Investigation of the Inhibition Effects of Some Antidepressants on Lactoperoxidase Enzyme

Abstract

Lactoperoxidase (LPO) (E.C.1.11.1.7), which is a component of human and animal milk, is an oxidoreductase that is found in milk, saliva and tears, especially protecting the gut systems and mammary glands of newborns. In this study, Bovine LPO enzyme was purified 447.57 times with 35.24% yield and 31.33 EU / mg protein specific activity using Amberlite CG-50 H + resin and affinity chromatography. Enzyme activity was measured using ABTS as a chromogenic substrate (pH 6.0). After purification the in vitro effects of some antidepressants (Sodium valproate, mirtazapine, risperidone) were investigated on lactoperoxidase. Ki values for these antidepressants were found as 296.4±119.3 µM and 0.90±0.40 µM, respectively. Sodium valproate did not show an inhibition effect on LPO. Risperidone exhibited noncompetitive inhibition, mirtazapine showed competitive inhibition.

Keywords

• Lactoperoxidase
• bovine milk
• antidepressant
• inhibition

References

1. Amornkul Y, Henning DR, 2007. Utilization of microfiltration or lactoperoxidase system or both for manufacture of Cheddar cheese from raw milk. Journal of dairy science, 90-11: 4988-5000.
2. Aune TM, Thomas EL, 1978. Oxidation of protein sulfhydryls by products of peroxidase-catalyzed oxidation of thiocyanate ion. Biochemistry, 17(6): 1005-1010.
3. Beser-Gördeles N, Öz F, 2003. Hastaların Ö. F. K. A. L. AD Düzeyleri, Y. Kalitesi. CÜ Hemşirelik Yüksek Okulu Dergisi, 7.
4. Brunton LL, Lazo JS, Parker KL, 2008. Goldman and Gilman. Nobel Tıp Kitapevleri 2015, Ankara.
5. Cals MM, Maıllıart P, Brıgnon G, Anglade P, Dumas BR, 1991. Primary structure of bovine lactoperoxidase, a fourth member of a mammalian heme peroxidase family. European Journal of Biochemistry, 198(3):733-739.
6. Camadan Y, Özdemir H, Gulcin İ, 2016. Purification and characterization of dihydropyrimidine dehydrogenase enzyme from sheep liver and determination of the effects of some anaesthetic and antidepressant drugs on the enzyme activity. Journal of enzyme inhibition and medicinal chemistry, 31(6): 1335-1341.
7. Elagamy EI, Ruppanner R, Ismail A, Champagne CP, R Assaf, 1996. Purification and characterization of lactoferrin, lactoperoxidase, lysozyme and immunoglobulins from camel's milk. International Dairy Journal, 6(2):129-145.
8. Emrich HM, Dose M, Von Zerssen D, 1985. The use of sodium valproate, carbamazepine and oxcarbazepine in patients with affective disorders. Journal of affective disorders, 8(3):243-250.

9. Expósito IL, Recio I, 2006. Antibacterial activity of peptides and folding variants from milk proteins. International Dairy Journal, 16(11):1294-1305.
10. Fang J, Bourin M, Baker GB, 1999. Metabolism of risperidone to 9-hydroxyrisperidone by human cytochromes P450 2D6 and 3A4. Naunyn-Schmiedeberg's archives of pharmacology, 359(2): 147-151.
11. Fonteh FA, Grandison AS, Lewis MJ, 2002. Variations of lactoperoxidase activity and thiocyanate content in cows' and goats' milk throughout lactation. The Journal of dairy research, 69(3): 401.
12. Gau J, Furtmüller PG, Obinger C, Prévost M, Van Antwerpen P, Arnhold J, Flemmig J, 2016. Flavonoids as promoters of the (pseudo-) halogenating activity of lactoperoxidase and myeloperoxidase. Free Radical Biology and Medicine, 97:307-319.
13. Georgiopoulos AM, Bryan TL, Wollan P, Yawn BP, 2001. Routine screening for postpartum depression. Journal of Family Practice, 50(2):117-117.
14. Grant S, Fitton A, 1994. Risperidone. Drugs, 48(2): 253-273.
15. Gülçin İ, Küfrevioglu ÖI, Oktay M, Büyükokuroglu ME, 2004. Antioxidant, antimicrobial, antiulcer and analgesic activities of nettle (Urtica dioica L.), Journal of Ethnopharmacol, 90(2,3):205–215.
16. Gülseren L, 1999. Doğum Sonrası Depresyon. Türk Psikiyatri Dergisi, 10(1):58-67.
17. Halliwell B, 1984. Oxygen radicals: a commonsense look at their nature and medical importance. Medicine Biology, 62, 71-77.
18. Huystee RV, 1987. Some molecular aspects of plant peroxidase biosynthetic studies. Annual review of plant physiology, 38(1):205-219.
19. İnal S, 2015. Afinite Kromatografisi Tekniği ile Peroksidaz Enziminin Kırmızı Pancardan (Beta Vulgaris) Saflaştırılması ve Karakterizasyonu (Master's thesis).
20. Koksal Z, Alim Z, Beydemir S, Ozdemir H, 2016. Potent inhibitory effects of some phenolic acids on lactoperoxidase. Journal of biochemical and molecular toxicology, 30(11): 533-538.
21. Koksal Z, Gulcin I, Ozdemir H, 2016. An important milk enzyme: lactoperoxidase. In Milk proteins-From structure to biological properties and health aspects. Intech Open, No:7; pp.243-250, Open Access.
22. Köksal Z, Alim Z, 2020. Lactoperoxidase, an antimicrobial enzyme, is inhibited by some indazoles. Drug and chemical toxicology, 43(1):22-26.
23. Köksal Z, Kalin R, Camadan Y, Usanmaz H, Almaz Z, Gülçin I, Ozdemir H, 2017. Secondary sulfonamides as effective lactoperoxidase inhibitors. Molecules, 22(6): 793.
24. Kumar R, Bhatia KL, Dauter Z, Betzel CH, Singh TP, 1995. Purification, crystallization and preliminary X-ray crystallographic analysis of lactoperoxidase from buffalo milk. Acta Crystallographica Section D: Biological Crystallography, 51(6):1094-1096.
25. Kussendrager KD, Van Hooijdonk ACM, 2000. Lactoperoxidase: physico-chemical properties, occurrence, mechanism of action and applications. British Journal of Nutrition, 84(S1):19-25.
26. Madureira AR, Pereira CI, Gomes AM, Pintado ME, Malcata FX, 2007. Bovine whey proteins–Overview on their main biological properties. Food Research International, 40(10): 1197-1211.
27. Murray L, Cooper PJ, 1997. Postpartum depression and child development. Psychological medicine, 27(2):253-260.
28. Oram JD, Reiter B, 1966. The inhibition of streptococci by lactoperoxidase, thiocyanate and hydrogen peroxide. The effect of the inhibitory system on susceptible and resistant strains of group N streptococci. Biochemical Journal, 100(2):373-381.
29. Owen JR, Nemeroff CB, 1998. New antidepressants and the cytochrome P450 system: focus on venlafaxine, nefazodone, and mirtazapine. Depression and anxiety, 7(S1): 24-32.
30. Özcan Bilge, 2014. Investıgatıon Of The Effects Of Some Chemical Substances On Acetylcholınesterase Enzyme Actıvıty Purıfıced From Human Erythroctes, Atatürk Üniversitesi Fen Bilimleri Enstitüsü, Doktora Tezi (Basılmış).
31. Özdemir H, Uğuz MT, 2005. In vitro effects of some anaesthetic drugs on lactoperoxidase enzyme activity. Journal of enzyme inhibition and medicinal chemistry, 20(5): 491-495.
32. Pistovcakova J, Dostálek M, Sulcova A, Jezova D, 2008. Tiagabine treatment is associated with neurochemical, immune and behavioural alterations in the olfactory bulbectomized rat model of depression. Pharmacopsychiatry, 41(02): 54-59.
33. Pütter J, Becker R, 1987. Methods of Enzymatic Analysis: Peroxidases Bergmeyer. Third edition, 286, VCH, New York, USA.
34. Ratner AJ, Prince A, 2000. Lactoperoxidase: new recognition of an “old” enzyme in airway defenses. American Journal of Respiratory Cell and Molecular Biology, 22(6):642-644.
35. Ray S, Stowe ZN, 2014. The use of antidepressant medication in pregnancy. Best Practice & Research: Clinical Obstetrics & Gynaecology, 28(1), 71-83
36. Reiter B, Härnulv G, 1984. Lactoperoxidase antibacterial system: natural occurrence, biological functions and practical applications. Journal of Food Protection, 47(9): 724-732.
37. Sanger TM, Grundy SL, Gibson PJ, Namjoshi MA, Greaney MG, Tohen MF, 2001. Long-term olanzapine therapy in the treatment of bipolar I disorder: an open-label continuation phase study. The Journal of Clinical Psychiatry, 62(4):273-81
38. Shindler JS, Bardsley WG, 1975. Steady-state kinetics of lactoperoxidase with ABTS as chromogen. Biochemical and Biophysical Research Communications, 67(4):1307-1312.
39. Sievers G, 1980. Structure of milk lactoperoxidase. A study using circular dichroism and difference absorption spectroscopy. Biochimica et Biophysica Acta (BBA)-Protein Structure, 624(1):249-259.
40. Stowe ZN, Nemeroff CB, 1997. Depression during pregnancy and the puerperium. Journal of Clinical Psychiatry, 58(15):26-32.
41. Thanabal V, La Mar GN, 1989. A nuclear Overhauser effect investigation of the molecular and electronic structure of the heme crevice in lactoperoxidase. Biochemistry, 28: 7038-7044.
42. Weber MF, Aalberts M, Schukken YH, 2016. An update on milk quality assurance for paratuberculosis in Dutch dairy herds.