Mechanism & inhibition kinetics of bioassay-guided fractions of Indian medicinal plants and foods as ACE inhibitors

10.1016/j.jtcme.2018.02.001

Mohammad Yaseen Khan；Vimal Kumar

Angiotensin converting enzyme ； Lineweaver-burk plots ； Enzyme kinetics ； Mode of inhibition

Journal of Traditional and Complementary Medicine

9卷1期（2019 / 01 / 01）

73 - 84

英文

Hypertension is a becoming a major threat to the world. Angiotensin converting enzyme (ACE) is a key part in the renin angiotensin aldosterone system (RAAS) which control blood pressure. Over expression of RAAS is related with vascular hypertension, ACE inhibition has turned into a noteworthy target for controlling hypertension. In the search of lead molecules from plant origin as a substitute for toxic synthetic drugs, 25 Indian medicinal plants and foods were screened for their ACE inhibitory activity. IC_(50) (50% inhibition of ACE) values of hydroalcoholic crude extracts and fraction were determined by a colorimetric method. Active fractions were further screened to determine the enzyme kinetics, mode, specificity and mechanism of inhibition. Standardization was done by determining total phenolics and flavonoids as gallic acid and quercetin equivalents/mg of extract respectively. Among 25 crude extracts, Cynara scolymus extract showed the best activity, IC_(50) value 356.62 mg/mL. ACE inhibition resulting from protein precipitation was highest in Coscinium fenestratum. Lineweaver-Burk plots revealed a competitive mode of inhibition for Punica granatum ethyl acetate fraction. Fractions of Cassia occidentalis, Cynara scolymus and Embelia ribes were found to be non-specific inhibitors of ACE. Embelia ribes, Cassia occidentalis and Coscinium fenestratum fractions inhibited the ACE by Zn^(2+) ion chelation. Research revealed the potential of tested plants fractions as ACE inhibitors along with their inhibition kinetics and mechanism of inhibition. These active plant fractions might find importance in the development of potential antihypertensive agents after further investigations using preclinical and clinical trials.

1. Actis-Goretta, L,Ottaviani, JI,Fraga, CG(2006).Inhibition of angiotensin converting enzyme activity by flavanol-rich foods.J Agric Food Chem,54,229-234.
2. Al, Shukor, N,Van Camp, J,Gonzales, GB(2013).Angiotensin-converting enzyme inhibitory effects by plant phenolic compounds: a study of structure activity relationships.J Agric Food Chem,61,11832-11839.
3. Alderman, CP(1996).Adverse effects of the angiotensin-converting enzyme inhibitors.Ann Pharmacother,30,55-61.
4. Ali, I,Khan, FG,Suri, KA(2010).In vitro antifungal activity of hydroxychavicol isolated from Piper betle L.Ann Clin Microbiol Antimic,9,7.
5. Bachmetov, L,Gal Tanamy, M,Shapira, A(2012).Suppression of hepatitis C virus by the flavonoid quercetin is mediated by inhibition of NS3 protease activity.J Viral Hepat,19,e81-e88.
6. Balasuriya, BN,Rupasinghe, HV(2011).Plant flavonoids as angiotensin converting enzyme inhibitors in regulation of hypertension.Functional Foods in Health and Disease,1,172-188.
7. Brain, KR(1976).Accumulation of L-DOPA in cultures from Mucuna pruriens.Plant Sci Lett,7,157-161.
8. Campbell, DJ(1995).Angiotensin converting enzyme (ACE) inhibitors and kinin metabolism: evidence that ACE inhibitors may inhibit a kininase other than ACE.Clin Exp Pharmacol Physiol,22,903-911.
9. Carmel, A,Yaron, A.(1978).An intramolecularly quenched fluorescent tripeptide as a fluorogenic substrate of angiotensin-I-converting enzyme and of bacterial dipeptidyl carboxypeptidase.Eur J Biochem,87,265-273.
10. Carson, PE(2000).Rationale for the use of combination angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker therapy in heart failure.Am Heart J.,140,361-366.
11. Chang, CC,Yang, MH,Wen, HM,Chern, JC(2002).Estimation of total flavonoid content in propolis by two complementary colorimetric methods.J Food Drug Anal,10,178-182.
12. Chen, CH,Lin, JY,Lin, CN,Hsu, SY(1992).Inhibition of angiotensin-I-converting enzyme by tetrahydroxyxanthones isolated from Tripterospermum lanceolatum.J Nat Prod,55,691-695.
13. Chen, J,Liu, S,Ye, R,Cai, G,Ji, B,Wu, Y(2013).Angiotensin-I converting enzyme (ACE) inhibitory tripeptides from rice protein hydrolysate: purification and characterization.Journal of Functional Foods,5,1684-1692.
14. Cushman, DW,Cheung, HS(1971).Spectrophotometric assay and properties of the angiotensin I-converting enzyme of rabbit lung.Biochem Pharmacol,20,1637-1648.
15. Dewanto, V,Wu, X,Liu, RH(2002).Processed sweet corn has higher antioxidant activity.J Agric Food Chem,50,4959-4964.
16. Dorer, FE,Kahn, JR,Lentz, KE,Levine, M,Skeggs, LT(1974).Hydrolysis of bradykinin by angiotensin-converting enzyme.Circ Res,34,824-827.
17. Dubey, NK,Kumar, R,Tripathi, P(2004).Global promotion of herbal medicine: India's opportunity.Curr Sci,86,37-41.
18. Elbl, G,Wagner, H(1991).A new method for the in vitro screening of inhibitors of angiotensin-converting enzyme (ACE), using the chromophore-and fluo-rophore-labelled substrate, dansyltriglycine.Planta Med,57,137-141.
19. Ercisli, S,Orhan, E(2007).Chemical composition of white (Morus alba), red (Morus rubra) and black (Morus nigra) mulberry fruits.Food Chem,103,1380-1384.
20. Guerrero, L,Castillo, J,Quinones, M(2012).Inhibition of angiotensin-converting ~ enzyme activity by flavonoids: structure-activity relationship studies.PLoS One,7,e49493.
21. Hebert, LA,Falkenhain, ME,Nahman, NS, Jr,Cosio, FG,O'Dorisio, TM(1999).Combination ACE inhibitor and angiotensin II receptor antagonist therapy in diabetic nephropathy.Am J Nephrol,19,1-6.
22. Hemels, ME,Bennett, HA,Bonari, L,Han, D,Traverso, ML,Einarson, TR(2003).HOPE study impact on ACE inhibitors use.Ann Pharmacother,37,640-645.
23. Holmquist, B,Bünning, P,Riordan, JF(1979).A continuous spectrophotometric assay for angiotensin converting enzyme.Anal Biochem,95,540-548.
24. Huggins, CG,Thampi, NS(1968).A simple method for the determination of angiotensin I converting enzyme.Life Sci,7,633-639.
25. Jaspard, E,Wei, L,Alhenc-Gelas, F(1993).Differences in the properties and enzymatic specificities of the two active sites of angiotensin I-converting enzyme (kininase II). Studies with bradykinin and other natural peptides.J Biol Chem,268,9496-9503.
26. Jimsheena, VK,Gowda, LR(2009).Colorimetric, high-throughput assay for screening angiotensin I-converting enzyme inhibitors.Anal Chem,81,9388-9394.
27. Kearney, PM,Whelton, M,Reynolds, K,Muntner, P,Whelton, PK,He, J(2005).Global burden of hypertension: analysis of worldwide data.Lancet,365217-365223.
28. Kim, IS,Yang, M,Lee, OH,Kang, SN(2011).The antioxidant activity and the bioactive compound content of Stevia rebaudiana water extracts.LWT-Food Science and Technology,44,1328-1332.
29. Lacaille-Dubois, MA,Franck, U,Wagner, H(2001).Search for potential angiotensin converting enzyme (ACE)-inhibitors from plants.Phytomedicine,8,47-52.
30. Liu, JC,Hsu, FL,Tsai, JC(2003).Antihypertensive effects of tannins isolated from traditional Chinese herbs as non-specific inhibitors of angiontensin converting enzyme.Life Sci.,73,1543-1555.
31. Liu, P,Kallio, H,Lü, D,Zhou, C,Yang, B(2011).Quantitative analysis of phenolic compounds in Chinese hawthorn (Crataegus spp.) fruits by high performance liquid chromatographyeelectrospray ionisation mass spectrometry.Food Chem,127,1370-1377.
32. Machado, TB,Pinto, AV,Pinto, MC(2003).In vitro activity of Brazilian medicinal plants, naturally occurring naphthoquinones and their analogues, against methicillin-resistant Staphylococcus aureus.Int J Antimicrob Agents,21,279-284.
33. Machado, TD,Leal, IC,Amaral, AC,Santos, K,Silva, MG,Kuster, RM(2002).Antimicrobial ellagitannin of Punica granatum fruits.J Braz Chem Soc,13,606-610.
34. Matthews, BW,Weaver, LH,Kester, WR(1974).The conformation of thermolysin.J Biol Chem,249,8030-8044.
35. Priyanto, AD,Doerksen, RJ,Chang, CI(2015).Screening, discovery, and characterization of angiotensin-I converting enzyme inhibitory peptides derived from proteolytic hydrolysate of bitter melon seed proteins.Journal of proteomics,128,424-435.
36. Rai, RV,Rajesh, PS,Kim, HM(2013).Medicinal use of Coscinium fenestratum (Gaertn.) Colebr.: an short review.Oriental Pharmacy and Experimental Medicine,13,1-9.
37. Segel, IH(1975).Enzyme Kinetics.New York:Wiley.
38. Shlipak, MG,Browner, WS,Noguchi, H,Massie, B,Frances, CD,McClellan, M(2001).Comparison of the effects of angiotensin convertingeenzyme inhibitors and beta blockers on survival in elderly patients with reduced left ventricular function after myocardial infarction.Am J Med.,110,425-433.
39. Somanadhan, B,Varughese, G,Palpu, P(1999).An ethnopharmacological survey for potential angiotensin converting enzyme inhibitors from Indian medicinal plants.J Ethnopharmacol,65,103-112.
40. Stanton, A(2003).Therapeutic potential of renin inhibitors in the management of cardiovascular disorders.Am J Cardiovasc Drugs,3,389-394.
41. Thippeswamy, BS,Mahendran, S,Biradar, MI(2011).Protective effect of embelin against acetic acid induced ulcerative colitis in rats.Eur J Pharmacol,654,100-105.
42. Unger, T,Gohlke, P(1994).Converting enzyme inhibitors in cardiovascular therapy: current status and future potential.Cardiovasc Res,28,146-158.
43. Vasan, RS,Larson, MG,Leip, EP(2001).Impact of high-normal blood pressure on the risk of cardiovascular disease.N Engl J Med.,345,1291-1297.
44. Wagner, H,Elbl, G,Lotter, H,Guinea, M(1991).Evaluation of natural products as inhibitors of angiotension I - converting enzyme (ACE).Pharmacol Lett,1,15-18.
45. Webb, JL(1963).Enzyme and Metabolic Inhibitors.New York, NY, USA:Academic Press.
46. Weir, MR,Dzau, VJ(1999).The renin-angiotensin-aldosterone system: a specific target for hypertension management.Am J Hypertens,12(S9),205S-213S.
47. Wood, RI(1995).Bronchospasm and cough as adverse reactions to the ACE inhibitors captopril, enalapril and lisinopril. A controlled retrospective cohort study.Br J Clin Pharmacol,39,265-270.
48. Wu, J,Aluko, RE,Muir, AD(2002).Improved method for direct high-performance liquid chromatography assay of angiotensin-converting enzyme-catalyzed reactions.J Chromatogr A.,950,125-130.
49. Yadav, JP,Arya, V,Yadav, S,Panghal, M,Kumar, S,Dhankhar, S(2010).Cassia occidentalis L.: a review on its ethnobotany, phytochemical and pharmacological profile.Fitoterapia,81,223-230.
50. Zhu, X,Zhang, H,Lo, R(2004).Phenolic compounds from the leaf extract of artichoke (Cynara scolymus L.) and their antimicrobial activities.J Agric Food Chem,52,7272-7278.