Acute and Chronic Toxicity of Thioacteamide and Alterations in Blood Cell Indices in Rats

Abstract

Background: Thioacetamide (TAA) has been used extensively in the development of suitable animal models of acute and chronic liver injury employing various doses, times and routes of its administration, particularly in drinking water due to its resemblance with human liver fibrosis and cirrhosis. The aim of this study was to investigate and compare hematological alteration during the acute and chronic liver inflammation. Methods: Acute Liver inflammation was induced in Wistar rats via intraperitoneal injection of thioacetamide and the animals were sacrificed 12 h after the TAA administration. Induction of chronic liver inflammation was performed by continuous administration of TAA in the drinking water (200 mg/L) during 18 weeks of experiment. After that all animals were sacrificed and Blood samples were collected for further analysis. Results: Single intra peritoneal injection of TAA (300 mg/kg B.W.) induced an acute condition with hematological changes including leukocytosis with marked neutrophilia (P = 0.0429), lymphopenia, thrombocytosis as well as increased hemoglobin concentration (P < 0.05) and decline of erythrocytic count (P = 0.0009). Eighteen weeks of uninterrupted supply of TAA (200 mg/L) in drinking water lead to chronic inflammation and the hematological alterations were leucopenia (P = 0.0197) accompanied with neutropenia and thrombocytopenia. Increase in RBCs (P = 0.0073) and Hb contents was also observed with a decline of red cell indices. Conclusion: Taken together these findings we can conclude that the animals respond differently under acute and chronic inflammatory condition with TAA administration. Leukocytosis with marked neutrophilia, thrombocytosis as well as increased hemoglobin concentration and decline of erythrocytic count were observed in acute while leucopenia accompanied with neutropenia and thrombocytopenia and increase in RBCs, Hb and Hct was also observed with a decline of other red cell indices during chronic phase.

Share and Cite:

M. Abbasi, T. Akhtar, I. Malik, S. Fatima, B. Khawar, K. Mujeeb, G. Mustafa, S. Hussain, J. Iqbal and N. Sheikh, "Acute and Chronic Toxicity of Thioacteamide and Alterations in Blood Cell Indices in Rats," Journal of Cancer Therapy, Vol. 4 No. 1, 2013, pp. 251-259. doi: 10.4236/jct.2013.41032.

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1] J. Chilakapati, K. Shankar, M. C. Korrapati, R. A. Hill and H. M. Mehendale, “Saturation Toxicokinetics of Thioacetamide: Role in Initiation of Liver Injury,” Drug Metabolism and Disposition, Vol. 33, No. 12, 2005, pp. 1877-1885.
[2] J. F. Childs and E. A. Siegler, “Compound for Control of Orange Decays,” Science, Vol. 102, No. 2538, 1945, pp. 68-69. doi:10.1126/science.102.2638.68
[3] O. G. Fitzhugh and A. A. Nelson, “Liver Tumors in Rats Fed Thiourea or Thioacetamide,” Science, Vol. 108, No. 2814, 1948, pp. 626-628. doi:10.1126/science.108.2814.626
[4] J. W. Lee, K. D. Shin, M. Lee, E. J. Kim, S. S. Han, M. Y. Han, et al., “Role of Metabolism by Flavin-Containing Monooxygenase in Thioacetamide-Induced Immunosuppression,” Toxicology Letters, Vol. 136, No. 3, 2003, pp. 163-172. doi:10.1016/S0378-4274(02)00333-8
[5] J. M. Yang, D. W. Han, C. M. Xie, Q. C. Liang, Y. C. Zhao and X. H. Ma, “Endotoxins Enhance Hepatocarcinogenesis Induced by Oral Intake of Thioacetamide in Rats,” World Journal of Gastroenterology, Vol. 4, No. 2, 1998, pp. 128-132.
[6] S. Chanda and M. Mehendale, “Role of Nutritional Fatty Acid and L-Carnitine in the Final Outcome of Thioacetamide Hepatotoxicity,” The FASEB Journal, Vol. 8, No. 13, 1994, pp. 1061-1068.
[7] W. R. Porter, M. J. Gudzinowicz and R. A. Neal, “Thioacetamide-Induced Hepatic Necrosis. II. Pharmacokinetics of Thioacetamide and Thioacetamide-S-Oxide in the Rat,” Journal of Pharmacology and Experimental Therapeutics, Vol. 208, No. 3, 1979, pp. 386-391.
[8] A. al-Bader, T. C. Mathew, M. Khoursheed, S. Asfar, H. al-Sayer and H. M. Dashti, “Thioacetamide Toxicity and the Spleen: Histological and Biochemical Analysis,” Anatomia, Histologia, Embryologia, Vol. 29, No. 1, 2000, pp. 3-8. doi:10.1046/j.1439-0264.2000.00207.x
[9] E. A. Barker and E. A. Smuckler, “Nonhepatic Thioacetamide Injury. II. The Morphologic Features of Proximal Renal Tubular Injury,” American Journal of Pathology, Vol. 74, No. 3, 1974, pp. 575-590.
[10] S. M. Latha, M. R. Pai and P. K. Pai, “Thioacetamide Toxicity and the Lung: Histological Analysis,” Indian Journal of Physiology and Pharmacology, Vol. 47, No. 4, 2003, pp. 476-478.
[11] M. A. Ortega, M. I. Torres, M. I. Fernandez, A. Rios, A. Sanchez-Pozo and A. Gil, “Hepatotoxic Agent Thioacetamide Induces Biochemical and Histological Alterations in Rat Small Intestine,” Digestive Diseases and Sciences, Vol. 42, No. 8, 1997, pp. 1715-1723. doi:10.1023/A:1018817600238
[12] A. A. Al-Bader, T. C. Mathew, H. Abul, M. Al-Mosawi, H. M. Dashti, D. Kumar, et al., “Thioacetamide Induced Changes in Trace Elements and Kidney Damage,” The Journal of Trace Elements in Experimental Medicine, Vol. 12, No. 1, 1999, pp. 1-14. doi:10.1002/(SICI)1520-670X(1999)12:1<1::AID-JTRA1>3.0.CO;2-L
[13] E. A. Barker and E. A. Smuckler, “Altered Microsome Function during Acute Thioacetamide Poisoning,” Molecular Pharmacology, Vol. 8, No. 3, 1972, pp. 318-326.
[14] E. Chieli and G. Malvaldi, “Role of the Microsomal Fad-Containing Monooxygenase in the Liver Toxicity of Thioacetamide S-Oxide,” Toxicology, Vol. 31, No. 1, 1984, pp. 41-52. doi:10.1016/0300-483X(84)90154-9
[15] T. Y. Low, C. K. Leow, M. Salto-Tellez and M. C. Chung, “A Proteomic Analysis of Thioacetamide-Induced Hepatotoxicity and Cirrhosis in Rat Livers,” Proteomics, Vol. 4, No. 12, 2004, pp. 3960-3974. doi:10.1002/pmic.200400852
[16] K. H. Kim, J. H. Bae, S. W. Cha, S. S. Han, K. H. Park and T. C. Jeong, “Role of Metabolic Activation by Cytochrome P450 in Thioacetamide-Induced Suppression of Antibody Response in Male BALB/c Mice,” Toxicology Letters, Vol. 114, No. 1-3, 2000, pp. 225-235. doi:10.1016/S0378-4274(00)00168-5
[17] N. Sanz, F. C. Diez, S. L. Fernandez, A. Alvarez and M. Cascales, “Necrogenic and Regenerative Responses of Liver of Newly Weaned Rats against a Sublethal Dose of Thioacetamide,” Biochimica et Biophysica Acta (BBA)— Protein Structure and Molecular Enzymology, Vol. 1384, No. 1, 1998, pp. 66-78. doi:10.1016/S0167-4838(97)00218-5
[18] A. Zaragoza, D. Andrs, D. Sarrin and M. Cascales, “Potentiation of Thioacetamide Hepatotoxicity by Phenobarbital Pretreatment in Rats. Inducibility of FAD Monooxygenase System and Age Effect,” Chemico-Biological Interactions, Vol. 124, No. 2, 2000, pp. 87-101. doi:10.1016/S0009-2797(99)00147-7
[19] F. Sun, S. Hayami, Y. Ogiri, S. Haruna, K. Tanaka, Y. Yamada, et al., “Evaluation of Oxidative Stress Based on Lipid Hydroperoxide, Vitamin C and Vitamin E during Apoptosis and Necrosis Caused by Thioacetamide in Rat Liver,” Biochimica et Biophysica Acta (BBA)—Molecular Basis of Disease, Vol. 1500, No. 2, 2000, pp. 181-185. doi:10.1016/S0925-4439(99)00100-3
[20] N. J. Waters, C. J. Waterfield, R. D. Farrant, E. Holmes and J. K. Nicholson, “Metabonomic Deconvolution Of Embedded Toxicity: Application to Thioacetamide Hepato- and Nephrotoxicity,” Chemical Research in Toxicology, Vol. 18, No. 4, 2005, pp. 639-654. doi:10.1021/tx049869b
[21] M. E. Caballero, J. Berlanga, D. Ramirez, P. Lopez-Saura, R. Gozalez, D. N. Floyd, et al., “Epidermal Growth Factor Reduces Multiorgan Failure Induced by Thioacetamide,” Gut, Vol. 48, No. 1, 2001, pp. 34-40. doi:10.1136/gut.48.1.34
[22] P. David, E. Alexandre, M. P. Chenard-Neu, P. Wolf, D. Jaeck and L. Richert, “Failure of Liver Cirrhosis Induction by Thioacetamide in Nagase Analbuminaemic Rats,” Laboratory Animals, Vol. 36, No. 2, 2002, pp. 158-164. doi:10.1258/0023677021912442
[23] A. Watanabe, M. A. Sohail, D. A. Gomes, A. Hashmi, J. Nagata, F. S. Sutterwala, S. Mahmood, M. N. Jhandier, Y. Shi, R. A. Flavell and W. Z. Mehal, “Inflammasomemediated Regulation of Hepatic Stellate Cells,” American Journal of Physiology—Gastrointestinal and Liver Physiology, Vol. 296, No. 6, 2009, pp. G1248-G1257. doi:10.1152/ajpgi.90223.2008
[24] S. K. Ramaiah, U. Apte and H. M. Mehendale, “Cytochrome P4502E1 Induction Increases Thioacetamide Liver Injury in Diet-Restricted Rats,” Drug Metabolism and Disposition, Vol. 29, No. 8, 2001, pp. 1088-1095.
[25] P. H. Rondo, A. Conde, M. C. Souza and A. Sakuma, “Iron Deficiency Anaemia and Blood Lead Concentrations in Brazilian Children,” Transactions of the Royal Society of Tropical Medicine and Hygiene, Vol. 105, No. 9, 2011, pp. 525-530. doi:10.1016/j.trstmh.2011.05.012
[26] M. Mulas, B. Perinu and A. H. D. Francesconi, “Evaluation of Spontaneous Oleander (Nerium oleander L.) as a Medicinal Plant,” Journal of Herbs, Spices & Medicinal Plants, Vol. 9, No. 2-3, 2002, pp. 121-125. doi:10.1300/J044v09n02_17
[27] P. M. Huet, L. Giroux, M. Laurens and D. Crenesse, “Effect of Cold Ischemia Warm Reperfusion on the Cirrhotic Rat Liver,” Liver Transplantation, Vol. 14, No. 4, 2008, pp. 486-493. doi:10.1002/lt.21392
[28] T. Matsuhashi, M. Otaka, M. Odashima, M. Jin, K. Komatsu, N. Konishi, I. Wada, T. Sato, Y. Horikawa, R. Ohba, J. Oyake, N. Hatakeyama and S. Watanabe, “Specific Type IV Phosphodiesterase Inhibitor Ameliorates Thioacetamide-Induced Liver Injury in Rats,” Journal of Gastroenterology and Hepatology, Vol. 20, No. 1, 2005, pp. 135-140. doi:10.1111/j.1440-1746.2004.03512.x
[29] V. Gayathri, S. Ananthi, C. Chandronitha, G. Ramakrishnan, R. L. Sundaram and H. R. Vasanthi, “Cardioprotective Effect of Nerium Oleander Flower Against Isoproterenol-Induced Myocardial Oxidative Stress in Experimental Rats,” Journal of Cardiovascular Pharmacology and Therapeutics, Vol. 16, No. 1, 2011, pp. 96-104. doi:10.1177/1074248410381759
[30] J. S. Kang, H. Wanibuchi, K. Morimura, R. Puatanachokchai, E. I. Salim, A. Hagihara, et al., “Enhancement by Estradiol 3-Benzoate in Thioacetamide-Induced Liver Cirrhosis of Rats,” Toxicological Sciences, Vol. 85, No. 1, 2005, pp. 720-726. doi:10.1093/toxsci/kfi113
[31] M. A. Constantinou, S. E. Theocharis and E. Mikros, “Application of Metabonomics on an Experimental Model of Fibrosis and Cirrhosis Induced by Thioacetamide in Rats,” Toxicology and Applied Pharmacology, Vol. 218, No. 1, 2007, pp. 11-19. doi:10.1016/j.taap.2006.10.007
[32] C. N. Yeh, A. Maitra, K. F. Lee, Y. Y. Jan and M. F. Chen, “Thioacetamide-Induced Intestinal-Type Cholangiocarcinoma in Rat: An Animal Model Recapitulating the Multi-Stage Progression of Human Cholangiocarcinoma,” Carcinogenesis, Vol. 25, No. 4, 2004, pp. 631-636. doi:10.1093/carcin/bgh037
[33] H. Shapiro, M. Ashkenazi, N. Weizman, M. Shahmurov, H. Aeed and R. Bruck, “Curcumin Ameliorates Acute Thioacetamide-Induced Hepatotoxicity,” Journal of Gastroenterology and Hepatology, Vol. 21, No. 2, 2006, pp. 358-366. doi:10.1111/j.1440-1746.2005.03984.x
[34] N. K. Gupta and V. K. Dixit, “Hepatoprotective Activity of Cleome Viscosa Linn. Extract against Thioacetamide-Induced Hepatotoxicity in Rats,” Natural Product Research, Vol. 23, No. 14, 2009, pp. 1289-1297. doi:10.1080/14786410802447302
[35] J. H. An, J. Seong, H. Oh, W. Kim, K. H. Han and Y. H. Paik, “Protein Expression Profiles in a Rat Cirrhotic Model Induced by Thioacetamide,” Korean Journal of Hepatology, Vol. 12, No. 1, 2006, pp. 93-102.
[36] X. Li, I. S. Benjamin and B. Alexander, “Reproducible Production of Thioacetamide-Induced Macronodular Cirrhosis in the Rat with No Mortality,” Journal of Hepatology, Vol. 36, No. 4, 2002, pp. 488-493. doi:10.1016/S0168-8278(02)00011-9
[37] M. J. Perez, A. Suarez, J. A. Gomez-Capilla, F. Sanchez-Medina and A. Gil, “Dietary Nucleotide Supplementation Reduces Thioacetamide-Induced Liver Fibrosis in Rats,” The Journal of Nutrition, Vol. 132, No. 4, 2002, pp. 652-657.
[38] T. M. Rahman and H. J. F. Hodgson, “The Effects of Early and Late Administration of Inhibitors of inducible Nitric Oxide Synthase in a Thioacetamide-Induced Model of Acute Hepatic Failure in the Rat,” Journal of Hepatology, Vol. 38, No. 5, 2003, pp. 583-590. doi:10.1016/S0168-8278(03)00050-3
[39] T. M. Rahman and H. J. Hodgson, “Animal Models of Acute Hepatic Failure,” International Journal of Experimental Pathology, Vol. 81, No. 2, 2000, pp. 145-157. doi:10.1046/j.1365-2613.2000.00144.x
[40] M. Belanger and R. Butterworth, “Acute Liver Failure: A Critical Appraisal of Available Animal Models,” Metabolic Brain Disease, Vol. 20, No. 4, 2005, pp. 409-423. doi:10.1007/s11011-005-7927-z
[41] P. Stankova, O. Kucera, H. Lotkova, T. Rousar, R. Endlicher and Z. Cervinkova, “The Toxic Effect of Thioacetamide on Rat Liver in Vitro,” Toxicology in Vitro, Vol. 24, No. 8, 2010, pp. 2097-2103. doi:10.1016/j.tiv.2010.06.011
[42] T. M. Chen, Y. M. Subeq, R. P. Lee, T. W. Chiou and B. G. Hsu, “Single Dose Intravenous Thioacetamide Administration as a Model of Acute Liver Damage in Rats,” International Journal of Experimental Pathology, Vol. 89, No. 4, 2008, pp. 223-231. doi:10.1111/j.1365-2613.2008.00576.x
[43] M. I. Torres, M. I. Fern+índez, A. Gil and A. Ríos, “Dietary Nucleotides Have Cytoprotective Properties in Rat Liver Damaged by Thioacetamide,” Life Sciences, Vol. 62, No. 1, 1997, pp. 13-22. doi:10.1016/S0024-3205(97)01033-3
[44] S. K. Natarajan, S. Thomas, P. Ramamoorthy, J. Basivireddy, A. B. Pulimood, A. Ramachandran, et al., “Oxidative Stress in the Development of Liver Cirrhosis: A Comparison of Two Different Experimental Models,” Journal of Gastroenterology and Hepatology, Vol. 21, No. 6, 2006, pp. 947-957. doi:10.1111/j.1440-1746.2006.04231.x
[45] W. Olipitz, D. Strunk, C. Beham-Schmid and H. Sill, “Neutrophilic Leukemoid Reaction as the Presenting Feature of de Novo and Therapy-Related Acute Leukemias,” Acta Haematologica, Vol. 111, No. 4, 2004, pp. 233-234. doi:10.1159/000077574
[46] A. Ballinger, “Gastroenterology and Anaemia,” Medicine, Vol. 35, No. 3, 2007, pp. 142-146.
[47] O. M. P. Jolobe, “Prevalence of Hypochromia (without Microcytosis) vs Microcytosis (without Hypochromia) in Iron Deficiency,” Clinical & Laboratory Haematology, Vol. 22, No. 2, 2000, pp. 79-80. doi:10.1046/j.1365-2257.2000.00293.x
[48] G. S. Travlos, R. W. Morris, M. R. Elwell, A. Duke, S. Rosenblum and M. B. Thompson, “Frequency and Relationships of Clinical Chemistry and Liver and Kidney Histopathology Findings in 13-Week Toxicity Studies in Rats,” Toxicology, Vol. 107, No. 1, 1996, pp. 17-29. doi:10.1016/0300-483X(95)03197-N
[49] D. W. Kaufman, J. P. Kelly, C. B. Johannes, A. Sandler, D. Harmon, P. D. Stolley, et al., “Acute Thrombocytopenic Purpura in Relation to the Use of Drugs,” Blood, Vol. 82, No. 9, 1993, pp. 2714-2718.
[50] J. N. George, G. E. Raskob, S. R. Shah, M. A. Rizvi, S. A. Hamilton, S. Osborne, et al., “Drug-Induced Thrombocytopenia: A Systematic Review of Published Case Reports,” Annals of Internal Medicine, Vol. 129, No. 11, 1998, pp. 886-890.
[51] D. B. Cines, J. B. Bussel, H. A. Liebman and E. T. Luning Prak, “The ITP Syndrome: Pathogenic and Clinical diversity,” Blood, Vol. 113, No. 26, 2009, pp. 6511-6521. doi:10.1182/blood-2009-01-129155
[52] D. Nantakomol, A. Palasuwan, M. Chaowanathikhom, S. Soogarun and M. Imwong, “Red Cell and Platelet Derived Microparticles Are Increased in g6pd Deficient Subjects,” European Journal of Haematology, Vol. 89, No. 5, 2012, pp. 423-429.
[53] S. Fatma, Batu &, zlem, E. Yildirim, K. Erol, S. Deliorman, et al., “Ciprofloxacin and Pefloxacin Suppress the Inflammatory Response in Rats,” Journal of Health Science, Vol. 49, No. 5, 2003, pp. 391-394. doi:10.1248/jhs.49.391
[54] A. C. A. Moura, E. L. F. Silva, M. C. A. Fraga, A. G. Wanderley, P. Afiatpour and M. B. S. Maia, “Antiinflammatory and Chronic Toxicity Study of the Leaves of Ageratum Conyzoides L. in Rats,” Phytomedicine, Vol. 12, No. 1-2, 2005, pp. 138-142. doi:10.1016/j.phymed.2003.12.003
[55] S. P. Hussain and C. C. Harris, “Inflammation and Cancer: An Ancient Link with Novel Potentials,” International Journal of Cancer, Vol. 121, No. 1-2, 2007, pp. 2373-2380. doi:10.1002/ijc.23173
[56] H. Lu, W. Ouyang and C. Huang, “Inflammation, a Key Event in Cancer Development,” Molecular Cancer Research, Vol. 4, No. 4, 2006, pp. 221-233. doi:10.1158/1541-7786.MCR-05-0261
[57] M. Balamurugan, K. Parthasarathi, E. L. Cooper and L. S. Ranganathan, “Earthworm Paste (Lampito mauritii, Kinberg) Alters Inflammatory, Oxidative, Haematological and Serum Biochemical Indices of Inflamed Rat,” European Review for Medical and Pharmacological Sciences, Vol. 11, No. 2, 2007, pp. 77-90.
[58] G. Bartosz, “Free Radicals in Biology and Medicine,” Cell Biology International, Vol. 24, No. 10, 2000, p. 764. doi:10.1006/cbir.1999.0607
[59] A. Z. Reznick, N. Shehadeh, Y. Shafir and R. M. Nagler, “Free Radicals Related Effects and Antioxidants in Saliva and Serum of Adolescents with Type 1 Diabetes Mellitus,” Archives of Oral Biology, Vol. 51, No. 8, 2006, pp. 640-648. doi:10.1016/j.archoralbio.2006.02.004
[60] K. Doi, S. Kurabe, N. Shimazu and M. Inagaki, “Systemic Histopathology of Rats with CCl4-Induced Hepatic Cirrhosis,” Laboratory Animals, Vol. 25, No. 1, 1991, pp. 21-25. doi:10.1258/002367 791780808121
[61] N. Sheikh, K. Tron, J. Dudas and G. Ramadori, “Cytokine-Induced Neutrophil Chemoattractant-1 is Released by the Noninjured Liver in a Rat Acute-Phase Model,” Laboratory Investigation, Vol. 86, No. 8, 2006, pp. 800-814.
[62] M. I. Al-Farwachi, M. S. Rhaymah and B. A. Al-Badrani, “Acute Toxicity of Nerium Oleander Aqueous Leaf Extract in Rabbits,” Iraqi Journal of Veterinary Sciences, Vol. 22, No. 1, 2008, pp. 1-4.

Copyright © 2024 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.