Toxicology of a Peruvian botanical remedy to support healthy liver function

Journal of Complementary and Integrative Medicine

Volume 13, Issue 2, 1 June 2016, Pages 163-173

  (Article)

Semple, H.A.^a, 

Sloley, B.D.^b, 

Cabanillas, J.^c, 

Chiu, A.^e, 

Aung, S.K.H.^f, 

Green, F.H.Y.^d 

 

^a  Alberta Innovates-Technology Futures, Vegreville, AB, Canada
^b  Phytovox Inc., Edmonton, AB, 

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Abstract

Background: The purpose of these studies was to determine the safety of a botanical treatment for supporting healthy liver function developed in Peru. The formulation, A4⁺, contains extracts of Curcuma longa L. rhizome (A4R), Cordia lutea Lam. flower (A4F) and Annona muricata L. leaf (A4L). The tests were used to support an application for a non-traditional Natural Health Product Licence from the Natural Health Product Directorate of Health Canada and future clinical trials. Methods: Besides reviewing the scientific and clinical information from Peru on the ingredients and conducting an initial Ames test for mutagenicity, we analysed A4⁺ for its chemical profile and tested genotoxicity (micronucleus test) and general toxicity (28-day repeated dose). Results: A4⁺ and extracts from the three plants provided distinctive chemical fingerprints. A4L contained acetogenins, requiring a second chromatographic method to produce a specific fingerprint. The Ames test proved positive at the highest concentration (5,000μg/mL) but A4⁺ showed no evidence of genotoxicity in the more specific mouse micronucleus test. The 28-day repeated dose (general toxicity) study in rats showed no toxicity at 2,000mg/kg. Conclusions: We conclude that under the conditions of these studies, A4⁺ shows no evidence of toxicity at the levels indicated. A no observed adverse effect level (NOAEL) of 2,000mg/kg was assigned. © 2016 by De Gruyter.

Author keywords

Annona muricata; Cordia lutea; Curcuma longa; herbal medicine; liver disease; toxicity testing

ISSN: 15533840Source Type: Journal Original language: English

DOI: 10.1515/jcim-2015-0054Document Type: Article

Publisher: Walter de Gruyter GmbH

References (33)

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• 
  1

  Natural Medicines. Graviola: Available at Accessed: 8 Jul 2015
  https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=1054
  

  •  
• 
  2

  NHPD Monograph for Turmeric (Curcuma Longa)
  Health Canada Available at Accessed: 23 Jul 2014
  http://webprod.hc-sc.gc.ca/nhpidbdipsn/monoReq.do?id=216
  

  •  
• 
  3

  Bussmann, R.W., Glenn, A., Sharon, D.

  Antibacterial activity of medicinal plants of Northern Peru - Can traditional applications provide leads for modern science?
  (2010) Indian Journal of Traditional Knowledge, 9 (4), pp. 742-753. Cited 11 times.
  http://nopr.niscair.res.in/bitstream/123456789/10330/1/IJTK%209%284%29%20742-753.pdf
  
• 
  4

  Cabanillas, J., Fong, F.
  (2012) Report to Sabell Corp
  January
  

  •  
• 
  5

  Akram, M., Shahab-Uddin Ahmed, A., Usmanghani, K., Hannan, A., Mohiuddin, E.
  Curcuma longa and curcumin: A review article
  (2010) Rom J Biol Plant Biol, 55, pp. 65-70.
  

  •  
• 
  6

  Krup, V., Prakash, L.H., Harini, A.
  Pharmacological activities of turmeric (Curcuma longa Linn): A review
  (2013) J Homeop Ayurv Med, 2, p. 133.
  

  •  
• 
  7

  Moghadamtousi, S.Z., Fadaeinasab, M., Nikzad, S., Mohan, G., Ali, H.M., Kadir, H.A.

  Annona muricata (Annonaceae): A review of its traditional uses, isolated acetogenins and biological activities
  (2015) International Journal of Molecular Sciences, 16 (7), pp. 15625-15658. Cited 4 times.
  http://www.mdpi.com/1422-0067/16/7/15625/pdf
  doi: 10.3390/ijms160715625
  

  • View at Publisher
• 
  8

  Priyanka, D., Shrikant, D.A.
  Review on medicinal fruit Bhokar of species Cordia dichotoma Forst
  (2010) Int J Pharm Biol Arch, 5, pp. 41-47.
  

  •  
• 
  9

  Gee, P., Maron, D.M., Ames, B.N.

  Detection and classification of mutagens: A set of base-specific Salmonella tester strains
  (1994) Proceedings of the National Academy of Sciences of the United States of America, 91 (24), pp. 11606-11610. Cited 95 times.
  doi: 10.1073/pnas.91.24.11606
  

  • View at Publisher
• 
  10

  Flückiger-Isler, S., Baumeister, M., Braun, K., Gervais, V., Hasler-Nguyen, N., Reimann, R., Van Gompel, J., (...), Engelhardt, G.

  Assessment of the performance of the Ames II™ assay: A collaborative study with 19 coded compounds
  (2004) Mutation Research - Genetic Toxicology and Environmental Mutagenesis, 558 (1-2), pp. 181-197. Cited 91 times.
  doi: 10.1016/j.mrgentox.2003.12.001
  

  • View at Publisher
• 
  11

  (1997)
  Environment Directorate Organisation for Economic Co-operation and Development. OECD Series on Principles of Good Laboratory Practice and Compliance Monitoring Number 1, OECD Principles on Good Laboratory Practice (as revised in Available at Accessed: 23 Jul 2014
  http://www.oecd-ilibrary.org/docserver/download/9760011e.pdf?expires=1406135926&id=id&accname=guest&checksum=BB3336A7ADDEAF494719029B8DA6EF92
  

  •  
• 
  12

  Working Group of Experts on Systemic Short-Term and (Delayed) Neurotoxicity, Organisation for Economic Co-operation and Development. OECD guideline on the testing of chemicals, # 407: repeated dose 28-day oral toxicity study in rodents Available at Accessed: 23 Jul 2014
  http://www.oecd-ilibrary.org/docserver/download/9740701e.pdf?expires=1406136283&id=id&accname=guest&checksum=BC2F7C38C8A92ABB47AF544A022AEAB4
  

  •  
• 
  13

  Organisation for Economic Co-operation and Development OECD guideline on the testing of chemicals 474: mammalian erythrocyte micronucleus test Available at Accessed: 8 Jul 2015
  http://www.oecdilibrary.org/environment/test-no-474-mammalian-erythrocytemicronucleus-test9789264224292-en
  

  •  
• 
  14

  Arita, M.
  Flavonoid Index
  Available at Accessed: 23 Jul 2014
  http://metabolomics.jp/wiki/Index:FL
  

  •  
• 
  15

  Kim, G.-S., Zeng, L., Alali, F., Rogers, L.L., Wu, F.-E., Sastrodihardjo, S., McLaughlin, J.L.

  Muricoreacin and murihexocin C, mono tetrahydrofuran acetogenins, from the leaves of Annona muricata
  (1998) Phytochemistry, 49 (2), pp. 565-571. Cited 40 times.
  doi: 10.1016/S0031-9422(98)00172-1
  

  • View at Publisher
• 
  16

  Kim, G.-S., Zeng, L., Alali, F., Rogers, L.L., Wu, F.-E., McLaughlin, J.L., Sastrodihardjo, S.

  Two new mono-tetrahydrofuran ring acetogenins, annomuricin E and muricapentocin, from the leaves of Annona muricata
  (1998) Journal of Natural Products, 61 (4), pp. 432-436. Cited 33 times.
  doi: 10.1021/np970534m
  

  • View at Publisher
• 
  17

  Wu, F.-E., Zeng, L., Gu, Z.-M., Zhao, G.-X., Zhang, Y., Schwedler, J.T., McLaughlin, J.L., (...), Sastrodihardjo, S.

  Muricatocins A and B, two new bioactive monotetrahydrofuran annonaceous acetogenins from the leaves of Annona muricata
  (1995) Journal of Natural Products, 58 (6), pp. 902-908. Cited 27 times.
  

  • View at Publisher
• 
  18

  Wu, F.-E., Zeng, L., Zhao, Z.-M., Zhao, G.-X., Zhang, Y., Schwedler, J.T., McLaughlin, J.L., (...), Sastrodihardjo, S.

  New bioactive monotetrahydrofuran annonaceous acetogenins, annomuricin C and muricatocin C, from the leaves of Annona muricata
  (1995) Journal of Natural Products, 58 (6), pp. 909-915. Cited 32 times.
  

  • View at Publisher
• 
  19

  Wu, F.E., Zhao, G.-X., Zeng, L., Zhang, Y., Schwedler, J.T., Mclaughlin, J.L., Sastrodihardjo, S.

  Additional bioactive acetogenins, annomutacin and (2,4-trans and cis)-10R-annonacin-a-ones, from the leaves of Annona muricata
  (1995) Journal of Natural Products, 58 (9), pp. 1430-1437. Cited 22 times.
  

  • View at Publisher
• 
  20

  Zeng, L., Wu, F.-E., Oberlies, N.H., McLaughlin, J.L., Sastrodihadjo, S.

  Five new monotetrahydrofuran ring acetogenins from the leaves of Annona muricata
  (1996) Journal of Natural Products, 59 (11), pp. 1035-1042. Cited 38 times.
  doi: 10.1021/np960447e
  

  • View at Publisher
• 
  21

  Organisation for Economic Co-operation and Development OECD guideline on the testing of chemicals 471: bacterial reverse mutation test Available at Accessed: 23 Jul 2014
  http://www.oecd-ilibrary.org/docserver/download/9747101e.pdf?expires=1406136533&id=id&accname=guest&checksum=3558F9E2E2441F70529DF6CE530A8788
  

  •  
• 
  22

  Alali, F.Q., Liu, X.-X., McLaughlin, J.L.

  Annonaceous acetogenins: Recent progress
  (1999) Journal of Natural Products, 62 (3), pp. 504-540. Cited 596 times.
  http://pubs.acs.org/journal/jnprdf
  doi: 10.1021/np980406d
  

  • View at Publisher
• 
  23

  Resende, F.A., Vilegas, W., Dos Santos, L.C., Varanda, E.A.

  Mutagenicity of flavonoids assayed by bacterial reverse mutation (Ames) test
  (2012) Molecules, 17 (5), pp. 5255-5268. Cited 27 times.
  http://www.mdpi.com/1420-3049/17/5/5255/pdf
  doi: 10.3390/molecules17055255
  

  • View at Publisher
• 
  24

  (1999) Quercetin, 73, p. 497.
  International Agency for Research on Cancer (IARC)-Summaries and Evaluations
  

  •  
• 
  25

  Harwood, M., Danielewska-Nikiel, B., Borzelleca, J.F., Flamm, G.W., Williams, G.M., Lines, T.C.

  A critical review of the data related to the safety of quercetin and lack of evidence of in vivo toxicity, including lack of genotoxic/carcinogenic properties
  (2007) Food and Chemical Toxicology, 45 (11), pp. 2179-2205. Cited 297 times.
  doi: 10.1016/j.fct.2007.05.015
  

  • View at Publisher
• 
  26

  Guideline on the Assessment of Genotoxic Constituents in Herbal Substances/Preparations' (EMEA/HMPC/107079/2007)
  European Medicines Agency Committee on Herbal Medicinal Products (HMPC). Overview of comments received on draft Available at Accessed: 23 Jul 2014
  http://www.ema.europa.eu/docs/enGB/documentlibrary/Other/2009/09/WC500003570.pdf
  

  •  
• 
  27

  Nagabhushan, M., Bhide, S.V.

  Nonmutagenicity of Curcumin and its Antimutagenic Action Versus Chili and Capsaicin
  (1986) Nutrition and Cancer, 8 (3), pp. 201-210. Cited 65 times.
  doi: 10.1080/01635588609513894
  

  • View at Publisher
• 
  28

  European Medicines Agency Committee on Herbal Medicinal Products (HMPC): Assessment Report on Curcuma Longa L. Rhizoma. Cited 2 times.
  Available at Accessed: 23 Jul 2014
  http://www.ema.europa.eu/docs/enGB/documentlibrary/Herbal-HMPCassessmentreport/2010/02/WC500070700.pdf
  

  •  
• 
  29

  Kelber, O., Steinhoff, B., Kraft, K.

  Assessment of genotoxicity of herbal medicinal products: A co-ordinated approach
  (2012) Phytomedicine, 19 (5), pp. 472-476. Cited 7 times.
  doi: 10.1016/j.phymed.2011.11.008
  

  • View at Publisher
• 
  30

  Krishna, G., Hayashi, M.

  In vivo rodent micronucleus assay: Protocol, conduct and data interpretation
  (2000) Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis, 455 (1-2), pp. 155-166. Cited 214 times.
  doi: 10.1016/S0027-5107(00)00117-2
  

  • View at Publisher
• 
  31

  Shelby, M.D., Gulati, D.K., Tice, R.R., Wojciechowski, J.P.

  Results of tests for micronuclei and chromosomal aberrations in mouse bone marrow cells with the human carcinogens 4-aminobiphenyl, treosulphan, and melphalan
  (1989) Environmental and Molecular Mutagenesis, 13 (4), pp. 339-342. Cited 19 times.
  

  • View at Publisher
• 
  32

  Gafner, S., Blumenthal, M.
  Perspectives on the potential hepatotoxicity of various herbs, including green tea extract
  (2014) HerbalGram, 104, pp. 52-59.
  

  •  
• 
  33

  Giknis, M.L., Clifford, C.B.
  (Charles River Laboratories): Clinical Laboratory Parameters for Crl:CD(SD) Rats
  Available at Accessed: 23 Jul 2014
  http://www.criver.com/files/pdfs/rms/cd/rmrmrclinicalparameterscdrat06.aspx
  

  •  

  Green, F.H.Y.; Snyder Institute for Chronic Diseases, Faculty of Medicine, University of Calgary, 3280 Hospital Drive N.W., Canada; email:fgreen@ucalgary.ca
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