The Protective Effect of Artocarpus altilis Leaf Extract on Rat Models of Diethylene Glycol-Induced Hepatotoxicity
Keywords:
ALT, AST, Artocarpus altilis, liver hypertrophy, MDA
Abstract
Diethylene glycol (DEG) is an alcohol derivative, which is metabolized into toxic products and is one of the main causes of liver disease. This paper aims to determine the hepatoprotective effect of AA by analyzing the levels of MDA, AST, ALT, and liver hypertrophy in the DEG-induced rat model. Twenty-five male rats were divided into 5 groups: normal, DEG (0.75% v/v), AA1 (DEG + AA 100 mg/kg BW), AA2 (DEG + AA 200 mg/kg BW), and AA3 (DEG + AA 400 mg/kg BW). Rats were given DEG for 28 days ad libitum, and AA was administered from days 14 to 28 orally. Twenty-eight days later, serum levels of MDA, ALT, AST, and liver hypertrophy were determined. DEG induction increased body weight and liver hypertrophy, levels of MDA, ALT, and AST, and decreased the AST/ALT ratio, whereas treatment with AA was shown to reverse to normal conditions which were observed for 28 days depending on the dose of AA (p < 0.05). We conclude that treatment with AA is an effective therapeutic option as a hepatoprotector in a rat model induced by DEG in a dose-dependent manner. Future challenges need to be developed as prospective complementary drugs or phytopharmaceuticals.
References
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Feyissa, T., Asres, K., & Engidawork, E., (2013), Renoprotective effects of the crude extract and solvent fractions of the leaves of Eucleadivinorum hierns against gentamicin-induced nephrotoxicity in rats. J. Ethnopharmacol,: 145:758–66. https://doi.org/10.1016/j.jep.2012.12.006.
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Grasso, P., & Hinton, R.H. Evidence for and possible mechanisms of non-genotoxic carcinogenesis in rodent liver. Mutation Res, 1991: 248(2), 271–290. https://doi.org/10.1016/0027-5107(91)90062-s
Green, R.M., & Flamm, S. (2002), AGA technical review on the evaluation of liver chemistry tests. Gastroenterol, 2002: 123(4), 1367–1384. https://doi.org/10.1053/gast.2002.36061
Hall, A.P., Elcombe, C.R., Foster, J.R., Harada, T., Kaufmann, W., Knippel, A., et al. (2012), Liver hypertrophy: a review of adaptive (adverse and non-adverse) changes--conclusions from the 3rd International ESTP Expert Workshop. Toxi Pathol,: 40(7), 971–994. https://doi.org/10.1177/0192623312448935
Heegazy A.M.S., & Fouad U.A., (2015), Evaluation of Lead Hepatotoxycity: Histological, Histochemical and Ultrastructural Study. Forensic Med Anat Res,: 2: 70-79
Jiang, Z., Wang, J., Xue, H., Wang, M., Jiang, H., Liang, Y., Dias, A.C., Gregory, M., Chen, C., Zhang, X., (2017). Protective effect of wild Corni fructus methanolic extract against acute alcoholic liver injury in mice. Redox Rep. 22, 338–345, http://dx.doi.org/10.1080/13510002.2016.1239867.
Kawamoto, T., Matsuno, K., Kayama, F., Hirai, M., Arashidani, K., Yoshikawa, M., et al., (1990), Effect of ethylene glycol monomethyl ether and diethylene glycol monomethyl ether on hepatic metabolizing enzymes. Toxicol, : 62(3), 265–274. https://doi.org/10.1016/0300-483x(90)90050-q
Kratz A., Pesce, M.A., Basner R.C., & Einstein A.J. (2014), Laboratory values of clinical importance. Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J(Eds.), Harrison's Principles of Internal Medicine, 19e. McGraw Hill, https://accesspharmacy.mhmedical.com/content.aspx?bookid=1130§ionid=79722706
Leise, M.D., Poterucha, J.J., & Talwalkar, J.A. (2014) Drug-induced liver injury. Mayo Clinic proceedings, :89(1), 95–106. https://doi.org/10.1016/j.mayocp.2013.09.016
Lin, C.S., Cai, Q.X., Huang, Z.L., Lin, B. L., Chong, Y.T., Zhao, Z.X., & Gao, Z.L. (2012), Diethylene glycol poisoning and liver function following accidental diethylene glycol injection. EXCLI Jl, :11, 98–107.
Lu, Y., & Cederbaum, A. I. (2018). Cytochrome P450s and Alcoholic Liver Disease. Curr. Pharm. Des., 24(14), 1502–1517. https://doi.org/10.2174/1381612824666180410091511
Ma, L., Gan, D., Wang, M., Zhang, Z., Jiang, C., Zeng, X., (2012). Optimization of extraction, preliminary characterization and hepatoprotective effects of polysaccharides fromStachys floridana Schuttl. ex Benth. Carbohydr. Polym. 87, 1390–1398, http://dx.doi.org/10.1016/j.carbpol.2011.09.032.
Maronpot, R.R., Yoshizawa, K., Nyska, A., Harada, T., Flake, G., Mueller, G., et al, (2010), Hepatic enzyme induction: histopathology. Toxicol Pathol,: 38(5), 776–795. https://doi.org/10.1177/0192623310373778
Mathurin, P., Bataller, R., (2015). Trends in the management and burden of alcoholic liver disease. J. Hepatol. 62, S38–S46, http://dx.doi.org/10.1016/j.jhep.2015.03.006.
Mayans, L. Nephrolithiasis. Prim. Care, (2019): 46 (2), 203–212. https://doi.org/10.1016/j.pop.2019.02.001
Mohd Ali, N., Mohd Yusof, H., Long, K., Yeap, S.K., Ho, W.Y., Beh, B.K., et al, (2013), Antioxidant and hepatoprotective effect of aqueous extract of germinated and fermented mung bean on ethanol-mediated liver damage. BioMed Res., Int.: 93613. https://doi.org/10.1155/2013/693613
Mohd Esa, K. K. Abdul Kadir, Z. Amom, & Azlan, A., (2013), Antioxidant activity of white rice, brown rice and germinated brown rice (in vivo and in vitro) and the effects on lipid peroxidation and liver enzymes in hyperlipidaemic rabbits,” Food Chem, vol. 141, no. 2, pp. 1306–1312.
Mukesh, SS., Hui, B.J. Subramaniam, K., Valeisamy, B.D. Yean, L.K. Balaji, K. (2014), Free Radic Antioxid, 4, 33-39
Ndrepepa, G. (2020). Aspartate aminotransferase and cardiovascular disease—a narrative review. J Lab Prec Med, 6. doi:10.21037/jlpm-20-93
Oh, R.C., Hustead, T.R., Ali, S.M., & Pantsari, M.W. (2017), Mildly Elevated Liver Transaminase Levels: Causes and Evaluation. Am Fam Physician: 96(11), 709–715.
Okuonghae, H.O., Ighogboja, I.S., Lawson, J.O., & Nwana, E.J. (1992). Diethylene glycol poisoning in Nigerian children. Annals Trop Paediatr, 12(3), 235–238. https://doi.org/10.1080/02724936.1992.11747577
Ray, L., Nanda, S. K., Chatterjee, A., Sarangi, R., & Ganguly, S. (2015), A comparative study of serum aminotransferases in chronic kidney disease with and without end-stage renal disease: Need for new reference ranges. Int. J. Appl. Basic Med.: 5(1), 31–35. https://doi.org/10.4103/2229-516X.149232
Schmeltzer, P.A., Kosinski, A.S., Kleiner, D.E., Hoofnagle, J.H., Stolz, A., Fontana, et al, (2016). Liver injury from nonsteroidal anti-inflammatory drugs in the United States. Liver Intl, 36(4), 603–609. https://doi.org/10.1111/liv.13032
Suroowan, S., & Mahomoodally, M. F. (2019). Herbal Medicine of the 21st Century: A Focus on the Chemistry, Pharmacokinetics and Toxicity of Five Widely Advocated Phytotherapies. Curr Top Med Chem, 19(29), 2718–2738. https://doi.org/10.2174/1568026619666191112121330
Susilo, J., Purwanto B., Doewes, M, Indarto, D., & Muktiwi, D.R., (2021), Bread Fruit Leaf Extract Composition And Its Effect On Oxalate And Leukocyte Profiles In Hyperoxaluric Rats Induced By Ethylene Glycol, IJPSR, 12(8): 1000-09. https://dx.doi.org/10.13040/IJPSR.0975-8232.12(8).1000-09
Susilo, J., Ulya, H, & Furdiyanti, N.H, (2018), Effect of Administration of Apium Graveolens L. Leaf Extract on Reduction of Creatinine and Urea Levels in Rat Serum Induced by Ethylene Glycol, Proceedings of the Unimus National Seminar, 1, 104- 113.10.
Thapa, B.R., & Walia, A. (2007), Liver function tests and their interpretation. Indian J. Paed, : 74(7), 663–671. https://doi.org/10.1007/s12098-007-0118-7
Wang, Y., Li, J., Ren, Y.Y., & Zhao, H. (2013), The levels of liver enzymes and atypical lymphocytes are higher in youth patients with infectious mononucleosis than in preschool children. Clin Mol Hepatol. : 19(4), 382–388. https://doi.org/10.3350/cmh.2013.19.4.382
Zeng, B., Su, M., Chen, Q., Chang, Q., Wang, W., Li, H., (2017). Protective effect of a polysaccharide from Anoectochilus roxburghii against carbon tetrachloride- induced acute liver injury in mice. J. Ethnopharmacol. 200, 124–135, http://dx.doi.org/10.1016/j.jep.2017.02.018.
Zhang J., Wang Q., Xu, C., Lu, Y. Hu, H., Qin,B., et al, (2017), MitoTEMPO prevents oxalate induced injury in NRK-52E cells via inhibiting mitochondrial dysfunction and modulating oxidative stress. Oxid. Med. Cell Longev.;:9. https://doi.org/10.1155/2017/7528090.7528090
Ayala, A., Muñoz, M. F., & Argüelles, S. (2014). Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxid. Med. Cell. Longev., 360438. https://doi.org/10.1155/2014/360438
Bastiansyah, E. Complete Guide to Reading Health Test Results. Penebar Plus; 2012, Jakarta
Botros, M., & Sikaris, K.A. (2013). The de ritis ratio: the test of time. Clin Biochem. Rev, : 34(3), 117–130.
Chan, E.W.C., Wong, S.K., Tangah, J., & Chan, H.T., (2018) Chemistry and Pharmacology of Artocarpin: An Isoprenyl Flavone from Artocarpus Species, Sys Rev Pharm.;9(1):58-63
Chen, Y.Y., Zhang, C.L., Zhao, X.L., Xie, K.Q., Zeng, T., (2014). Inhibition of cytochrome P4502E1 by chlormethiazole attenuated acute ethanol-induced fatty liver. Chem. Biol. Interact. 222, 18–26, http://dx.doi.org/10.1016/j.cbi.2014.08.009.
Davern, T.J., Chalasani, N., Fontana, R.J., Hayashi, P.H., Protiva, P., Kleiner, D. E., et al, Acute hepatitis E infection accounts for some cases of suspected drug-induced liver injury. Gastroenterol, 2011: 141(5), 1665–72.e729. https://doi.org/10.1053/j.gastro.2011.07.051
Doody, E. E., Groebner, J. L., Walker, J. R., Frizol, B. M., Tuma, D. J., Fernandez, D. J., & Tuma, P. L. (2017). Ethanol metabolism by alcohol dehydrogenase or cytochrome P450 2E1 differentially impairs hepatic protein trafficking and growth hormone signaling. Am. J. Physiol. Gastrointest. Liver Physiol. , 313(6), G558–G569. https://doi.org/10.1152/ajpgi.00027.2017
Ennulat, D., Magid-Slav, M., Rehm, S., & Tatsuoka, K.S. Diagnostic performance of traditional hepatobiliary biomarkers of drug-induced liver injury in the rat. Toxicol Sci, 2010: 116(2), 397–412. https://doi.org/10.1093/toxsci/kfq144
Feyissa, T., Asres, K., & Engidawork, E., (2013), Renoprotective effects of the crude extract and solvent fractions of the leaves of Eucleadivinorum hierns against gentamicin-induced nephrotoxicity in rats. J. Ethnopharmacol,: 145:758–66. https://doi.org/10.1016/j.jep.2012.12.006.
Francis P, & Navarro V.J. Drug Induced Hepatotoxicity. (Updated 2021 Mar 23). In: StatPearls (Internet). Treasure Island (FL): StatPearls Pub; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK557535/
Galvin, Z., McDonough, A., Ryan, J., & Stewart, S. (2015), Blood alanine aminotransferase levels >1,000 IU/l - causes and outcomes. Clin. Med (London, England), :15(3), 244–247. https://doi.org/10.7861/clinmedicine.15-3-244
Gan, D., Ma, L., Jiang, C., Wang, M., Zeng, X., (2012). Medium optimization and potential hepatoprotective effect of mycelial polysaccharides from Pholiota dinghuensis Bi against carbon tetrachloride-induced acute liver injury in mice. Food Chem. Toxicol. 50, 2681–2688, http://dx.doi.org/10.1016/j.fct.2012.05.003.
Giacomo Z., Vittorio C., Carlo N., Vincenzo S., Giuseppe L., Giovanni T., et al, (2016), The aspartate aminotransferase-to-alanine aminotransferase ratio predicts all-cause and cardiovascular mortality in patients with type 2 diabetes, Medicine,:95 ; 43, doi: 10.1097/MD.0000000000004821
Giannini, E.G., Testa, R., & Savarino, V. Liver enzyme alteration: a guide for clinicians. CMAJ : = journal de l'Association Medicale Canadienne, 2005: 172(3), 367–379. https://doi.org/10.1503/cmaj.1040752
Giknis, M.L.A & Cliford, C.B., (2008), Clinical laboratory parameters for Crl: Wi(Han) rats. Wilmington, MA, Charles River Lab. International, http://www.criver.com/files/pdfs/rms/wistarhan/rm_rm_r_wistar_han_clin_lab_parameters_08.aspx
Goorden, S.M., Buffart, T. E., Bakker, A., & Buijs, M. M. (2013), Leveraandoeningen bij volwassenen: ALAT en ASAT (Liver disorders in adults: ALT and AST). Nederlands tijdschrift voor geneeskunde, 157(43), A6443.
Grasso, P., & Hinton, R.H. Evidence for and possible mechanisms of non-genotoxic carcinogenesis in rodent liver. Mutation Res, 1991: 248(2), 271–290. https://doi.org/10.1016/0027-5107(91)90062-s
Green, R.M., & Flamm, S. (2002), AGA technical review on the evaluation of liver chemistry tests. Gastroenterol, 2002: 123(4), 1367–1384. https://doi.org/10.1053/gast.2002.36061
Hall, A.P., Elcombe, C.R., Foster, J.R., Harada, T., Kaufmann, W., Knippel, A., et al. (2012), Liver hypertrophy: a review of adaptive (adverse and non-adverse) changes--conclusions from the 3rd International ESTP Expert Workshop. Toxi Pathol,: 40(7), 971–994. https://doi.org/10.1177/0192623312448935
Heegazy A.M.S., & Fouad U.A., (2015), Evaluation of Lead Hepatotoxycity: Histological, Histochemical and Ultrastructural Study. Forensic Med Anat Res,: 2: 70-79
Jiang, Z., Wang, J., Xue, H., Wang, M., Jiang, H., Liang, Y., Dias, A.C., Gregory, M., Chen, C., Zhang, X., (2017). Protective effect of wild Corni fructus methanolic extract against acute alcoholic liver injury in mice. Redox Rep. 22, 338–345, http://dx.doi.org/10.1080/13510002.2016.1239867.
Kawamoto, T., Matsuno, K., Kayama, F., Hirai, M., Arashidani, K., Yoshikawa, M., et al., (1990), Effect of ethylene glycol monomethyl ether and diethylene glycol monomethyl ether on hepatic metabolizing enzymes. Toxicol, : 62(3), 265–274. https://doi.org/10.1016/0300-483x(90)90050-q
Kratz A., Pesce, M.A., Basner R.C., & Einstein A.J. (2014), Laboratory values of clinical importance. Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J(Eds.), Harrison's Principles of Internal Medicine, 19e. McGraw Hill, https://accesspharmacy.mhmedical.com/content.aspx?bookid=1130§ionid=79722706
Leise, M.D., Poterucha, J.J., & Talwalkar, J.A. (2014) Drug-induced liver injury. Mayo Clinic proceedings, :89(1), 95–106. https://doi.org/10.1016/j.mayocp.2013.09.016
Lin, C.S., Cai, Q.X., Huang, Z.L., Lin, B. L., Chong, Y.T., Zhao, Z.X., & Gao, Z.L. (2012), Diethylene glycol poisoning and liver function following accidental diethylene glycol injection. EXCLI Jl, :11, 98–107.
Lu, Y., & Cederbaum, A. I. (2018). Cytochrome P450s and Alcoholic Liver Disease. Curr. Pharm. Des., 24(14), 1502–1517. https://doi.org/10.2174/1381612824666180410091511
Ma, L., Gan, D., Wang, M., Zhang, Z., Jiang, C., Zeng, X., (2012). Optimization of extraction, preliminary characterization and hepatoprotective effects of polysaccharides fromStachys floridana Schuttl. ex Benth. Carbohydr. Polym. 87, 1390–1398, http://dx.doi.org/10.1016/j.carbpol.2011.09.032.
Maronpot, R.R., Yoshizawa, K., Nyska, A., Harada, T., Flake, G., Mueller, G., et al, (2010), Hepatic enzyme induction: histopathology. Toxicol Pathol,: 38(5), 776–795. https://doi.org/10.1177/0192623310373778
Mathurin, P., Bataller, R., (2015). Trends in the management and burden of alcoholic liver disease. J. Hepatol. 62, S38–S46, http://dx.doi.org/10.1016/j.jhep.2015.03.006.
Mayans, L. Nephrolithiasis. Prim. Care, (2019): 46 (2), 203–212. https://doi.org/10.1016/j.pop.2019.02.001
Mohd Ali, N., Mohd Yusof, H., Long, K., Yeap, S.K., Ho, W.Y., Beh, B.K., et al, (2013), Antioxidant and hepatoprotective effect of aqueous extract of germinated and fermented mung bean on ethanol-mediated liver damage. BioMed Res., Int.: 93613. https://doi.org/10.1155/2013/693613
Mohd Esa, K. K. Abdul Kadir, Z. Amom, & Azlan, A., (2013), Antioxidant activity of white rice, brown rice and germinated brown rice (in vivo and in vitro) and the effects on lipid peroxidation and liver enzymes in hyperlipidaemic rabbits,” Food Chem, vol. 141, no. 2, pp. 1306–1312.
Mukesh, SS., Hui, B.J. Subramaniam, K., Valeisamy, B.D. Yean, L.K. Balaji, K. (2014), Free Radic Antioxid, 4, 33-39
Ndrepepa, G. (2020). Aspartate aminotransferase and cardiovascular disease—a narrative review. J Lab Prec Med, 6. doi:10.21037/jlpm-20-93
Oh, R.C., Hustead, T.R., Ali, S.M., & Pantsari, M.W. (2017), Mildly Elevated Liver Transaminase Levels: Causes and Evaluation. Am Fam Physician: 96(11), 709–715.
Okuonghae, H.O., Ighogboja, I.S., Lawson, J.O., & Nwana, E.J. (1992). Diethylene glycol poisoning in Nigerian children. Annals Trop Paediatr, 12(3), 235–238. https://doi.org/10.1080/02724936.1992.11747577
Ray, L., Nanda, S. K., Chatterjee, A., Sarangi, R., & Ganguly, S. (2015), A comparative study of serum aminotransferases in chronic kidney disease with and without end-stage renal disease: Need for new reference ranges. Int. J. Appl. Basic Med.: 5(1), 31–35. https://doi.org/10.4103/2229-516X.149232
Schmeltzer, P.A., Kosinski, A.S., Kleiner, D.E., Hoofnagle, J.H., Stolz, A., Fontana, et al, (2016). Liver injury from nonsteroidal anti-inflammatory drugs in the United States. Liver Intl, 36(4), 603–609. https://doi.org/10.1111/liv.13032
Suroowan, S., & Mahomoodally, M. F. (2019). Herbal Medicine of the 21st Century: A Focus on the Chemistry, Pharmacokinetics and Toxicity of Five Widely Advocated Phytotherapies. Curr Top Med Chem, 19(29), 2718–2738. https://doi.org/10.2174/1568026619666191112121330
Susilo, J., Purwanto B., Doewes, M, Indarto, D., & Muktiwi, D.R., (2021), Bread Fruit Leaf Extract Composition And Its Effect On Oxalate And Leukocyte Profiles In Hyperoxaluric Rats Induced By Ethylene Glycol, IJPSR, 12(8): 1000-09. https://dx.doi.org/10.13040/IJPSR.0975-8232.12(8).1000-09
Susilo, J., Ulya, H, & Furdiyanti, N.H, (2018), Effect of Administration of Apium Graveolens L. Leaf Extract on Reduction of Creatinine and Urea Levels in Rat Serum Induced by Ethylene Glycol, Proceedings of the Unimus National Seminar, 1, 104- 113.10.
Thapa, B.R., & Walia, A. (2007), Liver function tests and their interpretation. Indian J. Paed, : 74(7), 663–671. https://doi.org/10.1007/s12098-007-0118-7
Wang, Y., Li, J., Ren, Y.Y., & Zhao, H. (2013), The levels of liver enzymes and atypical lymphocytes are higher in youth patients with infectious mononucleosis than in preschool children. Clin Mol Hepatol. : 19(4), 382–388. https://doi.org/10.3350/cmh.2013.19.4.382
Zeng, B., Su, M., Chen, Q., Chang, Q., Wang, W., Li, H., (2017). Protective effect of a polysaccharide from Anoectochilus roxburghii against carbon tetrachloride- induced acute liver injury in mice. J. Ethnopharmacol. 200, 124–135, http://dx.doi.org/10.1016/j.jep.2017.02.018.
Zhang J., Wang Q., Xu, C., Lu, Y. Hu, H., Qin,B., et al, (2017), MitoTEMPO prevents oxalate induced injury in NRK-52E cells via inhibiting mitochondrial dysfunction and modulating oxidative stress. Oxid. Med. Cell Longev.;:9. https://doi.org/10.1155/2017/7528090.7528090
Published
2024-06-10
How to Cite
Susilo, J., Purwanto, B., Doewes, M., & Indarto, D. (2024). The Protective Effect of Artocarpus altilis Leaf Extract on Rat Models of Diethylene Glycol-Induced Hepatotoxicity. Indonesian Journal of Pharmacy, 35(2), 315–324. https://doi.org/10.22146/ijp.4891
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Research Article
