K. Z. Wershana
Department of Zoology,
Faculty of Science,
Alexandria University,
Alexandria, Egypt
A. Y. Daabees
Department of Zoology,
Faculty of Science,
Alexandria University,
Alexandria, Egypt
W. M. Shaban
Department of Zoology,
Faculty of Science,
Alexandria University,
Alexandria, Egypt
ABSTRACT
The research was conducted to investigate some physiological, biochemical and histopathological side effects induced by the administration of an overdose (900mg kg‾1 b.wt.) of the analgesic and antipyretic drug acetaminophen (APAP) on male albino rabbit. The work was also designed to compare the influence of L-methionine (37.7mg L-methionine kg‾1 b.wt. repeated every 4 for 12hr. up to a total dose of 142.8mg kg‾1 b.wt.) and/or phenethyl isothiocyanate (150μmol kg‾1 b.wt.) on the hazardous side effects of this drug. The results indicated that the administration of an overdose of APAP induced remarkable decreases in the number of red blood cells, haemoglobin contents (Hb), and haematocrit values (Ht). In addition to the elevations in the total bilirubin in the plasma. Also it induced leucopenia, granulocytopenia, and monocytopenia, which may be due to suppression in the organs necessary for their production (bone marrow and lymphatic organs) on the other hand, it induced lymphocytosis. It also caused liver dysfunction, as indicated by the elevation in the activities of alanine and aspartate aminotransferase (AST, ALT) and alkaline phosphatase (ALP) in plasma and the histopathological studies. It resulted in perturbations in the renal functions as indicated by marked rises in the concentrations of plasma creatinine, urea and uric acid. The histopathological examination indicated alterations in the cortex and S3 segment (pars recta). Overdose of the drug caused hypoglycaemia, increases in the concentration of total lipids and triglycerides and hypocholesterolaemia. The administration of L-methionine following an overdose of APAP succeeded in preventing all the disturbances in the tested hepatic and renal functions. It also increased the plasma and urinary levels of the detoxified metabolites of APAP (APAP-GSH, APAP-Cys, and APAP-merc) and decreased the plasma level of the parent APAP. The administration of PEITC following an overdose of drug succeeded in decreasing the haemato- and hepatotoxicities of APAP but it has serious effects on the renal function. The estimation of the drug and its metabolites indicated increases in the plasma and urinary concentration of APAP-gluc and APAP-sulphate as compared with APAP-treated group, while the concentration of the other studied metabolites decreased. The level of the parent APAP decreased in the plasma and administration of L-methionine together with PEITC succeeded completely in preventing the hepatotoxicity and in modulating the haematotoxicity but not the renal toxicity of APAP. The prominent outcome of this investigation that L-methionine is still superior to either PEITC alone or when administrated in combination with PEITC in modulating most of the toxic side effects of APAP.
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How to cite this article
K. Z. Wershana, A. Y. Daabees and W. M. Shaban, 2001. The Role of Two Antidotes in the Prevention of Acetaminophen - induced Toxicity in Male Rabbits. Journal of Medical Sciences, 1: 157-175.
DOI: 10.3923/jms.2001.157.175
URL: https://scialert.net/abstract/?doi=jms.2001.157.175
DOI: 10.3923/jms.2001.157.175
URL: https://scialert.net/abstract/?doi=jms.2001.157.175
REFERENCES
- Akca, S., I. Suleymanlar, M. Tuncer, F. Ersoy and M. Suleymanlar, 1999. Isolated acute renal failure due to paracetamol intoxication in an alcoholic patient. Nephron, 83: 270-271.
PubMedDirect Link - Barham, D. and P. Trinder, 1972. An improved colour reagent for the determination of blood glucose by the oxidase system. Analyst, 97: 142-145.
CrossRefPubMedDirect Link - Beales, D., D.P. Hue and A.E.M. McLean, 1985. Lipid peroxidation, Protein synthesis and protection by Calcium EDTA in Paracetamol injury to isolated hepatocytes. Biochem. Pharmacol., 34: 19-23.
CrossRefPubMedDirect Link - Bartolone, J.B., W.P. Beierschmitt, R.B. Birge, S.G.E. Hart, S. Wyand, S.D. Cohen and E.A. Khairallah, 1989. Selective acetaminophen metabolite binding to hepatic and extrahepatic proteins: An in vivo and in vitro analysis. Toxicol. Applied Pharmacol., 99: 240-249.
CrossRefPubMedDirect Link - Clark, R., V. Borirakchanyavat, A.R. Davidson, R. Williams, R.P.H. Thompson, B. Widdop and R. Goulding, 1973. Hepatic damage and death from overdose of paracetamol. Lancet, 13: 66-70.
CrossRefPubMedDirect Link - Crome, P., J.A. Vale, G.N. Volans, B. Widdop and R. Goulding, 1976. Oral methionine in the treatment of severe paracetamol (Acetaminophen) overdose. Lancet, 308: 829-830.
CrossRefPubMedDirect Link - Cadenas, E. and A. Boveris, 1980. Enhancement of hydrogen peroxide formation by protophores and ionophores in antimycin-supplemented mitochondria. Biochem. J., 180: 31-37.
CrossRefPubMedDirect Link - Dixon, M.F., J. Nimmo and L.F. Prescott, 1971. Experimental paracetamol-induced hepatic necrosis: A histopathological study. J. Pathol., 103: 225-229.
CrossRefDirect Link - Davis, M., D. Labadarios and R.S. Williams, 1976. Metabolism of paracetamol after therapeutic and hepatotoxic doses in man. J. Int. Med. Res., 4: 40-45.
CrossRefPubMedDirect Link - Davis, M., C.J. Simmons, N.G. Harrison and R. Williams, 1976. Paracetamol overdose in man: Relationship between pattern of urinary metabolites and severity of liver damage. Q. J. Med., 45: 181-191.
CrossRefPubMedDirect Link - Davis, M.H. and R.C. Schnell, 1991. Oltipraz-induced amelioration of acetaminophen hepatotoxicity in hamsters: II. Competitive shunt in metabolism via glucuronidation. Toxicol. Applied Pharmacol., 109: 29-40.
CrossRefDirect Link - Hart, S.G.E., D.S. Wyand, E.A. Khairallah and S.D. Cohen, 1996. Acetaminophen nephrotoxicity in the CD-1 mouse. II. Protection by probenecid and AT-125 without diminution of renal covalent binding. Toxicol. Applied Pharmacol., 136: 161-169.
CrossRefPubMedDirect Link - Fischer, L.J., M.D. Green and A.W. Harrman, 1981. Levels of acetaminophen and its metabolites in mouse tissues after a toxic dose. J. Pharmacol. Exp. Ther., 219: 281-286.
PubMedDirect Link - Gemborys, M.W. and G.H. Mudge, 1981. Formation and disposition of the minor metabolites of acetaminophen in the hamster. Drug Metab. Dispos., 9: 340-351.
PubMedDirect Link - Gregus, Z., C. Madhu and C.D. Klaassen, 1988. Species variation in toxication and detoxication of acetaminophen in vivo: a comparative study of biliary and urinary excretion of acetaminophen metabolites. J. Pharmacol. Exp. Ther., 244: 91-99.
PubMedDirect Link - Gartland, K.P.R., C.T. Eason, F.W. Bonner and J.K. Nicholson, 1990. Effects of biliary cannulation and buthionine sulphoximine pretreatment on the nephrotoxicity of para-aminophenol in the Fischer 344 rat. Arch. Toxicol., 64: 14-25.
CrossRefDirect Link - Hazelton, G.A., J.J. Hjelle and C.D. Klaassen, 1986. Effects of butylated hydroxyanisole on acetaminophen hepatotoxicity and glucuronidation in vivo. Toxicol. Applied Pharmacol., 83: 474-485.
CrossRefPubMedDirect Link - Harvison, P.J., F.P. Guengerich, M.S. Rashed and S.D. Nelson, 1988. Cytochrome P-450 isozyme selectivity in the oxidation of acetaminophen. Chem. Res. Toxicol., 1: 47-52.
CrossRefDirect Link - Henretig, F.M., S.M. Selbst, C. Forrest, T.K. Kearney, H. Orel, S. Werner and T.A. Williams, 1989. Repeated acetaminophen overdosing: Causing hepatotoxicity in children clinical reports and literature review. Clin. Pediatrics, 28: 525-528.
Direct Link - Harrison, P.M., R. Keays, G.P. Bray, G.J.M. Alexander and R. Williams, 1990. Improved outcome of paracetamol-induced fulminant hepatic failure by late administration of acetylcysteine. Lancet, 335: 1572-1573.
CrossRefPubMedDirect Link - Hoivik, D.J., J.E. Manautou, A. Tveit, S.G.E. Hart, E.A. Khairallah and S.D. Cohen, 1995. Gender-related differences in susceptibility to acetaminophen-induced protein arylation and nephrotoxicity in the CD-1 mouse. Toxicol. Applied Pharmacol., 130: 257-271.
CrossRefPubMedDirect Link - International Committee for Standardization in Haematology, 1978. Recommendations for reference method for haemoglobinometry in human blood (ICSH standard EP 6/2: 1977) and specifications for international haemiglobincyanide reference preparation (ICSH standard EP 6/3: 1977). J. Clin. Pathol., 31: 139-143.
CrossRefPubMedDirect Link - Jaeschke, H., 1990. Glutathione disulfide formation and oxidant stress during acetaminophen-induced hepatotoxicity in mice in vivo: The protective effect of allopurinol. J. Pharmacol. Exp. Ther., 255: 935-943.
PubMedDirect Link - Jones, A.L., P.C. Hayes, A.T. Proudfoot, J.A. Vale, L.F. Prescott and E.P. Krenzelok, 1997. Should methionine be added to every paracetamol tablet? Br. Med. J., 315: 301-304.
PubMedDirect Link - Klos, C., M. Koob, C. Kramer and W. Dekant, 1992. p-aminophenol nephrotoxicity: Biosynthesis of toxic glutathione conjugates. Toxicol. Applied Pharmacol., 115: 98-106.
CrossRefPubMedDirect Link - Lin, M.C., E.J. Wang, C. Patten, M.J. Lee, F. Xiao, K.R. Reuhl and C.S. Yang, 1996. Protective effect of diallyl sulfone against acetaminophen-induced hepatotoxicity in mice. J. Biochem. Toxicol., 11: 11-20.
PubMedDirect Link - Litovitz, T.L., L. Felberg, R.A. Soloway, M. Ford and R. Geller, 1995. 1994 Annual report of the American association of poison control centers toxic exposure surveillance system. Am. J. Emergency Med., 13: 551-597.
CrossRefPubMedDirect Link - Lee, S.S.T., J.T.M. Buters, T. Pineau, P. Fernandez-Salguero and F.J. Gonzalez, 1996. Role of CYP2E1 in the hepatotoxicity of acetaminophen. J. Biol. Chem., 271: 12063-12067.
CrossRefPubMedDirect Link - Li, Y., E. Wang, L. Chen, A.P. Stein, K.R. Reuhl and C.S. Yang, 1997. Effects of phenethyl isothiocyanate on acetaminophen metabolism and hepatotoxicity in mice. Toxicol. Applied Pharmacol., 144: 306-314.
CrossRefPubMedDirect Link - McLean, A.E.M. and P.A. Day, 1975. The effect of diet on the toxicity of paracetamol and the safety of paracetamol-methionine mixtures. Biochem. Pharmacol., 24: 37-42.
CrossRefDirect Link - Morgan, E.T., D.R. Koop and M.J. Coon, 1983. Comparison of six rabbit liver cytochrome P-450 isozymes in formation of a reactive metabolite of acetaminophen. Biochem. Biophys. Res. Commun., 112: 8-13.
CrossRefPubMedDirect Link - De Morais, S.M. and P.G. Wells, 1988. Deficiency in bilirubin UDP-glucuronyl transferase as a genetic determinant of acetaminophen toxicity. J. Pharmacol. Exp. Ther., 247: 323-331.
PubMedDirect Link - Moller-Hartmann, W. and C.P. Siegers, 1991. Nephrotoxicity of paracetamol in the rat-mechanistic and therapeutic aspects. J. Applied Toxicol., 11: 141-146.
CrossRefPubMedDirect Link - Madhu, C. and C.D. Klaassen, 1991. Protective effect of pregnenolone-16α-carbonitrile on acetaminophen-induced hepatotoxicity in hamsters. Toxicol. Applied Pharmacol., 109: 305-313.
CrossRefPubMedDirect Link - Manautou, J.E., D.J. Hoivik, A. Tveit, S.G.E. Hart, E.A. Khairallah and S.D. Cohen, 1994. Clofibrate pretreatment diminishes acetaminophen's selective covalent binding and hepatotoxicity. Toxical. Applied Pharmacol., 129: 252-263.
CrossRefPubMedDirect Link - Neuvonen, P.J., M. Vartainen and O. Tokola, 1983. Comparison of activated charcoal and ipecac syrup in prevention of drug absorption. Eur. J. Clin. Pharmacol., 24: 557-562.
CrossRefPubMedDirect Link - Newton, J.F., C.H. Kuo, G.M. DeShone, D. Hoefle, J. Bernstein and J.B. Hook, 1985. The role of p-aminophenol in acetaminophen-induced nephrotoxicity: Effect of bis(p-nitrophenyl) phosphate on acetaminophen and p-aminophenol nephrotoxicity and metabolism in Fischer 344 rats. Toxicol. Applied Pharmacol., 81: 416-430.
PubMedDirect Link - Prescott, L.F., G.R. Sutherland, J. Park, I.J. Smith and A.T. Proudfoot, 1976. Cysteamine, methionine and penicillamine in the treatment of paracetamol poisoning. Lancet, 2: 109-113.
CrossRefPubMedDirect Link - Printen, K.J., M.C. Brummel, E.S. Cho and L.D. Stegink, 1979. Utilization of D-methionine during total parenteral nutrition in postsurgical patients. Am. J. Clin. Nutr., 32: 1200-1205.
PubMedDirect Link - Pearson, T.C. and D.L. Guthrie, 1982. Trapped plasma in the microhematocrit. Am. J. Clin. Pathol., 78: 770-772.
PubMedDirect Link - Perry, I.J., H. Refsum, R.W. Morris, S.B. Ebrahim, P.M. Meland and A.G. Sapher, 1995. Prospective study of serum total homocysteine concentration and risk of stroke in middle-aged British men. Lancet, 346: 1395-1398.
CrossRefPubMedDirect Link - Roeschlau, P., E. Bernt and W. Gruber, 1974. Enzymatic determination of total cholesterol in serum. Z. Klin. Chem. Klin. Biochem., 12: 226-226.
PubMedDirect Link - Slattery, J.T., T.I. McRorie, R. Reynolds, T.F. Kalhorn, E.D. Kharasch and A.C. Eddy, 1989. Lack of effect of cimetidine on acetaminophen disposition in humans. Clin. Pharmacol. Ther., 46: 591-597.
CrossRefPubMedDirect Link - Stoner, G.D., D.T. Morrissey, Y.H. Heur, E.M. Daniel, A.J. Galati and S.A. Wagner, 1991. Inhibitory effects of phenethyl isothiocyanate on N-nitrosobenzylmethylamine carcinogenesis in the rat esophagus. Cancer Res., 51: 2063-2068.
PubMedDirect Link - Tephly, T.R. and P. Hibbeln, 1971. The effect of cobalt chloride administration on the synthesis of hepatic microsomal cytochrome P-450. Biochem. Biophys. Res. Commun., 42: 589-595.
CrossRefDirect Link - Thomas, C.E. and D.J. Reed, 1988. Effect of extracellular Ca++ omission on isolated hepatocytes. II. Loss of mitochondrial membrane potential and protection by inhibitors of uniport Ca++ transduction. J. Pharmacol. Exp. Ther., 245: 501-507.
Direct Link - Tirmenstein, M.A. and S.D. Nelson, 1989. Acetaminophen-induced oxidation of protein thiols. Contribution of impaired thiol-metabolizing enzymes and the breakdown of adenine nucleotides. J. Biol. Chem., 265: 3059-3065.
PubMedDirect Link - Thornton, J.R. and M.S. Losowsky, 1989. Fatal variceal haemorrhage after paracetamol overdose. Gut, 30: 1424-1425.
Direct Link - Thornton, J.R. and M.S. Losowsky, 1990. Severe thrombocytopenia after paracetamol overdose. Gut, 31: 1159-1160.
PubMedDirect Link - Vercesi, A., B. Reynafarje and A.L. Lehninger, 1978. Stoichiometry of H+ ejection and Ca2+ uptake coupled to electron transport in rat heart mitochondria. J. Biol. Chem., 253: 6379-6385.
Direct Link - Vale, J.A. and A.T. Proudfoot, 1995. Paracetamol (acetaminophen) poisoning. Lancet, 346: 547-552.
PubMedDirect Link - Whitcomb, D.C. and G.D. Block, 1994. Association of acetaminophen hepatotoxicity with fasting and ethanol use. JAMA., 272: 1845-1850.
PubMedDirect Link - Li, Y., E.J. Wang, L. Chen, A.P. Stein, K.R. Reuhl and C.S. Yang, 1997. Effects of phenethyl isothiocyanate on acetaminophen metabolism and hepatotoxicity in mice. Toxicol. Applied Pharmacol., 144: 306-314.
CrossRefDirect Link - Zaher, H., J.T.M. Buters, J.M. Ward, M.K. Bruno and A.M. Lucas et al., 1998. Protection against acetaminophen toxicity in CYP1A2 and CYP2E1 double-null mice. Toxicol. Applied Pharmacol., 152: 193-199.
CrossRefPubMedDirect Link