Synergic and Additive Effects of the Combined Effect of Tyrosinase Inhibitors

Authors

  • Yuliia Shesterenko O.V. Bogatsky Physico-Chemical Institute, NAS of Ukraine, Ukraine https://orcid.org/0000-0002-1158-1512
  • Iryna Romanovska O.V. Bogatsky Physico-Chemical Institute, NAS of Ukraine, Ukraine https://orcid.org/0000-0002-3326-987X
  • Olexandr Karpenko O.V. Bogatsky Physico-Chemical Institute, NAS of Ukraine, Ukraine
  • Ivan Gaydarzhi Odesа Polytechnic National University, Ukraine

DOI:

https://doi.org/10.20535/ibb.2023.7.3.285689

Keywords:

tyrosinase, tyrosinase inhibutors, 3-(2-hydroxyphenylamino)-1,3-dihydro-indol-2-one, combined usage, synergism, additive action

Abstract

Background. Excessive melanin accumulation in the skin can lead to various diseases and cosmetic issues. While tyrosinase inhibitors are commonly used to reduce pigment biosynthesis, many of them are associated with significant side effects. When multiple drugs are used in combination, it can result in synergism, additive effects, or antagonism. Combining multiple tyrosinase inhibitors is considered a promising approach to minimize side effects and enhance therapeutic efficacy.

Objective. This study aims to investigate the combined use of tyrosinase inhibitors to determine the nature of their interaction, whether it's synergistic or additive.

Methods. We utilized tyrosinase isolated from Agaricus bisporus mushrooms. Enzyme inhibition by test compounds was assessed by measuring tyrosinase activity using tyrosine (30 min in 0.05 M Na-phosphate buffer solution, pH 6.5, 25 °C). To explore joint inhibition, compound solutions were mixed in pairs at various concentrations. The interaction was quantified using the combination index and isobolograms.

Results. To determine the effect of the combined action of agents on tyrosinase activity, we examined standard inhibitors of the enzyme (kojic acid, arbutin, phenylthiourea) and our discovered compound, 3-(2-hydroxyphenylamino)-1,3-dihydro-indol-2-one. Calculations of the combination index and isobolograms for all studied combinations of standard tyrosinase inhibitors revealed additive effects in all studied cases. Simultaneous use of kojic acid or arbutin with 3-(2-hydroxyphenylamino)-1,3-dihydro-indol-2-one demonstrated a synergistic effect. However, the mixture of phenylthiourea with the indole derivative demonstrated an additive effect.

Conclusions. The combined usage of tyrosinase inhibitors in various combinations displayed both additive and synergistic effects. The synergistic effect of using two inhibitors simultaneously presents significant opportunities for the development of more effective and cost-efficient treatments for hyperpigmentation by reducing the concentration of each inhibitor.

References

Brenner M, Hearing VJ. The protective role of melanin against UV damage in human skin. Photochem Photobiol. 2008;84(3):539-49. DOI: 10.1111/j.1751-1097.2007.00226.x

Nautiyal A, Wairkar S. Management of hyperpigmentation: Current treatments and emerging therapies. Pigment Cell Melanoma Res. 2021;34(6):1000-14. DOI: 10.1111/pcmr.12986

Kutlubay Z, Cesur SK, Aşkın Ö, Tüzün Y. The color of skin: brown diseases of the skin, nails, and mucosa. Clin Dermatol. 2019;37(5):487-506. DOI: 10.1016/j.clindermatol.2019.07.007

El-Nashar HAS, El-Din MIG, Hritcu L, Eldahshan OA. Insights on the Inhibitory Power of Flavonoids on Tyrosinase Activity: A Survey from 2016 to 2021. Molecules (Basel, Switzerland). 2021;26(24):7546. DOI: 10.3390/molecules26247546

Jakimiuk K, Sari S, Milewski R, Supuran CT, Şöhretoğlu D, Tomczyk M. Flavonoids as tyrosinase inhibitors in in silico and in vitro models: basic framework of SAR using a statistical modeling approach. J Enzyme Inhib Med Chem. 2022;37(1):421-30. DOI: 10.1080/14756366.2021.2014832

Li J, Feng L, Liu L, Wang F, Ouyang L, Zhang L, et al. Recent advances in the design and discovery of synthetic tyrosinase inhibitors. Eur J Med Chem. 2021;224:113744. DOI: 10.1016/j.ejmech.2021.113744

Zolghadri S, Beygi M, Mohammad TF, Alijanianzadeh M, Pillaiyar T, Garcia-Molina P, et al. Targeting tyrosinase in hyperpigmentation: Current status, limitations, and future promises. Biochem Pharmacol. 2023;212:115574. DOI: 10.1016/j.bcp.2023.115574

Nanok K, Sansenya S. Combination effects of rice extract and five aromatic compounds against α-glucosidase, α-amylase, and tyrosinase. J Biosci Biotechnol Eng. 2021;132(1):9-17. DOI: 10.1016/j.jbiosc.2021.02.003

Hseu YC, Cheng KC, Lin YC, Chen CY, Chou HY, Ma DL, et al. Synergistic effects of linderanolide B combined with arbutin, PTU or kojic acid on tyrosinase inhibition. Curr Pharm Biotechnol. 2015;16(12):1120-6. DOI: 10.2174/1389201016666150907112819

Jin YH, Lee SJ, Chung MH, Park JH, Park YI, Cho TH, et al. Aloesin and arbutin inhibit tyrosinase activity in a synergistic manner via a different action mechanism. Arch Pharmacal Res. 1999;22(3):232-6. DOI: 10.1007/bf02976355

Chen X, Haniu A, Kashiwagi T, Watanabe H, Watanabe T, Okamoto Y, et al. The evaluation of the synergistic effect of 3-(2,4-dihydroxyphenyl)propionic acid and l-ascorbic acid on tyrosinase inhibition. Z Naturforsch C J Biosci. 2017;72(3-4):119-21. DOI: 10.1515/znc-2016-0095

Wang Y, Hao M-M, Sun Y, Wang LF, Wang H, Zhang Y-J, et al. Synergistic promotion on tyrosinase inhibition by antioxidants. Molecules (Basel, Switzerland). 2018;23(1):106. DOI: 10.3390/molecules23010106

You Z, Li Y, Chen M, Wong VKW, Zhang K, Zheng X, et al. Inhibition of plant essential oils and their interaction in binary combinations against tyrosinase. Food Nutr Res. 2022;66. DOI: 10.29219/fnr.v66.8466

Romanovska II, Shesterenko YA, Sevast'yanov OV, Osetrov VE, Pashkin II. Phenol removal by tyrosinase, immobilized in modified poly-N-vinylpyrrolidone, with inorganic coagulants application. Int Rev Biophys Chem. 2011;2(2):54-60.

Hartree EF. Determination of protein: a modification of the Lowry method that gives a linear photometric response. Anal Biochem. 1972;48(2):422-7. DOI: 10.1016/0003-2697(72)90094-2

Stark GR, Dawson CR. Spectrophotometric microdetermination of copper in copper oxidases using oxalyldihydrazide. Anal Chem. 1958;30(2):191-4. DOI: 10.1021/ac60134a009

Ikehata K, Nicell JA. Color and toxicity removal following tyrosinase-catalyzed oxidation of phenols. Biotechnol Prog. 2000;16(4):533-40. DOI: 10.1021/bp0000510

Yu L. Inhibitory effects of (S)- and (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acids on tyrosinase activity. J Agric Food Chem. 2003;51(8):2344-7. DOI: 10.1021/jf0208379

Shi Y, Chen Q-X, Wang Q, Song K-K, Qiu L. Inhibitory effects of cinnamic acid and its derivatives on the diphenolase activity of mushroom (Agaricus bisporus) tyrosinase. Food Chem. 2005;92(4):707-12. DOI: 10.1016/j.foodchem.2004.08.031

Shesterenko YA, Romanovska II, Sevastyanov OV, Karpenko AS. Benzylidenanilines and related compounds as tyrosinase inhibitors. Odesa Natl Univ Herald Chem. 2018;23(4):56-63. DOI: 10.18524/2304-0947.2018.4(68).147821

Zolghadri S, Bahrami A, Hassan Khan MT, Munoz-Munoz J, Garcia-Molina F, Garcia-Canovas F, et al. A comprehensive review on tyrosinase inhibitors. J Enzyme Inhib Med Chem. 2019;34(1):279-309. DOI: 10.1080/14756366.2018.1545767

Wibowo JP, Batista FA, van Oosterwijk N, Groves MR, Dekker FJ, Quax WJ. A novel mechanism of inhibition by phenylthiourea on PvdP, a tyrosinase synthesizing pyoverdine of Pseudomonas aeruginosa. Int J Biol Macromol. 2020;146:212-21. DOI: 10.1016/j.ijbiomac.2019.12.252

Wang W, Gao Y, Wang W, Zhang J, Yin J, Le T, et al. Kojic acid showed consistent inhibitory activity on tyrosinase from mushroom and in cultured B16F10 cells compared with arbutins. Antioxidants (Basel). 2022 Mar 4;11(3):502. DOI: 10.3390/antiox11030502

Mermer A, Demirci S. Recent advances in triazoles as tyrosinase inhibitors. Eur J Med Chem. 2023;259:115655. DOI: 10.1016/j.ejmech.2023.115655

Feng D, Fang Z, Zhang P. The melanin inhibitory effect of plants and phytochemicals: A systematic review. Phytomedicine. 2022;107:154449. DOI: 10.1016/j.phymed.2022.154449

He M, Fan M, Yang W, Peng Z, Wang G. Novel kojic acid-1,2,4-triazine hybrids as anti-tyrosinase agents: Synthesis, biological evaluation, mode of action, and anti-browning studies. Food Chem. 2023;419:136047. DOI: 10.1016/j.foodchem.2023.136047

Oyama T, Yoshimori A, Ogawa H, Shirai Y, Abe H, Kamiya T, et al. The structural differences between mushroom and human tyrosinase cleared by investigating the inhibitory activities of stilbenes. J Mol Struct. 2023;1272:134180. DOI: 10.1016/j.molstruc.2022.134180

Masyita A, Salim E, Asri RM, Nainu F, Hori A, Yulianty R, et al. Molecular modeling and phenoloxidase inhibitory activity of arbutin and arbutin undecylenic acid ester. Biochem Biophys Res Commun. 2021;547:75-81. DOI: 10.1016/j.bbrc.2021.02.006

Ramsden CA, Riley PA. Mechanistic aspects of the tyrosinase oxidation of hydroquinone. Bioorg Med Chem Lett. 2014;24(11):2463-4. DOI: 10.1016/j.bmcl.2014.04.009

Nazir Y, Saeed A, Rafiq M, Afzal S, Ali A, Latif M, et al. Hydroxyl substituted benzoic acid/cinnamic acid derivatives: Tyrosinase inhibitory kinetics, anti-melanogenic activity, and molecular docking studies. Bioorg Med Chem Lett. 2020;30(1):126722. DOI: 10.1016/j.bmcl.2019.126722

Kurt BZ, Altundağ Ö, Gökçe M, Cakmak U, Tuncay FO, Kolcuoğlu Y, et al. Synthesis of naproxen thiadiazole urea hybrids and determination of their anti-melanoma, anti-migration, tyrosinase inhibitory activity, and molecular docking studies. J Mol Struct. 2024;1295:136618. DOI: 10.1016/j.molstruc.2023.136618

Zhao Y, Zhang T, Ning Y, Wang D, Li F, Fan Y, et al. Identification and molecular mechanism of novel tyrosinase inhibitory peptides from the hydrolysate of 'Fengdan' peony (Paeonia ostii) seed meal proteins: Peptidomics and in silico analysis. LWT. 2023;180:114695. DOI: 10.1016/j.lwt.2023.114695

Wang H, Zhang H, Zhang X, Yin Y, Ding G, Tang X, et al. Identification of coniferyl ferulate as the bioactive compound behind the xanthine oxidase inhibitory activity of Chuanxiong Rhizome. J Funct Foods. 2023;100:105378. DOI: 10.1016/j.jff.2022.105378

Wang Y, Chen L, Liu H, Xie J, Yin W, Xu Z, et al. Characterization of the synergistic inhibitory effect of cyanidin-3-O-glucoside and catechin on pancreatic lipase. Food Chem. 2023;404(Pt b):134672. DOI: 10.1016/j.foodchem.2022.134672

Yin Y, Sun S, Wang H, Guo M, Li Z, Lv C, et al. Mechanism of interaction between urolithin A and α-glucosidase: Analysis by inhibition kinetics, fluorescence spectroscopy, isothermal titration calorimetry, and molecular docking. J Mol Struct. 2023;1286:135567. DOI: 10.1016/j.molstruc.2023.135567

Ryazanova AD, Alekseev AA, Slepneva IA. The phenylthiourea is a competitive inhibitor of the enzymatic oxidation of DOPA by phenoloxidase. J Enzyme Inhib Med Chem. 2012 Feb;27(1):78-83. DOI: 10.3109/14756366.2011.576010

Chandorkar N, Tambe S, Amin P, Madankar C. Alpha arbutin as a skin lightening agent: a review. Int J Pharmaceut Res. 2021;13(2):3502-10. DOI: 10.31838/ijpr/2021.13.02.446

Published

2023-10-29

How to Cite

1.
Shesterenko Y, Romanovska I, Karpenko O, Gaydarzhi I. Synergic and Additive Effects of the Combined Effect of Tyrosinase Inhibitors. Innov Biosyst Bioeng [Internet]. 2023Oct.29 [cited 2024Dec.13];7(3):55-64. Available from: https://ibb.kpi.ua/article/view/285689

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