Toxicological assessment of ethanol seed extract of Citrus paradisi Macfad (grapefruit) on oxidative status, organ function and histoarchitecture in Wistar rats

Subject Areas : Journal of Medicinal Herbs, "J. Med Herb" (Formerly known as Journal of Herbal Drugs or J. Herb Drug)

گودویل  اودوم ¹ (گروه داروسازی و سم شناسی ، دانشکده داروسازی ، دانشگاه اویو ، نیجریه.)
اومینی  یمیتان ² (گروه داروسازی ، درمان و سم شناسی ، کالج دانشگاه ایالتی لاگوس ، لاگوس)
دانیال  اوبوت ³ (گروه دارویی و درمانی بالینی ، دانشکده علوم پایه بالینی ، دانشگاه اوویو ، نیجریه)
جون  ادوبانگ ⁴ (گروه دارویی و درمانی بالینی ، دانشکده علوم پایه بالینی ، دانشگاه اوویو ، نیجریه)
نکچی  اونیکو ⁵ (گروه داروسازی و سم شناسی ، دانشکده داروسازی ، دانشگاه اویو ، نیجریه)
امانوئل  ابانگو ⁶ (گروه دارویی و درمانی ، دانشکده پزشکی بالینی پایه ، دانشگاه ایالتی ابیا ، اوتورو ، نیجریه)
ساندی  سویمی ⁷ (گروه پاتولوژی و پزشکی قانونی ، کالج دانشگاه ایالتی لاگوس ، لاگوس ، نیجریه)

Received: 2020-12-08 Accepted : 2021-04-04 Published : 2021-05-01

Keywords: Toxicity, Oxidative stress, Citrus paradisi, DNA modification, Mitochondrial dysfunction,

Abstract :

Background & Aim:Citrus paradisi Macfad (Rutaceae) seed extract (CPE) is used in folkloric medicine for the management of diabetes, blood deficiencies and as immune booster, which may require long term usage. This study aimed to evaluate the toxicity profile of ethanol seed extract of grapefruit in adult Wistar rats in order to determine its safety profile in whole organism’s systems.Experimental: Acute toxicity study was conducted using OECD–425 procedure. Subchronic toxicity study (90 days) was conducted using 40 adult male Wistar rats, randomly divided into four groups (10/group) and orally-treated daily, thus: Group I-Control (normal saline, 10 ml/kg), Groups II-IV received CPE (4, 40 and 400) mg/kg body weight, respectively. On the 92nd day, animals (6/group) were euthanized under diethyl ether anaesthesia and sacrificed. Vital organs were eviscerated, blotted, weighed and stored for oxidative stress measurement; some samples of the organs were fixed in formalin for histopathological examination. Other animals (4/group) were retained for reversibility studies.Results: Results showed significant increase and decrease in weights of the kidneys and spleen, respectively. Significant increase in malondialdehyde level and decreases in superoxide dismutase, glutathione and catalase activities were recorded. Histopathology of the kidney, liver, and lungs showed some degree of pathologies. Reversibility studies showed reversal of test effects on extract discontinuation. Despite the diverse biological usefulness of ethanol seed extract of C. paradisi (CPE), it may also induce an array of toxicities especially on long term use.Recommended applications/industries: Contrary to the tradomedical claims that CPE is absolutely safe, the study revealed that CPE may induce oxidative stress and organ toxicity especially on long term use. It is imperative the plant seed extract and its derivatives be used with utmost caution, and where possible be avoided.

References:

Brede, C. and Labhasetwar, V. 2013. Applications of nanoparticles in the detection and treatment of kidney diseases. Advances in Chronic Kidney Disease, 20(6): 101-153.

Chance, B. and Maehly, A.C. 1955. Assay of catalases and peroxidases. Methods in Enzymology, 2: 764-775.

Colado, M.I., O’Shea, E., Granados, R., Misra, A., Murray, T.K. and Green, A.R. 1997. A study to correlate rotenone induced biochemical changes and cerebral damage in brain areas with neuromuscular coordination in rats. British Journal of Pharmacology, 121(4): 827-833.

Draper, H.H., Dhanakoti, S.N., Hadley, M. and Piche, L.A. 1988. Malondialdehyde in biological systems. In: Cellular Antioxidant Defense Mechanism (Chow, C.K. Eds.).Comptes Rendus Chimie de l' Boca Raton, pp. 97-100.

Dudkina, N.V., Balabaskaran, N.P., Kane, L.A., Vaneyk, J.E., Boekema, E.J., Mather, M.W. and Vaidya, A.B. 2010. Highly divergent mitochondrial ATP synthase complexes in Tetrahymena thermophilia. PLos Biology, 8(7): 140-158.

Farah, A.O., Nooraain, H., Noriham, A., Azizah, A.H. and Nurul, H.R. 2013. Acute and oral subacute toxicity study of ethanolic extract of Cosmos caudatus leaf in Sprague Dawley rats. International Journal of Biosciences, Biochemistry and Bioinformatics, 3(4): 301-305.

Ganda, A., Onat, D., Demmer, R.T., Wan, E., Vittorio, T.J., Sabbah, H.N. and Colombo, P.C. 2010. Venous congestion and endothelial cell activation in acute decompensated heart failure. Current Heart Failure Reports, 7(2): 11767-11897

Girotti, A.W. 1985. Mechanism of lipid peroxidation. Journal of Free Radical in Biology and Medicine, 1(2): 87-95.

Goudah, A., Abo-EL-Sooud, K. and Yousef, M.A. 2015. Acute and subchronic toxicity assessment model of Ferula assa-foetida gum in rodents. Veterinary World, 8(5): 584-589.

Halliwell, B. and Gutteridge, J.M.C. 2007. Free Radicals in Biology and Medicine, 4^th ed. Oxford University Press, New York.

Halliwell, B. and Gutteridge, J.M.C. 2015. Free Radicals in Biology and Medicine, 5^th ed. Oxford University Press, New York.

Hemnani, T. and Parihar, M.S. 1998. Reactive oxygen species and oxidative DNA damage. Indian Journal of Physiology and Pharmacology, 42: 440-452.

Jollow, D.J., Michell, J.R., Zampaglionic and Gillete, J.R. 1974. Bromobenzene-induced liver necrosis: protective role of glutathione and evidence for 3, 4-bromobenzene oxide as hepatotoxic metabolite. Pharmacology, 11: 151-169.

Kakkar, P., Das, B. and Viswanathan, P.N. 1984. A modified spectrophotometric assay of superoxide dismutase. Indian Journal of Biochemistry and Biophysics,21(2): 130 – 132.

Kim, J., Seok, Y.M., Jung, K.J. and Park, K.M. 2009. Reactive oxygen species/oxidative stress contributes to progression of kidney fibrosis following transient ischemic injury in mice. American Journal of Physiology and Renal Physiology, 297(2): 461-470.

Lowry, O.H., Rosebrough, N.J., Farr, A.L. and Randall, R.J. 1951. Protein measurement with the folin phenol reagent. Journal of Biology and Chemistry, 193: 265-275.

Mason, J., Joeris, B., Welsch, J. and Kriz, W. 1989. Vascular congestion in ischemic renal failure: the role of cell swelling. Mineral and Electrolyte Metabollism, 15(3): 114-124.

OECD, (2001) Acute oral toxicity (AOT, Test Guideline 425) statistical programme (AOT425StatPPgm). http://www.oecd.org/OECD/pages/home/displaygeneral/0,3380,EN-document-524-nodirectorate-no-24-6775-8 (accessed 15 May 2019).

Ping, K.Y., Darah, I., Chen, Y., Sreeramanan, S. and Sasidharan, S. 2013. Acute and subchronic toxicity study of Euphorbia hirta L. methanol extract in rats. Biomedical Research International, 2: 1-14.

Riede, U. and Werner, M. 2004. Color Atlas of Pathology. Thieme Medical publishers, New York.

Slater, T.F. 1984. Overview of the methods used for detecting lipid peroxidation. In: Methods in Enzymology: Oxygen Radicals in Biological Systems (Packer, L. Eds.). Academic, London, pp. 283-293.

Taib, I.S., Budin, S.B., Ghazali, A.R., Jayusman, P.A., Louis, S.R. and Mohamed, J. 2013. Fenitrothion induced oxidative stress and morphological alterations of sperm and testes in male Sprague-Dawley rats. CLINICS, 68(1): 93-100.

Tanira, M.O.M., Agell, A.M., Tariq, M., Mohsin, A. and Shah, A.H. 1988. Evaluation of some pharmacological, microbiological and physical properties of Ziziphus spina Christi. International Journal of Crude Drug Research, 26: 56-60.

Udom, G.J., Yemitan, O.K., Umoh, E.E., Mbagwu, H.O.C., Ukpe, E.E. and Thomas, P.S. 2018. Hepatoprotective properties of ethanol seed extract of Citrus paradisi Macfad (grapefruit) against paracetamol-induced hepatotoxicity in Wistar rats. Journal of Herbal Drugs, 8(4): 219-225.

Valko, M., Morris, H. and Cronin, M.T.D. 2005. Metals, toxicity and oxidative stress. Current Medicinal Chemistry, 5(4): 29-35.

Wang, J., Zhu, H. and Liu, Z. 2013. Antioxidative effects of hesperetin against lead acetate-induced oxidative stress in rats. Indian Journal of Pharmacology, 45(4): 395-398.

Yemitan, O.K. and Adeyemi, O.O. 2004. Toxicity studies of the aqueous root extract of Lecaniodiscus cupanioides. Nigerian Journal of Health and Biomedical Sciences, 3: 20-23.

Yemitan, O.K., Adeyemi, O.O. and Izegbu, M.C. 2015. Toxicological and reversibility assessment of Dalbergia saxatilis root extracts on body and organ weights, hepatic functions and peroxidation in rats. European Journal of Medicinal Plants, 11(4): 1-13.