Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
권호 표지
DOI QR코드

DOI QR Code

Sub-acute toxicity study on hydromethanolic leaves extract of Combretum hypopilinum (Combretaceae) Diels in Wistar rats

  • Ahmad, Mubarak Hussaini (Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Ahmadu Bello University) ;
  • Zezi, Abdulkadir Umar (Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Ahmadu Bello University) ;
  • Anafi, Sherifat Bola (Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Ahmadu Bello University) ;
  • Alshargi, Omar Yahya (College of Pharmacy, Riyadh Elm University) ;
  • Mohammed, Mustapha (School of Pharmaceutical Sciences, Universiti Sains Malaysia) ;
  • Mustapha, Sagir (Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Ahmadu Bello University) ;
  • Bala, Auwal Adam (Department of Pharmacology, College of Medicine and Health Sciences, Federal University Dutse) ;
  • Muhammad, Surajuddeen (Faculty of Veterinary Medicine, Ahmadu Bello University) ;
  • Julde, Sa'adatu Muhammad (Department of Pharmacology and Therapeutics, Bayero University Kano) ;
  • Wada, Abubakar Sadiq (Department of Pharmacology and Therapeutics, Bayero University Kano) ;
  • Jatau, Abubakar Ibrahim (School of Pharmacy and Pharmacology, University of Tasmania)
  • Received : 2021.05.18
  • Accepted : 2022.03.25
  • Published : 2022.10.15
⟨ Previous Next ⟩

Abstract

The plant Combretum hypopilinum Diels (Combretaceae) has been utilized in Nigeria and other African nations to treat many diseases including liver, inflammatory, gastrointestinal, respiratory, infectious diseases, epilepsy and many more. Pharmacological investigations have shown that the plant possesses anti-infective, antidiarrhoeal, hepatoprotective, anti-inflammatory, anticancer, sedative, antioxidant, and antiepileptic potentials. However, information on its toxicity profile is unavailable despite the plant's therapeutic potential. As such, this work aimed to determine the acute and sub-acute oral toxic effects of the hydromethanolic leaves extract of C. hypopilinum. The preliminary phytochemical evaluation was carried out based on standard procedures. The acute toxicity evaluation was conducted by oral administration of the extract at the dose of 5000 mg/kg based on the guideline of the Organization of Economic Co-operation and Development (OECD) 423. To investigate the sub-acute toxicity effects, the extract was administered orally to the animals daily for 28-consecutive days at the doses of 250, 500, and 1000 mg/kg. Mortality, body weight and relative organ weight were observed. The hepatic, renal, haematological, and lipid profile parameters were investigated. The liver, kidney, heart, lung, small intestine, and stomach were checked for any histopathological alterations. The results of the phytochemical investigation showed cardiac glycosides, tannins, steroids, flavonoids, alkaloids, saponins, and triterpenes. Based on the acute toxicity investigation outcome, no death and signs of toxic effects were observed. The result showed that the oral median lethal dose (LD50) of the extract was more than the 5000 mg/kg. The extract remarkably reduced the weekly body weight of the animals at 500 mg/kg in the first and second weeks. It also significantly decreased the relative kidney weight, alkaline phosphatase, glucose, potassium, and low-density lipoprotein. There was a remarkable elevation in the percentage of eosinophils, basophils, monocytes, and granulocyte. There were histopathological abnormalities on the kidney, lung, stomach, and small intestine. The extract is relatively safe on acute exposure but moderately toxic at higher doses on sub-acute administration, particularly to the kidney.

Keywords

Acknowledgement

The authors are thankful to all staff of the Department of Pharmacology and Therapeutics, Ahmadu Bello University, Nigeria, for their support during this research. We are also thankful to all members of Pharmacy Scholars Initiative (PSI), a mentorship forum for their support. We appreciate the support of the University of Tasmania, Australia (via Studiosity) for the English language editing of the manuscript.

References

  1. Easmin MS, Sarker MZI, Ferdosh S, Shamsudin SH, Yunus KB, Uddin MS et al (2015) Bioactive compounds and advanced processing technology: Phaleria macrocarpa (sheff.) Boerl, a review. J Chem Technol Biotechnol 90:981-991. https://doi.org/10.1002/jctb.4603
  2. Jimenez-estrada M, Velazquez-contreras C, Garibay-escobar A, Sierras-canchola D, Lapizco-vazquez R, Ortiz-sandoval C et al (2013) In vitro antioxidant and antiproliferative activities of plants of the ethnopharmacopeia from northwest of Mexico. BMC Complement Altern Med. https://doi.org/10.1186/1472-6882-13-12
  3. Kale OE, Awodele O, Akindele AJ (2019) Subacute and subchronic oral toxicity assessments of Acridocarpus smeathmannii (DC.) Guill. & Perr. root in Wistar rats. Toxicol Rep 6:161-175. https://doi.org/10.1016/j.toxrep.2019.01.005
  4. Atanasov AG, Waltenberger B, Pferschy-Wenzig EM, Linder T, Wawrosch C, Uhrin P et al (2015) Discovery and resupply of pharmacologically active plant-derived natural products: a review. Biotechnol Adv 33:1582-1614. https://doi.org/10.1016/j.biotechadv.2015.08.001
  5. Hassan MM, Khan SA, Shaikat AH, Hossain E, Hoque A (2013) Analgesic and anti-inflammatory effects of ethanol extracted leaves of selected medicinal plants in animal model. Vet World 6:68-71. https://doi.org/10.5455/vetworld.2013.68-71
  6. Ahmad L, He Y, Hao JC, Semotiuk A, Liu QR, Mazari P (2017) Toxic pyrrolizidine alkaloids provide a warning sign to overuse of the ethnomedicine Arnebia benthamii. J Ethnopharmacol 210:88-94. https://doi.org/10.1016/j.jep.2017.08.009
  7. Ouedraogo M, Baudoux T, Stevigny C, Nortier J, Colet J, Efferth T et al (2012) Review of current and " omics " methods for assessing the toxicity (genotoxicity, teratogenicity and nephrotoxicity) of herbal medicines and mushrooms. J Ethnopharmacol 140:492-512. https://doi.org/10.1016/j.jep.2012.01.059
  8. Lahlou S, Israili ZH (2008) Acute and chronic toxicity of a lyophilised aqueous extract of Tanacetum vulgare leaves in rodents. J Ethnopharmacol 117:221-227. https://doi.org/10.1016/j.jep.2008.01.024
  9. Ndhlala AR, Ncube B, Okem A, Mulaudzi RB, Van Staden J (2013) Toxicology of some important medicinal plants in southern Africa. Food Chem Toxicol 62:609-621. https://doi.org/10.1016/j.fct.2013.09.027
  10. Ahmad MH, Zezi AU, Anafi SB, Danraka RN, Alhassan Z (2020) Evaluation of antidiarrhoeal activity of methanol extract of Combretum hypopilinum Diels (Combretaceae) leaves in mice. Adv Pharm J 5:54-61. https://doi.org/10.31024/apj.2020.5.2.3
  11. Ahmad MH, Jatau AI, Khalid GM, Alshargi OY (2021) Traditional uses, phytochemistry, and pharmacological activities of Cochlospermum tinctorium A. Rich (Cochlospermaceae): a review. Futur J Pharm Sci 7:1-13. https://doi.org/10.1186/s43094-020-00168-1
  12. Brown AC (2017) Kidney toxicity related to herbs and dietary supplements: Online table of case reports. Part 3 of 5 series. Food Chem Toxicol 107:502-519. https://doi.org/10.1016/j.fct.2016.07.024
  13. Reduan FH, Mohd R, Nurul S, Ahmad S, Noordin S, Mustapha M (2020) Acute and subacute dermal toxicity of ethanolic extract of Melastoma malabathricum leaves in Sprague-Dawley rats. Toxicol Res 36:203-210. https://doi.org/10.1007/s43188-019-00013-5
  14. Hedberg I, Hedberg O, Madati PJ, Mshigeni KE, Mshiu EN, Samuelsson G (1982) Inventory of plants used in traditional medicine in Tanzania. I. Plants of the families Acanthaceae-Cucurbitaceae. J Ethnopharmacol 6:29-60. https://doi.org/10.1016/0378-8741(82)90070-8
  15. Idoh K, Dosseh K, Kpatcha T, Agbonon A, Gbeassor M (2018) Protective effect of Combretum hypopilinum Diels: root bark extract against CCl4-Induced Hepatotoxicity in Wistar rats. Pharmacogn Res 10:325-331. https://doi.org/10.4103/pr.pr-27-17
  16. Ahmad MH, Zezi AU, Anafi SB, Alhassan Z, Mohammed M, Danraka RN (2021) Mechanisms of antidiarrhoeal activity of methanol leaf extract of Combretum hypopilinum Diels (combretaceae): involvement of opioidergic and (α1 and β)-adrenergic pathways. J Ethnopharmacol 269:113750. https://doi.org/10.1016/j.jep.2020.113750
  17. Fyhrquist P, Mwasumbi L, Haeggstrom C, Vuorela H, Hiltunen R (2008) Antifungal activity of selected species of terminalia, Pteleopsis and Combretum ( Combretaceae ) collected in Tanzania antifungal activity of selected species of Terminalia, Pteleopsis and Combretum (Combretaceae) collected in Tanzania. Pharm Biol 42:308-317. https://doi.org/10.1080/13880200490511891
  18. Eloff JN (1999) The antibacterial activity of 27 southern African members of the Combretaceae. S Afr J Sci 95:148-152
  19. Abreu PM, Martins ES, Kayser O, Bindseil KU, Siems K, Seemann A et al (1999) Antimicrobial, antitumor and antileishmania screening of medicinal plants from Guinea-Bissau. Phytomedicine 6:187-195. https://doi.org/10.1016/S0944-7113(99)80008-7
  20. Stark TD, Mtui DJ, Balemba OB (2013) Ethnopharmacological survey of plants used in the traditional. Animals 3:158-227. https://doi.org/10.3390/ani30 10158
  21. Marquardt P, Seide R, Vissiennon C, Schubert A, Birkemeyer C, Ahyi V et al (2020) Phytochemical characterization and in vitro antiiflammatory, antioxidant and antimicrobial activity of Combretum collinum Fresen leaves extracts from Benin. Molecules 25:288. https://doi.org/10.3390/molecules25020288
  22. Anderson DMW, Howlett JF, McNab CGA (1987) Amino acid composition of gum exudates from some African Combretum, Terminalia and Anogeissus species. Phytochemistry 26:837-839. https://doi.org/10.1016/S0031-9422(00)84798-6
  23. Rogers CB, Coombes PH (1999) Acidic triterpene glycosides in trichome secretions differentiate subspecies of Combretum collinum in South Africa. Biochem Syst Ecol 27:321-323. https://doi.org/10.1016/S0305-1978(98)00084-2
  24. Anderson DMW, Bell PC (1977) The composition of the gum exudates from some combretum species; the botanical nomenclature and systematics of the Combretaceae. Carbohydr Res 57:215-221. https://doi.org/10.1016/S0008-6215(00)81932-1
  25. Odda J, Kristensen S, Kabasa J, Waako P (2009) Larvicidal activity of Combretum collinum Fresen against Aedes aegypti. J Vector Borne Dis 45:321-324
  26. Kabiru A, Aminu U, Musa Y, Amali MA, Hassan S, Suleiman A et al (2020) Sedative and anti-convulsant effects of the stem bark extract of Combretum hypopilinum in laboratory animals. J Pharmacol Toxicol 15:58-64. https://doi.org/10.3923/jpt.2020.58.64
  27. Sofowora A (1993) Medicinal plants and traditional medicine in Africa, 2nd edn. Spectrum Books Ltd, Ibadan
  28. Organisation for Economic Cooperation and Development (OECD) (2001) Guidelines for the testing of chemicals: health effect test no. 423. Acute oral toxicity-acute toxic class method. OECD, Paris
  29. Organisation for Economic Cooperation and Development (OECD) (2008) Guidelines for the testing of chemicals: guideline 407: repeated dose 28-day oral toxicity in rodents. Office of Economic and Community Development, Paris
  30. Jn N, Tume C, Kdjo N, Ff B, Sf L, Jp D et al (2019) Acute and sub-chronic toxicity evaluation of Triplotaxis stellulifera (Beuth ) Hutch and Crasssocephalum bougheyanum C. D. Adams methanol extract on mice biochemistry and analytical biochemistry. Biochem Anal Biochem 8:1-10. https://doi.org/10.35248/2161-1009.19.8.385
  31. Kpemissi M, Metowogo K, Melila M, Veerapur VP, Negru M, Taulescu M et al (2020) Acute and subchronic oral toxicity assessments of Combretum micranthum (Combretaceae) in Wistar rats. Toxicol Rep 7:162-168. https://doi.org/10.1016/j.toxrep.2020.01.007
  32. Jothy SL, Zakaria Z, Chen Y, Lau YL, Latha LY, Sasidharan S (2011) Acute oral toxicity of methanolic seed extract of Cassia fistula in mice. Molecules 16:5268-5282. https://doi.org/10.3390/molecules16065268
  33. Ahmad MH, Zezi AU, Bola AS, Alhassan Z, Mohammed M, Danraka RN (2020) Mechanisms of antidiarrhoeal activity of methanol leaf extract of Combretum hypopilinum Diels (combretaceae): involvement of opioidergic and (α1 and β)-adrenergic pathways. J Ethnopharmacol 269:113750. https://doi.org/10.1016/j.jep.2020.113750
  34. Kpemissi M, Eklu-Gadegbeku K, Veerapur VP, Negru M, Taulescu M, Chandramohan V et al (2019) Nephroprotective activity of Combretum micranthum G. Don in cisplatin induced nephrotoxicity in rats: in-vitro, in-vivo and in-silico experiments. Biomed Pharmacother 116:108961. https://doi.org/10.1016/j.biopha.2019.108961
  35. Musila MN, Ngai DN, Mbiri JW, Njagi SM, Mbinda WM, Ngugi MP (2017) Acute and sub-chronic oral toxicity study of methanolic extract of Caesalpinia volkensii (Harms). J Drug Metab Toxicol 8:1-8. https://doi.org/10.4172/2157-7609.1000222
  36. Li Y, Kandhare AD, Mukherjee AA, Bodhankar SL (2019) Acute and sub-chronic oral toxicity studies of hesperidin isolated from orange peel extract in Sprague Dawley rats. Regul Toxicol Pharmacol 105:77-85. https://doi.org/10.1016/j.yrtph.2019.04.001
  37. Bamgbose SO, Dramane KL (1977) Studies on combretum species. II. Preliminary report on studies on four seeds of combretum species. Planta Med 32:350-356. https://doi.org/10.1055/s-0028-1097611
  38. Prasanth KM, Suba V, Ramireddy B, Srinivasa BP (2015) Acute and subchronic oral toxicity assessment of the ethanolic extract of the root of Oncoba spinosa (Flacourtiaceae) in rodents. Trop J Pharm Res 14:1849-1855. https://doi.org/10.4314/tjpr.v14i10.16
  39. Piao Y, Liu Y, Xie X (2013) Change trends of organ weight background data in Sprague Dawley rats at different ages. J Toxicol Pathol 26:29-34. https://doi.org/10.1293/tox.26.29
  40. Bamgboye EL, Mabayoje M, Odutola TA, Mabadeje B (1993) Acute renal failure at the lagos university teaching hospital: a 10-year review. Ren Fail 15:77-80. https://doi.org/10.3109/08860229309065577
  41. Kadiri S, Arije A, Salako BL (1999) Traditional herbal preparations and acute renal failure in South West. Trop Doct 29:244-246. https://doi.org/10.1177/004947559902900419
  42. El Kabbaoui M, Chda A, El-Akhal J, Azdad O, Mejrhit N, Aarab L et al (2017) Acute and sub-chronic toxicity studies of the aqueous extract from leaves of Cistus ladaniferus L. in mice and rats. J Ethnopharmacol 209:147-156. https://doi.org/10.1016/j.jep.2017.07.029
  43. Ray CS, Singh B, Jena I, Behera S, Ray S (2017) Low alkaline phosphatase (ALP) in adult population an indicator of zinc (zn) and magnesium (mg) deficiency. Curr Res Nutr Food Sci 5:347-352. https://doi.org/10.12944/CRNFSJ.5.3.20
  44. Kandemir FM, Yildirim S, Caglayan C, Kucukler S, Eser G (2019) Protective effects of zingerone on cisplatin-induced nephrotoxicity in female rats. Environ Sci Pollut Res 26:22562-22574. https://doi.org/10.1007/s11356-019-05505-3
  45. Oyagbemi AA, Omobowale TO, Azeez IO, Abiola JO, Adedokun RAM, Nottidge HO (2013) Toxicological evaluations of methanolic extract of Moringa oleifera leaves in liver and kidney of male Wistar rats. J Basic Clin Physiol Pharmacol 24:307-312. https://doi.org/10.1515/jbcpp-2012-0061
  46. Zhao Y, Zhai D, Chen X, Yang J, Song X, He H et al (2007) Ketoprofen glucuronidation and bile excretion in carbon tetrachloride and alpha-naphthylisothiocyanate induced hepatic injury rats. Toxicology 230:145-150. https://doi.org/10.1016/j. tox. 2006. 11.008
  47. Olorunnisola OS, Bradley G, Afolayan AJ (2012) Acute and subchronic toxicity studies of methanolic extract of Tulbaghia violacea rhizomes in Wistar rats. Afr J Biotechnol 11:14934-14940. https://doi.org/10.5897/AJB12.1565
  48. Jatsa HB, Bertin J, Fassi K, Kenfack MC, Feussom NG (2018) Acute and sub-chronic oral toxicity studies of the leaves aqueous extract of Clerodendrum umbellatum Poir. on mice acute and sub-chronic oral toxicity studies of the leaves aqueous extract of Clerodendrum umbellatum Poir. on mice. Am J Physiol Biochem Pharmacol 7:75-78. https://doi.org/10.5455/ajpbp.20180616012821
  49. Herve E, Nomane E, Goze B, Leandre K, Angoue K, Yapo P (2020) Effects of subacute oral administration of aqueous extract of Macaranga barteri Mull Arg ( Euphorbiaceae ) leaf on anthropometric and haematological parameters in rats. Toxicol Res. https://doi.org/10.1007/s43188-020-00048-z
  50. Arsad SS, Esa NM, Hamzah H, Othman F (2013) Evaluation of acute, subacute and subchronic oral toxicity of Rhaphidophora decursiva ( Roxb.) Schott extract in male Sprague Dawley rats. J Med Plants Res 7:3030-3040. https://doi.org/10.5897/JMPR2013.2611
  51. Yuet Ping K, Darah I, Chen Y, Sreeramanan S, Sasidharan S (2013) Acute and subchronic toxicity study of Euphorbia hirta L. methanol extract in rats. Biomed Res Int. https://doi.org/10.1155/2013/182064
  52. Bhushan B, Sardana S, Bansal G (2014) Acute and sub-acute toxicity study of Clerodendrum inerme, Jasminum mesnyi Hance and Callistemon citrinus. J Acute Dis 3:324-327. https://doi.org/10.1016/S2221-6189(14)60069-X
  53. Li J, Xia Y, Kuter DJ (1999) Interaction of thrombopoietin with the platelet c-mpl receptor in plasma: binding, internalization stability and pharmacokinetics. Br J Haematol 106:345-356. https://doi.org/10.1046/j.1365-2141.1999.01571.x
  54. Ugwah-oguejiofor CJ, Okoli OC, Ugwah MO, Umaru ML, Ogbulie CS, Mshelia HE et al (2019) Acute and sub-acute toxicity of aqueous extract of aerial parts of Caralluma dalzielii N E. Brown in mice and rats. Heliyon 5:e01179. https://doi.org/10.1016/j.heliyon.2019.e01179
  55. Reena G, Sanjiv D, Bhupinder K (2012) Sub-chronic toxicity study of aqueous extract of Clerodendrum Phlomidis leaves. Int J Drug Dev Res 4:197-207
  56. Traesel GK, Menegati SEL, dos Santos AC, Carvalho Souza RI, Villas Boas GR, Justi PN et al (2016) Oral acute and subchronic toxicity studies of the oil extracted from pequi (Caryocar brasiliense, Camb.) pulp in rats. Food Chem Toxicol 97:224-231. https://doi.org/10.1016/j. fct. 2016. 09. 018
  57. Dixon LJ, Barnes M, Tang H, Pritchard MT, Nagy LE (2013) Kupffer cells in the liver. Compr Physiol 3:785-797. https://doi.org/10.1002/cphy.c120026