An Initial Investigation of the Potential of Robusta Coffee, Arabica Coffee, and Caffeine in Asthma Treatment through the Evaluation of 5-Lipoxygenase Inhibition Activity
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Submitted
19 December 2022
19 December 2022
Published
29 February 2024
29 February 2024
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Abstract
Numerous studies have documented the potential of coffee to aid in asthma prevention. Nevertheless, research into how coffee influences asthma management has not been available. One known mechanism by which asthma medications work involves inhibiting 5-lipoxygenase (5-LOX) activity. This study aims to determine the potency of Coffea canephora var. Robusta extract (CRE), Coffea arabica extract (CAE), and caffeine are the primary isolates against 5-LOX activity. Extraction was performed by a reflux procedure using 96% ethanol with a sample-total solvent ratio of 1 : 10, an extraction time of 1 hour, and the extraction was conducted in triplicate. Fractionation was carried out by liquid-liquid partition using a chloroform-water system. Caffeine further purification was performed by the sublimation method, and the inhibition of 5-LOX activity was evaluated using the spectrophotometric method at λ = 234 nm. Apigenin was used as a positive control. From the experiment conducted, the IC50 of the CRE, CAE, caffeine, and apigenin against 5-LOX was 32.2 ± 1.4, 42.1 ± 2.3, 14.3 ± 1.6, and 7.4 ± 1.7 µg/mL, respectively. Continued efforts to isolate bioactive compounds from coffee extract led to the discovery of caffeine, which exhibited a more potent inhibitory effect on 5-LOX. The inhibition of 5-LOX activity by caffeine occurs in a non-competitive manner.
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References
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15. Freedman ND, Park Y, Abnet CC, Hollenbeck AR, Sinha R. Association of coffee drinking with total and cause-specific mortality. N Engl J Med. 2012;366(20):1891–904. DOI: 10.1056/nejmoa1112010; PMCID: PMC3439152; PMID: 22591295
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18. Jung S, Kim MH, Park JH, Jeong Y, Ko KS. Cellular Antioxidant and Anti-Inflammatory Effects of Coffee Extracts with Different Roasting Levels. J Med Food. 2017;20(6):626–35. DOI: 10.1089/jmf.2017.3935; PMID: 28581877
19. Ikan R. Natural Products: A Laboratory Guide. Cambridge (US): Academic Press; 1991.
20. Irfanah L, Yuwono M, Primaharinastiti R. Optimization and Prevalidation of TLC-Densitometry Method for Fucoidan Analysis in Sargassum sp. Aqueous Extract. J Farmasi Ilmu Kefarmasian Indones. 2023;10(2):210-6. DOI: 10.20473/jfiki.v10i22023.210-216
21. Young JCOC. True Melting Point Determination. Chem Educator. 2013;18:203-8. DOI: 10.1333/s00897132500a
22. Subardini DS, Elya B, Noviani A. Lipoxygenase inhibitory assay of ethyl acetate fraction from star fruit leaves (Averrhoa Carambola L.) from three regions in West Java. Int J Appl Pharm. 2020;12(Special 1):119-21. DOI: 10.22159/ijap.2020.v12s1.FF025
23. Nabilah, Elya B, Djajadisastra J. Lipoxygenase inhibitory assay of Averrhoa carambola L. Leaves extract. Int J ChemTech Res. 2017;10(1):342–7.
24. Alaba CSM, Chichioco-Hernandez CL. 15-Lipoxygenase inhibition of Commelina benghalensis, Tradescantia fluminensis, Tradescantia zebrina. Asian Pac J Trop Biomed. 2014;4(3):184–8. DOI: 10.1016/s2221-1691(14)60229-x; PMCID: PMC3868787; PMID: 25182435
25. Patay ÉB, Bencsik T, Papp N. Phytochemical overview and medicinal importance of Coffea species from the past until now. Asian Pac J Trop Med. 2016;9(12):1127–35. DOI: 10.1016/j.apjtm.2016.11.008; PMID: 27955739
26. Monteiro JP, Alves MG, Oliveira PF, Silva BM. Structure-Bioactivity Relationships of Methylxanthines: Trying to Make Sense of All the Promises and the Drawbacks. Molecules. 2016;21(8):974. DOI: 10.3390/molecules21080974; PMCID: PMC6273298; PMID: 27472311
27. Park JB, Peters R, Novotny JA. Impact of roasting on javamide-I/-II in Arabica and Robusta coffee beans. Food Chem. 2023;412:135586. DOI: 10.1016/j.foodchem.2023.135586; PMID: 36739725
28. Ky CL, Louarn J, Dussert S, Guyot B, Hamon S, Noirot M. Caffeine, trigonelline, chlorogenic acids and sucrose diversity in wild Coffea arabica L. and C. canephora P. accessions. Food Chem. 2001;75(2):223–30. DOI: 10.1016/s0308-8146(01)00204-7
29. Gawlik-Dziki U, Świeca M, Dziki D, Kowalska I, Pecio Ł, Durak A, et al. Lipoxygenase inhibitors and antioxidants from green coffee—mechanism of action in the light of potential bioaccessibility. Food Res Int. 2014;61:48–55. DOI: 10.1016/j.foodres.2014.05.002
30. Tomy MJ, Dileep K V, Prasanth S, Preethidan DS, Sabu A, Sadasivan C, et al. Cuminaldehyde as a lipoxygenase inhibitor: in vitro and in silico validation. Appl Biochem Biotechnol. 2014;174(1):388–97. DOI: 10.1007/s12010-014-1066-0; PMID: 25080377
31. Purkiewicz A, Pietrzak-Fiećko R, Sörgel F, Kinzig M. Caffeine, Paraxanthine, Theophylline, and Theobromine Content in Human Milk. Nutrients. 2022;14(11):2196. DOI: 10.3390/nu14112196; PMCID: PMC9182860; PMID: 35683994
32. Oñatibia-Astibia A, Martínez-Pinilla E, Franco R. The potential of methylxanthine-based therapies in pediatric respiratory tract diseases. Respir Med. 2016;112:1–9. DOI: 10.1016/j.rmed.2016.01.022; PMID: 26880379
33. Kitzberger CSG, Scholz MB dos S, Benassi M de T. Bioactive compounds content in roasted coffee from traditional and modern Coffea arabica cultivars grown under the same edapho-climatic conditions. Food Res Int. 2014;61:61–6. DOI: 10.1016/j.foodres.2014.04.031
34. Carter GW, Young PR, Albert DH, Bouska J, Dyer R, Bell RL, et al. 5-lipoxygenase inhibitory activity of zileuton. J Pharmacol Exp Ther. 1991;256(3):929–37. PMID: 1848634
35. Picone S, Bedetta M, Paolillo P. Caffeine citrate: when and for how long. A literature review. J Matern Fetal Neonatal Med. 2012;25(Suppl 3):11–4. DOI: 10.3109/14767058.2012.712305; PMID: 23016611
36. Aranda JV, Turmen T. Methylxanthines in apnea of prematurity. Clin Perinatol. 1979;6(1):87–108. PMID: 383366
37. Mukhtar I, Iftikhar A, Imran M, Ijaz MU, Irfan S, Anwar H. The Competitive Absorption by the Gut Microbiome Suggests the First-Order Absorption Kinetics of Caffeine. Dose Response. 2021;19(3):15593258211033111. DOI: 10.1177/15593258211033111; PMCID: PMC8375357; PMID: 34421438
38. Lu W, Zhao X, Xu Z, Dong N, Zou S, Shen X, et al. Development of a new colorimetric assay for lipoxygenase activity. Anal Biochem. 2013;441(2):162–8. DOI: 10.1016/j.ab.2013.06.007; PMID: 23811155
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2. Habib N, Pasha MA, Tang DD. Current Understanding of Asthma Pathogenesis and Biomarkers. Cells. 2022;11(17):2764. DOI: 10.3390/cells11172764; PMCID: PMC9454904; PMID: 36078171
3. Ayola-Serrano NC, Roy N, Fathah Z, Anwar MM, Singh B, Ammar N, et al. The role of 5-lipoxygenase in the pathophysiology of COVID-19 and its therapeutic implications. Inflamm Res. 2021;70(8):877-89. DOI: 10.1007/s00011-021-01473-y; PMCID: PMC8176665; PMID: 34086061
4. Sinha S, Doble M, Manju SL. 5-Lipoxygenase as a drug target: A review on trends in inhibitors structural design, SAR and mechanism based approach. Bioorg Med Chem. 2019;27(17):3745-59. DOI: 10.1016/j.bmc.2019.06.040; PMID: 31331653
5. Mashima R, Okuyama T. The role of lipoxygenases in pathophysiology; new insights and future perspectives. Redox Biol. 2015;6:297–310. DOI: 10.1016/j.redox.2015.08.006; PMCID: PMC4556770; PMID: 26298204
6. Giménez-Bastida JA, González-Sarrías A, Laparra-Llopis JM, Schneider C, Espín JC. Targeting Mammalian 5-Lipoxygenase by Dietary Phenolics as an Anti-Inflammatory Mechanism: A Systematic Review. Int J Mol Sci. 2021;22(15):7937. DOI: 10.3390/ijms22157937; PMCID: PMC8348464; PMID: 34360703
7. Wisastra R, Dekker FJ. Inflammation, Cancer and Oxidative Lipoxygenase Activity are Intimately Linked. Cancers. 2014;6(3):1500-21. DOI: 10.3390/cancers6031500; PMCID: PMC4190552; PMID: 25037020
8. Duroudier NP, Tulah AS, Sayers I. Leukotriene pathway genetics and pharmacogenetics in allergy. Allergy. 2009;64(6):823–39. DOI: 10.1111/j.1398-9995.2009.02015.x; PMID: 19416143
9. Poeckel D, Funk CD. The 5-lipoxygenase/leukotriene pathway in preclinical models of cardiovascular disease. Cardiovasc Res. 2010;86(2):243–53. DOI: 10.1093/cvr/cvq016; PMID: 20093252
10. Rossi A, Pergola C, Koerberle A, Hoffmann M, Dehm F, Bramanti P, et al. The 5-lipoxygenase inhibitor, zileuton, suppresses prostaglandin biosynthesis by inhibition of arachidonic acid release in macrophages. Br J Pharmacol. 2010;161(3):555-70. DOI: 10.1111/j.1476-5381.2010.00930.x; PMCID: PMC2990155; PMID: 20880396
11. Sharanya CS, Abhithaj J, Arun KG, Eeda KR, Bhat V, Variyar EJ, et al. Lipoxygenase inhibitory synthetic derivatives of methyl gallate regulate gene expressions of COX-2 and cytokines to reduce animal model arthritis. Sci Rep. 2023;13(1):10644. DOI: 10.1038/s41598-023-37613-z; PMCID: PMC10313808; PMID: 37391468
12. Schneider I, Bucar F. Lipoxygenase inhibitors from natural plant sources. Part 1: Medicinal plants with inhibitory activity on arachidonate 5-lipoxygenase and 5-lipoxygenase[sol ]cyclooxygenase. Phytother Res. 2005;19(2):81–102. DOI: 10.1002/ptr.1603; PMID: 15852496
13. Perrois C, Strickler SR, Mathieu G, Lepelley M, Bedon L, Michaux S, et al. Differential regulation of caffeine metabolism in Coffeaarabica (Arabica) and Coffea canephora (Robusta). Planta. 2015;241(1):179–91. DOI: 10.1007/s00425-014-2170-7; PMCID: PMC4282694; PMID: 25249475
14. Bresciani L, Calani L, Bruni R, Brighenti F, Rio DD. Phenolic composition, caffeine content and antioxidant capacity of coffee silverskin. Food Res Int. 2014;61:196–201. DOI: 10.1016/j.foodres.2013.10.047
15. Freedman ND, Park Y, Abnet CC, Hollenbeck AR, Sinha R. Association of coffee drinking with total and cause-specific mortality. N Engl J Med. 2012;366(20):1891–904. DOI: 10.1056/nejmoa1112010; PMCID: PMC3439152; PMID: 22591295
16. Złotek U, Karaś M, Gawlik-Dziki U, Szymanowska U, Baraniak B, Jakubczyk A. Antioxidant activity of the aqueous and methanolic extracts of coffee beans (Coffea arabica L.). Acta Sci Pol Technol Aliment. 2016;15(3):281–8. DOI: 10.17306/j.afs.2016.3.27; PMID: 28071027
17. Welsh EJ, Bara A, Barley E, Cates CJ. Caffeine for asthma. Cochrane Database Syst Rev. 2010;2010(1):CD001112. DOI: 10.1002/14651858.cd001112.pub2; PMCID: PMC7053252; PMID: 20091514
18. Jung S, Kim MH, Park JH, Jeong Y, Ko KS. Cellular Antioxidant and Anti-Inflammatory Effects of Coffee Extracts with Different Roasting Levels. J Med Food. 2017;20(6):626–35. DOI: 10.1089/jmf.2017.3935; PMID: 28581877
19. Ikan R. Natural Products: A Laboratory Guide. Cambridge (US): Academic Press; 1991.
20. Irfanah L, Yuwono M, Primaharinastiti R. Optimization and Prevalidation of TLC-Densitometry Method for Fucoidan Analysis in Sargassum sp. Aqueous Extract. J Farmasi Ilmu Kefarmasian Indones. 2023;10(2):210-6. DOI: 10.20473/jfiki.v10i22023.210-216
21. Young JCOC. True Melting Point Determination. Chem Educator. 2013;18:203-8. DOI: 10.1333/s00897132500a
22. Subardini DS, Elya B, Noviani A. Lipoxygenase inhibitory assay of ethyl acetate fraction from star fruit leaves (Averrhoa Carambola L.) from three regions in West Java. Int J Appl Pharm. 2020;12(Special 1):119-21. DOI: 10.22159/ijap.2020.v12s1.FF025
23. Nabilah, Elya B, Djajadisastra J. Lipoxygenase inhibitory assay of Averrhoa carambola L. Leaves extract. Int J ChemTech Res. 2017;10(1):342–7.
24. Alaba CSM, Chichioco-Hernandez CL. 15-Lipoxygenase inhibition of Commelina benghalensis, Tradescantia fluminensis, Tradescantia zebrina. Asian Pac J Trop Biomed. 2014;4(3):184–8. DOI: 10.1016/s2221-1691(14)60229-x; PMCID: PMC3868787; PMID: 25182435
25. Patay ÉB, Bencsik T, Papp N. Phytochemical overview and medicinal importance of Coffea species from the past until now. Asian Pac J Trop Med. 2016;9(12):1127–35. DOI: 10.1016/j.apjtm.2016.11.008; PMID: 27955739
26. Monteiro JP, Alves MG, Oliveira PF, Silva BM. Structure-Bioactivity Relationships of Methylxanthines: Trying to Make Sense of All the Promises and the Drawbacks. Molecules. 2016;21(8):974. DOI: 10.3390/molecules21080974; PMCID: PMC6273298; PMID: 27472311
27. Park JB, Peters R, Novotny JA. Impact of roasting on javamide-I/-II in Arabica and Robusta coffee beans. Food Chem. 2023;412:135586. DOI: 10.1016/j.foodchem.2023.135586; PMID: 36739725
28. Ky CL, Louarn J, Dussert S, Guyot B, Hamon S, Noirot M. Caffeine, trigonelline, chlorogenic acids and sucrose diversity in wild Coffea arabica L. and C. canephora P. accessions. Food Chem. 2001;75(2):223–30. DOI: 10.1016/s0308-8146(01)00204-7
29. Gawlik-Dziki U, Świeca M, Dziki D, Kowalska I, Pecio Ł, Durak A, et al. Lipoxygenase inhibitors and antioxidants from green coffee—mechanism of action in the light of potential bioaccessibility. Food Res Int. 2014;61:48–55. DOI: 10.1016/j.foodres.2014.05.002
30. Tomy MJ, Dileep K V, Prasanth S, Preethidan DS, Sabu A, Sadasivan C, et al. Cuminaldehyde as a lipoxygenase inhibitor: in vitro and in silico validation. Appl Biochem Biotechnol. 2014;174(1):388–97. DOI: 10.1007/s12010-014-1066-0; PMID: 25080377
31. Purkiewicz A, Pietrzak-Fiećko R, Sörgel F, Kinzig M. Caffeine, Paraxanthine, Theophylline, and Theobromine Content in Human Milk. Nutrients. 2022;14(11):2196. DOI: 10.3390/nu14112196; PMCID: PMC9182860; PMID: 35683994
32. Oñatibia-Astibia A, Martínez-Pinilla E, Franco R. The potential of methylxanthine-based therapies in pediatric respiratory tract diseases. Respir Med. 2016;112:1–9. DOI: 10.1016/j.rmed.2016.01.022; PMID: 26880379
33. Kitzberger CSG, Scholz MB dos S, Benassi M de T. Bioactive compounds content in roasted coffee from traditional and modern Coffea arabica cultivars grown under the same edapho-climatic conditions. Food Res Int. 2014;61:61–6. DOI: 10.1016/j.foodres.2014.04.031
34. Carter GW, Young PR, Albert DH, Bouska J, Dyer R, Bell RL, et al. 5-lipoxygenase inhibitory activity of zileuton. J Pharmacol Exp Ther. 1991;256(3):929–37. PMID: 1848634
35. Picone S, Bedetta M, Paolillo P. Caffeine citrate: when and for how long. A literature review. J Matern Fetal Neonatal Med. 2012;25(Suppl 3):11–4. DOI: 10.3109/14767058.2012.712305; PMID: 23016611
36. Aranda JV, Turmen T. Methylxanthines in apnea of prematurity. Clin Perinatol. 1979;6(1):87–108. PMID: 383366
37. Mukhtar I, Iftikhar A, Imran M, Ijaz MU, Irfan S, Anwar H. The Competitive Absorption by the Gut Microbiome Suggests the First-Order Absorption Kinetics of Caffeine. Dose Response. 2021;19(3):15593258211033111. DOI: 10.1177/15593258211033111; PMCID: PMC8375357; PMID: 34421438
38. Lu W, Zhao X, Xu Z, Dong N, Zou S, Shen X, et al. Development of a new colorimetric assay for lipoxygenase activity. Anal Biochem. 2013;441(2):162–8. DOI: 10.1016/j.ab.2013.06.007; PMID: 23811155
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Yuniarta TA, Handayani R. An Initial Investigation of the Potential of Robusta Coffee, Arabica Coffee, and Caffeine in Asthma Treatment through the Evaluation of 5-Lipoxygenase Inhibition Activity. Borneo J Pharm [Internet]. 2024Feb.29 [cited 2025Mar.28];7(1):80-8. Available from: https://journal.umpr.ac.id/index.php/bjop/article/view/4448
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