Estimation of vitamin C human protective dose for acetaminophen toxicity, using acute animal toxicity study

Abstract = 826 times | PDF = 576 times

Main Article Content

Mudhaffar I. Al-Farras Khalid K. Abdul-Razzak Mohammed Yacoub Wael M. Hananeh


Acetaminophen (APAP) is the main cause of fulminant hepatic failure. Vitamin C is a natural antioxidant with protective potentials against APAP toxic damage. In this animal study, and after an LD50 determination and selection of suitable lethal dose, the investigation was done to select a proper protective dose of vitamin C against lethal APAP dose. All 6 animal groups received a lethal dose of APAP (3250 mg/kg), group II, III and IV received 500, 1000 and 1500 mg/kg vitamin C respectively, group V received 1200 mg/kg N-Acetylcysteine (NAC), and group VI receive 1000 mg/kg vitamin C and 1200 mg/kg NAC. Mortality was recorded and liver histopathology was carried out. The results showed, the mortality rate in the group I was 68.75% and 37.5%, 31.25% in group II and III respectively, while group IV Showed a higher mortality rate and in group V and VI it was 25%. There was also a gradual reduction in the grade of histopathological damage in all groups, ranging from 2.4 ± 0.55 in group I to 0.4 ± 0.55 in group V and VI. In conclusion, vitamin C showed an increasing reduction in mortality and more histopathological protection, and it was more significant at 1000 mg/kg. NAC adds no more protection or reduction in mortality. The estimated protective dose of vitamin C was 700 to1127 mg for each gram of APAP. Incorporation of this dose of vitamin C with APAP preparations may be considered as a promising method for reducing mortality or severity of APAP intoxication.


Acetaminophen, Vitamin C, liver, protective dose, in vivo study


Download data is not yet available.

Article Details


[1] R. Jalan, R.Williams, J. Bernuau, “Comment: Paracetamol: are therapeutic doses entirely safe?,” The Lancet, vol. 368, pp. 2195-2196, 2006.
[2] G. Ostapowicz, RJ. Fontana, FV. Schiodt, A. Larson, TJ. Davern, SH. Han, et al, “Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States,” Ann Intern Med, vol. 137, pp. 947-54, 2002.
[3] J. Kurtovic, SM. Riordan, “Paracetamol-induced hepatotoxicity at recommended dosage,” J Intern Med, vol. 253, pp. 240-3, 2003.
[4] AJ. Makin, J. Wendon, R. Williams, “A 7-year experience of severe acetaminophen-induced hepatotoxicity (1987–1993),” Gastroenterology, vol. 109, pp. 1907–1916, 1995.
[5] M. Iqbal, W. J. Cash, S. Sarwar, P. A. et al, “Paracetamol overdose: the liver unit perspective Iron,” J Med Sci, vol. 181, pp. 439–443, 2012.
[6] A. Jones, “Over-the-counter analgesics: a toxicology perspective” Am J Ther, vol. 9, pp. 245–257. 2002.
[7] NM. Obeidat, RF. Abutayeh, KA. Hadidi, “Poisoning in Jordan: analysis of three years data from Jordan National drug and poison information center,” J Med J, vol. 44, pp. 298- 304, 2010.
[8] LF. Prescott, “Paracetamol (Acetaminophen) a Critical Bibliographic Review,” Taylor & Francis Ltd. London, pp. 67-102, 1996.
[9] JG. Bessems, NP. Vermeulen, “Paracetamol (acetaminophen)-induced toxicity: molecular and biochemical mechanisms, analogues and protective approaches,” Crit Rev Toxicol, vol. 31, pp. 55-138, 2001.
[10] Jr. Richie, CA. Lang, TS. Chen, “Acetaminophen-induced depletion of glutathione and cysteine in aging mouse kidney,” Biochem Pharmacol, vol. 44, pp. 129–135, 1992.
[11] I. Manov, M. Hirsh, TC. Ianccu, “Acetaminophen hepatotoxicity and mechanism of its protection by N-acetylcysteine: a study of Hep3B cells,” Exp Toxicol Pathol, vol. 53, pp. 489–500, 2002.
[12] G. Sener, O. Tosun, AÖ. Şehirli, et al, “Melatonin and N-acetylcysteine have beneficial effects during hepatic ischemia and reperfusion,” Life Sciences, vol. 72, pp. 2707-18, 2003.
[13] N. De Vries, S. De Flora, “N-Acetyl-l-Cysteine” J Cell Biochem Suppl, vol. 17, pp. 270-7, 1993.
[14] JO. Miners, R. Drew, DJ. Birkett, “Mechanism of action of paracetamol protective agents in mice in vivo,” Biochem Pharmaco, vol. 33, pp. 2995-3000, 1984.
[15] M. Zafarullah, WQ. Li, J. Sylvester, et al., “Molecular mechanisms of N-acetylcysteine actions,” Cell Mol Life Sci, vol. 60, pp. 6-20, 2003.
[16] C. Romero-Ferret, G. Mottot, J. Legros, et al., “Effect of vitamin C on acute paracetamol poisoning,” Toxicol Lett, vol. 18, pp. 153-6. 1983.
[17] DQ. Wang, BG. Ding, YQ. Ma, et al., “Studies on protective effect of total flavonoids of Astragalus on liver damage induced by paracetamol,” Zhongguo Zhong Yao Za Zhi, vol. 26, pp. 483-6, 2001.
[18] AA. Adeneye, JO. Olagunju, “Protective Effect of Oral Ascorbic Acid (Vitamin C) Against Acetaminophen-Induced Hepatic Injury in Rats,” African Journal of Biomedical Research, vol. 11, pp. 183-190, 2008.
[19] E. Ganesh, A. Chowdhury, T. Malarvani, et al., “Microscopical observation and biochemical analysis of liver for hepatoprotective effect of vitamin E & C in albino rats,” Int J Adv Lif Sci, vol.3, May – July, 2012. [Online]. Available; http:// www.
[20] PI. Dargan, AL. Jones, “Management of paracetamol poisoning,” Trends Pharmacol Sci, vol. 24, pp. 154-7, 2003.
[21] GG. Graham, RO. Day, A. Graudins, et al., “FDA proposals to limit the hepatotoxicity of paracetamol (acetaminophen): are they reasonable?,” Inflammopharmacology, vol. 18, pp. 47-55, 2010.
[22] AL. Jones, PI. Dargan, “Advances, challenges, and controversies in poisoning,” Emerg Med J, vol. 19, pp. 190-2, 2002.
[23] L. James, P. Mayeux, J. Hinson, “Acetaminophen-induced hepatotoxicity,” Drug Metab Dispos, vol. 31, pp. 1499-1506, 2003.
[24] MATERIAL SAFETY DATA SHEET NAME OF PRODUCT: Acetaminophen, [Online]. Available: [Accessed: Dec 2012].
[25] LC. Miller, ML. Tainter, “Estimation of LD50 and its error by means of log-probit graph paper,” Proc Soc Exp Bio Med, vol. 57, pp. 261, 1944.
[26] Ghosh MN. In Statistical Analysis, Fundamentals of Experimental Pharmacology, 2nd ed, Scientific Book Agency Calcutta, 1984, pp187–9.
[27] LF. Prescott, P. Roscoe, N. Wright, et al., “Plasma-paracetamol half-life and hepatic necrosis in patients with paracetamol overdosage,” Lancet, vol. 13, pp. 1(7698):519-22, 1971.
[28] AM. Larson, J. Polson, RJ. Fontana, et al, “Acute Liver Failure Study Group Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study,” Hepatology, vol. 42(6), pp. 1364-72, 2005.
[29] HL. Bonkovsky, RE. Kane, DP. Jones, et al., “Acute hepatic and renal toxicity from low doses of acetaminophen in the absence of alcohol abuse or malnutrition: evidence for increased susceptibility to drug toxicity due to cardiopulmonary and renal insufficiency,” Hepatology, vol. 19(5), pp. 1141-8, 1994.
[30] MW. Roomi, T. Kalinovsky, V. Ivanov, et al., “A nutrient mixture prevents acetaminophen hepatic and renal toxicity in ICR mice,” Hum Exp Toxicol, vol. 27 (3), pp. 223-30, 2008.
[31] A. Adejuwon, O. Olagunju, “Protective Effect of Oral Ascorbic Acid (Vitamin C) Against Acetaminophen-Induced Hepatic Injury in Rats,” African Journal of Biomedical Research, vol. 11, pp. 183-190, 2008.
[32] A. Mitra, AP. Kulkarni, VC. Ravikumar, et al., “Effect of ascorbic acid esters on hepatic glutathione levels in mice treated with a hepatotoxic dose of acetaminophen,” J Biochem Toxicol, vol. 6, pp. 93-100, 1991.
[33] D. Jonker, VS. Lee, RJ. Hargreaves, et al.,“Comparison of the effects of ascorbyl palmitate and L-ascorbic acid on paracetamol-induced hepatotoxicity in the mouse,” Toxicology, 5vol. 2, pp. 287-95, 1988.
[34] C. Madhu, Z. Gregus, “Klaassen, Biliary excretion of acetaminophen-glutathione as an index of toxic activation of acetaminophen: effect of chemicals that alter acetaminophen hepatotoxicity,” J Pharmacol Exp Ther, vol. 248, pp. 1069-77, 1989.
[35] M. Paolini, L. Pozzetti, G. Pedulli, et al., “The nature of prooxidant activity of vitamin C,” Life Sci, vol. 64(23), pp. 273-8, 1999.
[36] KK. Abdul-Razzak, KH. Alzoubi, SA. Abdo, et al, “High-dose vitamin C: Does it exacerbate the effect of psychosocial stress on liver? Biochemical and histological study,” Exp Toxicol Pathol, vol. 64, pp. 367-71, 2012.
[37] KK. Abdul-Razzak, MF. Yacoub, WM. Hananeh, et al., “Mega-dose vitamin C: Is it harmful to the liver? Biochemical and histological study in rats. Jordan Journal of Pharmaceuticals Sciences,” vol. 5, pp. 8-12, 2012.
[38] P. Abraham, “Mega dose of vitamin c augments the nephrotoxicity of paracetamol,” Nephrology, vol. 10, pp. 623-625, 2005.
[39] Guidance for Industry, “Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers,” U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER). July 2005. [Online]. Available: [Accessed on Jan 2013].
[40] RC1. Dart, AR. Erdman, KR. Olson, G. Christianson, AS. Manoguerra, PA. Chyka et al., “Acetaminophen poisoning: an evidence-based consensus guideline for out-of-hospital management,” Clinical toxicology (Philadelphia, Pa.), vol. 44 (1), pp. 1–18, 2006.