Acute, sub-acute, sub-chronic and chronic toxicity studies of four important Nigerian ethnomedicinal plants in rats

Abdullah M. Tauheed1, Mohammed Mamman1, Amran Ahmed2, Na’imatu A. Sani3, М. М. Сулейман1, Mohamed Sulaiman4, E.O. Balogun5
1Department of Veterinary Pharmacology and Toxicology, Faculty of Veterinary Medicine, Ahmadu Bello University, Zaria, Kaduna State, Nigeria
2Department of Pharmacognosy and Drug Development, Faculty of Pharmaceutical Sciences, Ahmadu Bello University, Zaria, Kaduna State, Nigeria
3Department of Veterinary Physiology and Biochemistry, Faculty of Veterinary Medicine, Bayero University, Kano, Nigeria
4Department of Veterinary Anatomy, Faculty of Veterinary Medicine, Ahmadu Bello University, Zaria, Kaduna State, Nigeria
5Department of Biochemistry, Faculty of Life Sciences, Ahmadu Bello University, Zaria, Kaduna State, Nigeria

Tóm tắt

AbstractBackground

Azadirachta indica,Khaya senegalensis,Anogeissus leiocarpusandTamarindus indicaare important ethnomedicinal plants used for health mitigation since the history of mankind. They are used discretionarily in folkloric medicine on the premise that they are natural products devoid of synthetic preservatives. However, nature endows plants with metabolites for warding off potential attacks from animals and the environment. Some of these metabolites are responsible for toxicity of some plants. Furthermore, drug-induced liver injuries and nephrotoxicity are the leading causes of pharmaceutical attrition of promising drug candidates in clinical trials. Thus, we aimed to evaluate the safety of four ethnomedicinal plants in short-, medium- and long-term usage.

Methods

Rats dosed once with 5000 mg/kg extracts of each of these plants served as acute study (AS) while rats dosed daily with 2000 mg/kg for 2, 12 and 14 weeks served as sub-acute (SAS), sub-chronic (SCS) and chronic (CS) studies, respectively. Rats administered distilled water served as the negative control (NC).

Results

A. leiocarpusandT. indicasignificantly reduced percentage weight gain in the SCS compared to the NC.A. leiocarpussignificantly (P< 0.05) increased transaminases and alkaline phosphatase in the AS only; and total protein (TP) in the AS, SAS, SCS and CS compared to the NC.K. senegalensissignificantly (P< 0.05) increased alanine aminotransferase but significantly (P< 0.05) decreased TP in the AS only compared to the NC. However,A. indica and T. indicasignificantly (P< 0.05) increased globulin and aspartate transaminase in the CS only. WhereasA. leiocarpusandK. senegalensissignificantly (P< 0.05) increased urea and creatinine in the AS than SAS, SCS and CS; Na+and K+were significantly higher in the SCS and CS studies compared to the NC. The histological lesions seen ranged from cellular degeneration, congestion, fibrosis to necrosis.

Conclusion

Thus, nonlethal, reversible toxic insults occur in short-term usage (AS); while, insidious lethal toxic effects occur in medium-term (SAS) and long-term usage (SCS and CS). The ability of these plant to maintain adequate hematological parameters, bodyweight and absence of mortality may explain free usage of preparations made from these plants in folkloric medicine.

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Tài liệu tham khảo

Newman DJ, Cragg GM. Natural products as sources of new drugs from 1981 to 2014. J Nat Prod. 2016;79:629–61.

World Health Organisation. Traditional medicine strategy: 2014–2023. http://www.who.int/medicines/publications/traditional/trm_strategy14_23/en/. 2013. Accessed 10 May 2020 at 11:51AM GMT.

Harvey AL, Edrada-Ebel R, Quinn RJ. The re-emergence of natural products for drug discovery in the genomics era. Nat Rev Drug Disc. 2015;14:111–29.

Thomford NE, Senthebane DA, Rowe A, Munro D, Seele P, Maroyi A, et al. Natural products for drug discovery in the 21st century : innovations for novel drug discovery. Int J Mol Sci. 2018;19:1578–607.

Schnellman R. Toxic responses of the kidney. In: Klaassen CD, editor. Casarett and Doull’s toxicology: the basic science of poisons. New York: McGraw-Hill; 2008. p. 235–72.

Weiler S, Merz M, Kullak-Ublick GA. Drug-induced liver injury: The dawn of biomarkers. F1000 Prime Reports. 2015;7:34.

Aulbach AD, Amuzie CJ. Biomarkers in nonclinical drug development. In: Faqi AS, editor. A comprehensive guide to toxicology in nonclinical drug development. London: Academic Press, Elsevier; 2017. p. 447–71.

Boone L, Meyer D, Cusick P, Ennulat D, Bolliger AP, Everds N, et al. Selection and interpretation of clinical pathology indicators of hepatic injury in preclinical studies. Vet Clin Pathol. 2005;34:182–8. https://doi.org/10.1111/j.1939-165x.2005.tb00041.x.

Dieterle F, Sistare F, Goodsaid F, Papaluca M, Ozer J, Webb C, et al. 2010. Renal biomarker qualification submission: a dialog between the FDA-EMEA and predictive safety testing consortium. Nat Biotechnol. 2010;28:455–62. https://doi.org/10.1038/nbt.1625.

Bhadoriya SS, Ganeshpurkar A, Narwaria J, Rai G, Jain AP. Tamarindus indica: extent of explored potential. Pharm Rev. 2011;5:73–81.

Singh D, Baghel US, Gautam A, Baghel DS, Yadav D, Malik J, et al. The genus Anogeissus: a review on ethnopharmacology, phytochemistry and pharmacology. J Ethnopharmacol. 2016;194:30–56.

Takin MC, Attindehou S, Sezan A, Attakpa SE, Baba-Moussa L. Bioactivity, therapeutic utility and toxicological risks of Khaya senegalensis. Indian J Pharmaceut Biol Res. 2013;1:122–9.

Tiwari R, Verma AK, Chakraborty S, Dhama K, Singh SV. Neem (Azadirachta indica) and its potential for safeguarding health of animals and humans: a review. J Biol Sci. 2014;14:110–23.

Weng JK, Philippe RN, Noel JP. The rise of chemodiversity in plants. Sci. 2012;336:1667–70.

Tauheed AM, Mamman M, Ahmed A, Suleiman MM, Balogun EO. In vitro and in vivo antitrypanosomal efficacy of combination therapy of Anogeissus leiocarpus, Khaya senegalensis and potash. J Ethnopharmcol. 2020;258:112805 https://doi.org/10.1016/j.jep.2020.112805.

Organisation for Economic Co-operation and Development. OECD guidelines for the testing of chemicals. OECD/OCDE. 2008;425:1–27.

Aleksunes LM, Eaton DK. Principles of toxicology. In: Klaassen CD, editor. Casarett and Doull’s toxicology: the basic science of poisons. New York: McGraw-Hill Education; 2019. p. 25–64.

Bain BJ, Bates I, Laffan MA, Lewis SM. Dacie and Lewis practical hematology. 12th ed. Edinburgh: Churchill Livingstone; 2016.

Lorke DA. New approach to practical acute toxicity testing. Arch Toxicol. 1983;54:275–87.

Tauheed AM, Shittu SH, Suleiman MM, Habibu B, Kawu MU, Kobo PI, et al. In vivo ameliorative effects of methanol leaf extract of Lawsonia inermis Linn on experimental Trypanosoma congolense infection in Wistar rats. Int J Vet Sci Med. 2016;4:33–40.

Peters JM, Boyd EM. Organ weights and water levels of the rat following reduced food intake. J Nut. 1966;90:354–60.

Buchholz T, Melzig MF. Medicinal plants traditionally used for treatment of obesity and diabetes mellitus – screening for pancreatic lipase and α-amylase inhibition. Phytother Res. 2016;30:260–6.

Onu A, Saidu Y, Ladan MJ, Bilbis LS, Aliero AA, Sahabi SM. Effect of aqueous stem bark extract of Khaya senegalensis on some biochemical, haematological, and histopathological parameters of rats. J Toxicol. 2013:1–9.

Tantulo U, Fotedar R. Comparison of growth, osmoregulatory capacity, ionic regulation and organosomatic indices of black tiger prawn (Penaeus monodon Fabricius, 1798) juveniles reared in potassium fortified inland saline water and ocean water at different salinities. Aquaculture. 2006;258:594–605.

Amacher DE, Schomaker SJ, Burkhardt JE. The relationship among enzyme induction, liver weight, and histological change in beagle toxicology studies. Food Chem Toxicol. 2001;39:817–25. https://doi.org/10.1016/s0278-6915(01)00030-8.

Blair PC, Thompson MB, Wilson RE, Esber HH, Maronpot RR. Correlation of changes in serum analytes and hepatic histopathology in rats exposed to carbon tetrachloride. Toxicol Letters. 1991;55:149–59. https://doi.org/10.1016/0378-4274(91)90129-t.

Meyer DJ, Harvey JW. Hepatobiliary and skeletal muscle enzymes and liver function tests. In: Meyer DJ, Harvey JW, editors. Veterinary laboratory medicine: interpretation and diagnosis. USA: St. Louis MO Saunders; 2004. p. 169–92.

Rudat J, Brucher BR, Syldatk C. Transaminases for the synthesis of enantiopure beta-amino acids. AMB Express. 2012;2:2–10.

Wada H, Snell EE. Enzymatic transamination of pyridoxamine. II. Crystalline pyridoxamine-pyruvate transaminase. J Biol Chem. 1962;237:133–7.

Linder A, Fjell C, Levin A, Walley KR, Russell JA, Boyd JH. Small acute increases in serum creatinine are associated with decreased long-term survival in the critically ill. Am J Resp Critical Care Med. 2014;189:1075–81.

Coca SG, Parikh CR. Urinary biomarkers for acute kidney injury: perspectives on translation. Clin J Am Soc Nephrol. 2008;3:481–90.

Kidney Disease Improving Global Outcome (KDIGO). Kidney Disease: Improving Global Outcomes Work Group. KDIGO clinical practice guideline for acute kidney injury. 2012. http://www.kidney-international.org. Accessed 10 Dec 2020.

Chandrasoma P, Talorr CR. Concise pathology. 2nd ed. Appleton and Lange: Stamford; 1998.

Sani NA, Kawu MU, Bako IG, Sulaiman MH. Mammogenic and lactogenic effects of leaf extract and fractions of Launaea taraxacifolia and resveratrol in lactating Wistar rats. Trop J Nat Prod Res. 2020;4:8–13.

World Health Organisation. PAN pesticides database. San Francisco: Pesticide Action Network, North America; 2001.