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Effects of insulin treatment on hepatic CYP1A1 and CYP2E1 activities and lipid peroxidation levels in streptozotocin-induced diabetic rats

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Abstract

Introduction

Reactive oxygen species (ROS) and lipid peroxidation (LPO) levels may increase in diabetic state and lead to oxidative stress, which plays a critical role in the progression of diabetes. There are various sources of ROS, including cytochrome P450 monooxygenases (CYP450s), which may be modulated in terms of their activities and expressions under diabetic conditions. This study is aimed to investigate the effects of streptozotocin-induced diabetes and insulin treatment on hepatic cytochrome P450 1A1 (CYP1A1) and cytochrome P450 2E1 (CYP2E1) activities and LPO levels. Methods: CYP1A1 and CYP2E1 activities were measured with ethoxyresorufin O-deethylase and p-nitrophenol hydroxylase activities, respectively. LPO levels were then corroborated via thiobarbituric acid reactive substances. Results: In diabetic rats, a marked 2.1- and 2.4-fold increase in hepatic CYP1A1 activity and 1.8- and 1.6-fold increase in hepatic CYP2E1 activity were observed compared to controls and insulin-treated diabetic rats, respectively. Hepatic LPO levels in diabetic rats did not significantly change compared to controls. However, in insulin-treated diabetic rats, LPO levels are 0.92- and 0.89-fold remarkably decrease compared to controls and diabetics, respectively. Conclusion: The present study suggests that insulin might have a useful role in the modulation of CYP1A1 and CYP2E1 activities as well as LPO levels in the liver of diabetic rats.

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Data svailability

Data are accessible upon request from the authors.

Abbreviations

CYP1A1:

cytochrome P450 1A1

CYP2E1:

cytochrome P450 2E1

CYP450:

cytochrome P450 monooxygenase

EROD:

7-ethoxyresorufinO-deethylase

Fe++ :

Iron(II)

KCI:

potassiumchloride

LPO:

lipid peroxidation

M:

molarity

MDA:

malondialdehyde

MgCI2 :

magnesiumchloride

mins:

minutes

mM:

millimolar

N:

normality

NADP+ :

nicotinamideadenine dinucleotide phosphate

NaOH:

sodiumhydroxide

nm:

nanometer

ºC:

degreesCelsius

pNP:

p-nitrophenol

ROS:

reactive oxygen species

TBARS:

thiobarbituricacid reactive substances

Tris.HCl:

trishydrochloride

U/mL:

unitspermillilitre

v/v:

volume/volume

w/v:

weight/volume

µL:

microliter

References

  1. Raza H, Ahmed I, John A, Sharma AK. Modulation of xenobiotic metabolism and oxidative stress in chronic streptozotocin-induced diabetic rats fed with Momordica charantia fruit extract. J Biochem Mol Toxicol. 2000;14(3):131–9.

    Article  CAS  Google Scholar 

  2. Raza H, Prabu SK, Robin MA, Avadhani NG. Elevated mitochondrial cytochrome P450 2E1 and glutathione S-transferase A4-4 in streptozotocin-induced diabetic rats: tissue-specific variations and roles in oxidative stress. Diabetes. 2004;53(1):185–94.

    Article  CAS  Google Scholar 

  3. König M, Bulik S, Holzhütter H-G. Quantifying the contribution of the liver to glucose homeostasis: a detailed kinetic model of human hepatic glucose metabolism. PLoS Comput Biol. 2012;8(6):e1002577.

    Article  Google Scholar 

  4. Niedowicz DM, Daleke DL. The role of oxidative stress in diabetic complications. Cell Biochem Biophys. 2005;43(2):289–330. https://doi.org/10.1385/cbb:43:2:289.

    Article  CAS  PubMed  Google Scholar 

  5. Cederbaum AI. Role of Cytochrome P450 and oxidative stress in alcohol-induced liver injury. React Oxygen Species. 2017;4(11):303–19.

    Google Scholar 

  6. Memişoğulları R. Diyabette serbest radikallerin rolü ve antioksidanların etkisi düzce. Tıp Fakültesi Dergisi. 2005;3:30–9.

    Google Scholar 

  7. Dib M, Garrel C, Favier A, Robin V, Desnuelle C. Can malondialdehyde be used as a biological marker of progression in neurodegenerative disease? J Neurol. 2002;249(4):367–74. https://doi.org/10.1007/s004150200025.

    Article  CAS  PubMed  Google Scholar 

  8. Hall ED, Wang JA, Bosken JM, Singh IN. Lipid peroxidation in brain or spinal cord mitochondria after injury. J Bioenerg Biomembr. 2016;48(2):169–74.

    Article  CAS  Google Scholar 

  9. Manikandan P, Nagini S. Cytochrome P450 structure, function and clinical significance: a review. Curr Drug Targets. 2018;19(1):38–54.

    Article  CAS  Google Scholar 

  10. Guengerich FP. The 1992 Bernard B. Brodie Award Lecture. Bioactivation and detoxication of toxic and carcinogenic chemicals. Drug Metab Dispos Biol Fate Chem. 1993;21(1):1–6.

    CAS  PubMed  Google Scholar 

  11. Puga A, Nebert DW, McKinnon RA, Menon AG. Genetic polymorphisms in human drug-metabolizing enzymes: potential uses of reverse genetics to identify genes of toxicological relevance. Crit Rev Toxicol. 1997;27(2):199–222. https://doi.org/10.3109/10408449709021619.

    Article  CAS  PubMed  Google Scholar 

  12. Stiborova M, Martinek V, Rydlova H, Koblas T, Hodek P. Expression of cytochrome P450 1A1 and its contribution to oxidation of a potential human carcinogen 1-phenylazo-2-naphthol (Sudan I) in human livers. Cancer Lett. 2005;220(2):145–54. https://doi.org/10.1016/j.canlet.2004.07.036.

    Article  CAS  PubMed  Google Scholar 

  13. Lu Y, Cederbaum AI. CYP2E1 and oxidative liver injury by alcohol. Free Radic Biol Med. 2008;44(5):723–38. https://doi.org/10.1016/j.freeradbiomed.2007.11.004.

    Article  CAS  PubMed  Google Scholar 

  14. Gandhi A, Moorthy B, Ghose R. Drug disposition in pathophysiological conditions. Curr Drug Metab. 2012;13(9):1327–44.

    Article  CAS  Google Scholar 

  15. Tolman KG, Fonseca V, Dalpiaz A, Tan MH. Spectrum of liver disease in type 2 diabetes and management of patients with diabetes and liver disease. Diabetes Care. 2007;30(3):734–43. https://doi.org/10.2337/dc06-1539.

    Article  CAS  PubMed  Google Scholar 

  16. Wang Z, Hall SD, Maya JF, Li L, Asghar A, Gorski JC. Diabetes mellitus increases the in vivo activity of cytochrome P450 2E1 in humans. Br J Clin Pharmacol. 2003;55(1):77–85.

    Article  CAS  Google Scholar 

  17. Kim SK, Novak RF. The role of intracellular signaling in insulin-mediated regulation of drug metabolizing enzyme gene and protein expression. Pharmacol Ther. 2007;113(1):88–120. https://doi.org/10.1016/j.pharmthera.2006.07.004.

    Article  CAS  PubMed  Google Scholar 

  18. Kim YJ, Park HS, Park MH, Suh SH, Pang MG. Oxidative stress-related gene polymorphism and the risk of preeclampsia. Eur J Obstet Gynecol Reprod Biol. 2005;119(1):42–6. https://doi.org/10.1016/j.ejogrb.2004.06.009.

    Article  CAS  PubMed  Google Scholar 

  19. Caro AA, Cederbaum AI. Oxidative stress, toxicology, and pharmacology of CYP2E1. Annu Rev Pharmacol Toxicol. 2004;44:27–42. https://doi.org/10.1146/annurev.pharmtox.44.101802.121704.

    Article  CAS  PubMed  Google Scholar 

  20. Walsh AA, Szklarz GD, Scott EE. Human cytochrome P450 1A1 structure and utility in understanding drug and xenobiotic metabolism. J Biol Chem. 2013;288(18):12932–43. https://doi.org/10.1074/jbc.M113.452953.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wang T, Chen M, Yan YE, Xiao FQ, Pan XL, Wang H. Growth retardation of fetal rats exposed to nicotine in utero: possible involvement of CYP1A1, CYP2E1, and P-glycoprotein. Environ Toxicol. 2009;24(1):33–42. https://doi.org/10.1002/tox.20391.

    Article  CAS  PubMed  Google Scholar 

  22. Oh SJ, Choi JM, Yun KU, Oh JM, Kwak HC, Oh JG, Lee KS, Kim BH, Heo TH, Kim SK. Hepatic expression of cytochrome P450 in type 2 diabetic Goto-Kakizaki rats. Chemico-Biol Interact. 2012;195(3):173–9. https://doi.org/10.1016/j.cbi.2011.12.010.

    Article  CAS  Google Scholar 

  23. Borbas T, Benko B, Dalmadi B, Szabo I, Tihanyi K. Insulin in flavin-containing monooxygenase regulation. Flavin-containing monooxygenase and cytochrome P450 activities in experimental diabetes. Eur J Pharm Sci. 2006;28(1–2):51–8. https://doi.org/10.1016/j.ejps.2005.12.011.

    Article  CAS  PubMed  Google Scholar 

  24. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951;193(1):265–75.

    Article  CAS  Google Scholar 

  25. Reinke LA, Moyer MJ. p-Nitrophenol hydroxylation. A microsomal oxidation which is highly inducible by ethanol. Drug Metab Dispos Biol Fate Chem. 1985;13(5):548–52.

    CAS  PubMed  Google Scholar 

  26. Başaran R, Özdamar ER, Eke BC. A study on the optimization of CYP2E1 enzyme activity in C57Bl/6 mouse brain and liver. FABAD J Pharm Sci. 2012;37(4):191–6.

    Google Scholar 

  27. Burke MD, Thompson S, Elcombe CR, Halpert J, Haaparanta T, Mayer RT. Ethoxy-, pentoxy- and benzyloxyphenoxazones and homologues: a series of substrates to distinguish between different induced cytochromes P-450. Biochem Pharmacol. 1985;34(18):3337–45.

    Article  CAS  Google Scholar 

  28. Wills ED. Lipid peroxide formation in microsomes. Relationship of hydroxylation to lipid peroxide formation. Biochem J. 1969;113(2):333–41.

    Article  CAS  Google Scholar 

  29. Bishayee S, Balasubramanian AS. Lipid peroxide formation in rat brain. J Neurochem. 1971;18(6):909–20.

    Article  CAS  Google Scholar 

  30. Wills ED. Mechanisms of lipid peroxide formation in animal tissues. Biochem J. 1966;99(3):667–76.

    Article  CAS  Google Scholar 

  31. Sadi G, Baloglu MC, Pektas MB. Differential gene expression in liver tissues of streptozotocin-induced diabetic rats in response to resveratrol treatment. PLoS One. 2015;10(4):e0124968. https://doi.org/10.1371/journal.pone.0124968.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. de Souza Bastos A, Graves DT, de Melo Loureiro AP, Junior CR, Corbi SC, Frizzera F, Scarel-Caminaga RM, Camara NO, Andriankaja OM, Hiyane MI, Orrico SR. Diabetes and increased lipid peroxidation are associated with systemic inflammation even in well-controlled patients. J Diabetes Complicat. 2016;30(8):1593–9. https://doi.org/10.1016/j.jdiacomp.2016.07.011.

    Article  PubMed Central  Google Scholar 

  33. He Q, Li JK, Li F, Li RG, Zhan GQ, Li G, Du WX, Tan HB. Mechanism of action of gypenosides on type 2 diabetes and non-alcoholic fatty liver disease in rats. World J Gastroenterol. 2015;21(7):2058–66. https://doi.org/10.3748/wjg.v21.i7.2058.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Morel Y, de Waziers I, Barouki R. A repressive cross-regulation between catalytic and promoter activities of the CYP1A1 and CYP2E1 genes: role of H(2)O(2). Mol Pharmacol. 2000;57(6):1158–64.

    CAS  PubMed  Google Scholar 

  35. Skovso S, Damgaard J, Fels JJ, Olsen GS, Wolf XA, Rolin B, Holst JJ. (2015) Effects of insulin therapy on weight gain and fat distribution in the HF/HS-STZ rat model of type 2 diabetes. Int J Obes. 2005;39(10):1531–8. https://doi.org/10.1038/ijo.2015.92.

    Article  CAS  Google Scholar 

  36. Shankar K, Vaidya VS, Apte UM, Manautou JE, Ronis MJ, Bucci TJ, Mehendale HM. Type 1 diabetic mice are protected from acetaminophen hepatotoxicity. Toxicol Sci. 2003;73(2):220–34. https://doi.org/10.1093/toxsci/kfg059.

    Article  CAS  PubMed  Google Scholar 

  37. Kanikarla-Marie P, Jain SK. Hyperketonemia and ketosis increase the risk of complications in type 1 diabetes. Free Radic Biol Med. 2016;95:268–77.

    Article  CAS  Google Scholar 

  38. Barnett C, Petrides L, Wilson J, Flatt P, Ioannides C. Induction of rat hepatic mixed-function oxidases by acetone and other physiological ketones: their role in diabetes-induced changes in cytochrome P450 proteins. Xenobiotica. 1992;22(12):1441–50.

    Article  CAS  Google Scholar 

  39. Lieber CS. Cyp2e1: from ash to nash. Hepatol Res. 2004;28(1):1–11.

    Article  CAS  Google Scholar 

  40. Park SY, Kim CH, Lee JY, Jeon JS, Kim MJ, Chae SH, Kim HC, Oh SJ, Kim SK. Hepatic expression of cytochrome P450 in Zucker diabetic fatty rats. Food Chem Toxicol. 2016;96:244–53. https://doi.org/10.1016/j.fct.2016.08.010.

    Article  CAS  PubMed  Google Scholar 

  41. Woodcroft KJ, Hafner MS, Novak RF. Insulin signaling in the transcriptional and posttranscriptional regulation of CYP2E1 expression. Hepatology. 2002;35(2):263–73. https://doi.org/10.1053/jhep.2002.30691.

    Article  CAS  PubMed  Google Scholar 

  42. Shimojo N, Ishizaki T, Imaoka S, Funae Y, Fujii S, Okuda K. Changes in amounts of cytochrome P450 isozymes and levels of catalytic activities in hepatic and renal microsomes of rats with streptozocin-induced diabetes. Biochem Pharmacol. 1993;46(4):621–7.

    Article  CAS  Google Scholar 

  43. Yamazoe Y, Murayama N, Shimada M, Yamauchi K, Kato R. Cytochrome P450 in livers of diabetic rats: regulation by growth hormone and insulin. Arch Biochem Biophys. 1989;268(2):567–75.

    Article  CAS  Google Scholar 

  44. Bukan N, Sancak B, Yavuz Ö, Koca C, Tutkun F, Özçelikay AT, Altan N. Lipid peroxidation and scavenging enzyme levels in the liver of streptozotocin-induced diabetic rats. Indian J Biochem Biophys. 2003;40:447–50.

    CAS  PubMed  Google Scholar 

  45. Mukherjee B, Mukherjee JR, Chatterjee M. Lipid peroxidation, glutathione levels and changes in glutathione-related enzyme activities in streptozotocin-induced diabetic rats. Immunol Cell Biol. 1994;72(2):109–14. https://doi.org/10.1038/icb.1994.17.

    Article  CAS  PubMed  Google Scholar 

  46. Niki E. Lipid peroxidation: physiological levels and dual biological effects. Free Radic Biol Med. 2009;47(5):469–84.

    Article  CAS  Google Scholar 

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Author notes

  1. Benay Can Eke

    Present address: Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Ankara University, Yenimahalle, Ankara, 06560, Turkey

Authors and Affiliations

  1. Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Ankara University, Yenimahalle, Ankara, 06560, Turkey

    Gökçe Kuzgun & Rahman Başaran

  2. Department of Pharmacology, Faculty of Pharmacy, Ankara University, Yenimahalle, Ankara, 06560, Turkey

    Ebru Arıoğlu İnan

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  1. Gökçe Kuzgun
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  2. Rahman Başaran
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  3. Ebru Arıoğlu İnan
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  4. Benay Can Eke
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Contributions

G.K., R.B., and B.C.E. contributed to the concept, design, and analysis of data. E.A.I. has carried out all injections. G.K. and R.B. performed the experimental works. G.K., R.B., and B.C.E. participated in drafting the article.

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Correspondence to Benay Can Eke.

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Ethical statement

All procedures used in this study was approved by the Ankara University Local Ethics Committee for Animal Experiments (2010-56-283).

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Kuzgun, G., Başaran, R., Arıoğlu İnan, E. et al. Effects of insulin treatment on hepatic CYP1A1 and CYP2E1 activities and lipid peroxidation levels in streptozotocin-induced diabetic rats. J Diabetes Metab Disord 19, 1157–1164 (2020). https://doi.org/10.1007/s40200-020-00616-y

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