disease. Philos Trans R Soc Lond B Biol Sci 2013; 368:20120431.
11. Shah RR, Smith RL. Inflammation-induced phenoconversion of polymorphic drug metabolizing enzymes: hypothesis with implications for personalized medicine. Drug Metab Dispos 2015; 43:400-410.
12. Shah RR, Smith RL. Addressing phenoconversion: the Achilles’ heel of personalized medicine. Br J Clin Pharmacol 2015; 79:222-240.
13. Vahabzadeh M, Mohammadpour A. Effect of diabetes mellitus on the metabolism of drugs and toxins. J Clin Toxicol 2015; 5:1-8.
14. Wu Y, Ding Y, Tanaka Y, Zhang W. Risk factors contributing to type 2 diabetes and recent advances in the treatment and prevention. Int J Med Sci 2014; 11:1185-1200.
15. Dostalek M, Court MH, Yan B, Akhlaghi F. Significantly reduced cytochrome P450 3A4 expression and activity in liver from humans with diabetes mellitus. Br J Pharmacol 2011; 163:937-947.
16. Matzke GR, Frye RF, Early JJ, Straka RJ, Carson SW. Evaluation of the influence of diabetes mellitus on antipyrine metabolism and CYP1A2 and CYP2D6 activity. Pharmacotherapy 2000; 20:182-190.
17. Bergheim I, Bode C, Parlesak A. Decreased expression of cytochrome P450 protein in non-malignant colonic tissue of patients with colonic adenoma. BMC Gastroenterol 2005; 5:34.
18. Hart SN, Cui Y, Klaassen CD, Zhong XB. Three patterns of cytochrome P450 gene expression during liver maturation in mice. Drug Metab Dispos 2009; 37:116-121.
19. Yang X, Zhang B, Molony C, Chudin E, Hao K, Zhu J, et al. Systematic genetic and genomic analysis of cytochrome P450 enzyme activities in human liver. Genome Res 2010; 20:1020-1036.
20. Werner SM. Patient safety and the widespread use of herbs and supplements. Front Pharmacol 2014; 5:142.
21. Brantley SJ, Argikar AA, Lin YS, Nagar S, Paine MF. Herb-drug interactions: challenges and opportunities for improved predictions. Drug Metab Dispos 2014; 42:301-317.
22. Hussain MS. Patient counseling about herbal-drug interactions. Afr J Tradit Complement Altern Med 2011; 8:152-163.
23. Allen RW, Schwartzman E, Baker WL, Coleman CI, Phung OJ. Cinnamon use in type 2 diabetes: an updated systematic review and meta-analysis. Ann Fam Med 2013; 11:452-459.
24. Medagama AB. The glycaemic outcomes of Cinnamon, a review of the experimental evidence and clinical trials. Nutr J 2015; 14:108.
25. Hosseinzadeh HMH. Cinnamon effects on metabolic syndrome: a review based on its mechanisms. Iran J Basic Med Sci 2016; 19:1258-1270.
26. Liao JC, Deng JS, Chiu CS, Hou WC, Huang SS, Shie PH, et al. Anti-inflammatory activities of cinnamomum cassia constituents in vitro and in vivo. Evid Based Complement Alternat Med 2012; 2012:429320.
27. Kelak JA, Cheah WL, Safii R. Patient’s decision to disclose the use of traditional and complementary medicine to medical doctor: A descriptive phenomenology study. Evid Based Complement Alternat Med 2018; 2018:4735234.
28. Mohammadi S, Nezami A, Esmaeili Z, Rouini MR, Ardakani YH, Lavasani H, et al. A disposition kinetic study of tramadol in intoxicated rats induced by ethanol and acetaminophen in perfused rat liver model. Alcohol 2018; 77:49-57.
29. Denisenko NP, Sychev DA, Sizova ZM, Smirnov VV, Ryzhikova KA, Sozaeva ZA, et al. Urine metabolic ratio of omeprazole in relation to CYP2C19 polymorphisms in Russian peptic ulcer patients. Pharmgenomics Pers Med 2017; 10:253-259.
30. Lin Y,  YW,  XH,  MW,  JY,  XY, et al. Evaluation of lentinan effects on cytochrome P450 activity in rats by a cocktail method. Iran J Basic Med Sci 2018; 22:296-301.
31. Szkudelski T. Streptozotocin-nicotinamide-induced diabetes in the rat. Characteristics of the experimental model. Exp Biol Med (Maywood) 2012; 237:481-490.
32. Tracy TS, Chaudhry AS, Prasad B, Thummel KE, Schuetz EG, Zhong XB, et al. Interindividual variability in cytochrome P450-mediated drug metabolism. Drug Metab Dispos 2016; 44:343-351.
33. Shah RR, Gaedigk A. Precision medicine: does ethnicity information complement genotype-based prescribing decisions? Ther Adv Drug Saf 2018; 9:45-62.
34. Brewer CT, Chen T. Hepatotoxicity of herbal supplements mediated by modulation of cytochrome P450. Int J Mol Sci 2017; 18.
35. Kimura M, Ieiri I, Wada Y, Mamiya K, Urae A, Iimori E, et al. Reliability of the omeprazole hydroxylation index for CYP2C19 phenotyping: possible effect of age, liver disease and length of therapy. Br J Clin Pharmacol 1999; 47:115-119.
36. Schlender L, Martinez YV, Adeniji C, Reeves D, Faller B, Sommerauer C, et al. Efficacy and safety of metformin in the management of type 2 diabetes mellitus in older adults: a systematic review for the development of recommendations to reduce potentially inappropriate prescribing. BMC Geriatr 2017; 17:227.
37. Eskens BJ, Zuurbier CJ, van Haare J, Vink H, van Teeffelen JW. Effects of two weeks of metformin treatment on whole-body glycocalyx barrier properties in db/db mice. Cardiovasc Diabetol 2013; 12:175.
38. Abdel-Razzak Z, Loyer P, Fautrel A, Gautier JC, Corcos L, Turlin B, et al. Cytokines down-regulate expression of major cytochrome P-450 enzymes in adult human hepatocytes in primary culture. Mol Pharmacol 1993; 44:707-715.
39. Cameron AR, Morrison VL, Levin D, Mohan M, Forteath C, Beall C, et al. Anti-inflammatory effects of metformin irrespective of diabetes status. Circ Res 2016; 119:652-665.
40. Ranasinghe P, Perera S, Gunatilake M, Abeywardene E, Gunapala N, Premakumara S, et al. Effects of Cinnamomum zeylanicum (Ceylon cinnamon) on blood glucose and lipids in a diabetic and healthy rat model. Pharmacognosy Res 2012; 4:73-79.
41. Hong JW, Yang GE, Kim YB, Eom SH, Lew JH, Kang H. Anti-inflammatory activity of cinnamon water extract in vivo and in vitro LPS-induced models. BMC Complement Altern Med 2012; 12:237.
42. Rao Z, Xu F, Wen T, Wang F, Sang W, Zeng N. Protective effects of essential oils from Rimulus cinnamon on endotoxin poisoning mice. Biomed Pharmacother 2018; 101:304-310.
43. Tuzcu Z, Orhan C, Sahin N, Juturu V, Sahin K. Cinnamon polyphenol extract inhibits hyperlipidemia and inflammation by modulation of transcription factors in high-fat diet-fed rats. Oxid Med Cell Longev 2017; 2017:1583098.