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Carnitine deficiency: a possible risk factor in paracetamol hepatotoxicity

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Abstract

We have addressed in the current study the postulate whether or not carnitine deficiency would represent a risk factor in hepatotoxicity. Carnitine-deficient male Swiss albino rats were obtained following administration of d-carnitine (500 mg/kg, IP) for 10 consecutive days. Serum and liver carnitine levels, both total and free, were assessed to confirm carnitine depletion. Hepatotoxicity was induced by challenging animals with a single dose of paracetamol (1 g/kg, IP). Serum tumor necrosis factor (TNF-α) concentration, and serum activities of aspartate amino transferase (AST), alanine amino transferase (ALT) and alkaline phosphatase (ALP) were undertaken as biomarkers for toxicity. Liver contents of reduced glutathione (GSH), malondialdehyde (MDA), total nitric oxide (NO) and myeloperoxidase (MPO) activities were also investigated. Histopathological examination of liver sections was achieved to confirm the biochemical alterations. d-carnitine altered all biochemical markers and also induced mild tissue inflammation with dilatation and congestion of central and portal veins. Paracetamol produced an obvious hepatotoxicity model that was well characterized biochemically and morphologically. Combined administration of d-carnitine and paracetamol synergistically provoked marked toxicity that was more profound than either agent given alone. The present work was further extended to elucidate any hepatoprotective effect of carnitine supplementation in such toxicity paradigm. It was apparent that l-carnitine notably ameliorated all biochemical markers and also mitigated the gross histologic alterations induced by paracetamol. Data obtained so far would suggest that carnitine deficiency could possibly be a sequela as well as a causative clue for paracetamol hepatotoxicity.

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References

  • Abdel Salam OM, Baiuomy AR, El-Shenawy SM, Hassan NS (2005) Effect of pentoxifylline on hepatic injury caused in the rat by the administration of carbon tetrachloride or acetaminophen. Pharmacol Rep 57(5):596–603

    PubMed  CAS  Google Scholar 

  • Abdel-Zaher AO, Abdel-Rahman MM, Hafez MM, Omran FM (2007) Role of nitric oxide and reduced glutathione in the protective effects of aminoguanidine, gadolinium chloride and oleanolic acid against acetaminophen-induced hepatic and renal damage. Toxicology 234(1–2):124–134

    Article  PubMed  CAS  Google Scholar 

  • Al-Majed AA (2007) Carnitine deficiency provokes cisplatin-induced hepatotoxicity in rats. Basic Clin Pharmacol Toxicol 100(3):145–150

    Article  PubMed  CAS  Google Scholar 

  • Al-Majed AA, Sayed-Ahmed MM, Al-Yahya AA, Aleisa AM, Al-Rejaie SS, Al-Shabanah OA (2006) Propionyl-l-carnitine prevents the progression of cisplatin-induced cardiomyopathy in a carnitine-depleted rat model. Pharmacol Res 53(3):278–286

    Article  PubMed  CAS  Google Scholar 

  • Arrigoni-Martelli E, Caso V (2001) Carnitine protects mitochondria and removes toxic acyls from xenobiotics. Drugs Exp Clin Res 27(1):27–49

    PubMed  CAS  Google Scholar 

  • Bourdi M, Masubuchi Y, Reilly TP, Amouzadeh HR, Martin JL, George JW, Shah AG, Pohl LR (2002) Protection against acetaminophen-induced liver injury and lethality by interleukin 10: role of inducible nitric oxide synthase. Hepatology 35:289–298

    Article  PubMed  CAS  Google Scholar 

  • Broderick TL (2006) Hypocarnitinaemia induced by sodium pivalate in the rat is associated with left ventricular dysfunction and impaired energy metabolism. Drugs R D 7(3):153–161

    Article  PubMed  CAS  Google Scholar 

  • Bykov I, Järveläinen H, Lindros K (2003) l-carnitine alleviates alcohol-induced liver damage in rats: role of tumor necrosis factor-alpha. Alcohol 38(5):400–406

    CAS  Google Scholar 

  • Carter LA, Abney TO, Lapp DF (1995) Biosynthesis and metabolism of carnitine. J Child Neurol 10:(2S)3–7.

    Google Scholar 

  • Chaturvedi P, Machacha CN (2007) Efficacy of Raphanus sativus in the treatment of paracetamol-induced hepatotoxicity in albino rats. Br J Biomed Sci 64(3):105–108

    PubMed  CAS  Google Scholar 

  • DeVivo DC (2002) Effect of l-carnitine treatment for valproate-induced hepatotoxicity. Neurology 58(3):507–508

    PubMed  Google Scholar 

  • Ellman GL (1959) Tissue sulfhydryl groups. Arch Biochem Biophys 74:214–226

    Google Scholar 

  • Yen FL, Wu TH, Lt Lin, Lin C (2007) Hepatoprotective and antioxidant effects of Cuscuta chinensis against acetaminophen-induced hepatotoxicity in rats. J Ethnopharmacol 111(1):123–128

    Article  PubMed  Google Scholar 

  • Grypioti AD, Theocharis SE, Demopoulos CA, Papadopoulou-Daifoti Z, Basayiannis AC, Mykoniatis MG (2006) Effect of platelet-activating factor (PAF) receptor antagonist (BN52021) on acetaminophen-induced acute liver injury and regeneration in rats. Liver Int 26(1):97–105

    Article  PubMed  CAS  Google Scholar 

  • Grypioti AD, Mykoniatis M, Demopoulos CA, Kostopanagiotou G (2007) Recombinant platelet-activating factor-acetylhydrolase attenuates paracetamol-induced liver oxidative stress, injury, and regeneration. Dig Dis Sci 52(1):192–199

    Article  PubMed  CAS  Google Scholar 

  • Hartz AL (1947) Simultaneous histologic fixation and gross demonstration of calcification. Am J Clin Pathol 17:750–755

    CAS  Google Scholar 

  • Hinson JA, Reid AB, McCullough SS, James LP (2004) Acetaminophen-induced hepatotoxicity: role of metabolic activation, reactive oxygen/nitrogen species, and mitochondrial permeability transition. Drug Metab Rev 36(3–4):805–822

    Article  PubMed  CAS  Google Scholar 

  • Jaeschke H, Gores GJ, Cederbaum AI, Hinson JA, Pessayre D, Lemasters JJ (2002) Mechanisms of hepatotoxicity. ToxIcol Sci 65:166–176

    Article  PubMed  CAS  Google Scholar 

  • James LP, Mayeux PR, Hinson JA (2003) Acetaminophen-induced hepatotoxicity. Drug Metab Dispos 31:1499–1506

    Article  PubMed  CAS  Google Scholar 

  • Kaplowitz N (2004) Acetaminophen hepatoxicity: what do we know, what don’t we know, and what do we do next? Hepatology 40(1):23–26

    Article  PubMed  CAS  Google Scholar 

  • Karakoç E, Erdem S, Sökmensüer C, Kansu T (2006) Encephalopathy due to carnitine deficiency in an adult patient with gluten enteropathy. Clin Neurol Neurosurg 108(8):794–797

    Article  PubMed  Google Scholar 

  • Kato A, Gabay C, Okaya T, Lentsch AB (2002) Specific role of interleukin-1 in hepatic neutrophil recruitment after ischemia/reperfusion. Am J Pathol 161(5):1797–1803

    PubMed  CAS  Google Scholar 

  • Klein B, Read PA, Babson AL (1960) Rapid method for the quantitative determination of serum alkaline phosphatase. Clin Chem 6:269–275

    PubMed  CAS  Google Scholar 

  • Laskin DL, Gardner CR, Price VF, Jollow DJ (1995) Modulation of macrophage functioning abrogates the acute hepatotoxicity of acetaminophen. Hepatology 21:1045–1050

    Article  PubMed  CAS  Google Scholar 

  • Lee WM (2004) Acetaminophen and the U.S. Acute Liver Failure Study Group: lowering the risks of hepatic failure. Hepatology 40(1):6–9

    CAS  Google Scholar 

  • Longo N, Amat Di San Filippo C, Pasquali M (2006) Disorders of carnitine transport and the carnitine cycle. Am J Med Genet C Semin Med Genet 142(2):77–85

    Google Scholar 

  • LoVecchio F, Shriki J, Samaddar R (2005) L-carnitine was safely administered in the setting of valproate toxicity. Am J Emerg Med 23(3):321–322

    Article  PubMed  Google Scholar 

  • Maddrey WC (2005) Drug-induced hepatotoxicity. J Clin Gastroenterol 39:S83–S89

    Article  PubMed  Google Scholar 

  • Mahadevan SB, McKiernan PJ, Davies P, Kelly DA (2006) Paracetamol-induced hepatotoxicity. Arch Dis Child 91(7):598–603

    Article  PubMed  CAS  Google Scholar 

  • Manktelow A, Meyer A (1986) Lack of correlation between decreases chemotaxis and susceptibility to infection in burned rats. J Trauma 26:143–148

    Article  PubMed  CAS  Google Scholar 

  • Miranda KM, Espey MG, Wink DA (2001) A rapid, simple spectrophotometric method for simultaneous detection of nitrate and nitrite. Nitric Oxide 5(1):62–71

    Article  PubMed  CAS  Google Scholar 

  • Moreno FA, Macey H, Schriber B (2005) Carnitine levels in valproic acid-treated psychiatric patients: a cross-sectional study. J Clin Psychiatry 66(5):555–558

    Article  PubMed  CAS  Google Scholar 

  • Nezu J, Tamai I, Oku A, Ohashi R, Yabuuchi H, Hashimoto N, Nikaido H, Sai Y, Koizumi A, Shoji Y, Takada G, Matsuishi T, Yoshino M, Kato H, Ohura T, Tsujimoto G, Hayakawa J, Shimane M, Tsuji A (1999) Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion-dependent carnitine transporter. Nat Genet 21(1):91–4

    Article  PubMed  CAS  Google Scholar 

  • Pastorino JG, Snyder JW, Serroni A, Hoek JB, Farber JL (1993) Cyclosporin and carnitine prevent the anoxic death of cultured hepatocytes by inhibiting the mitochondrial permeability transition. J Biol Chem 268(19):13791–13798

    PubMed  CAS  Google Scholar 

  • Pons R, De Vivo DC (1995) Primary and secondary carnitine deficiency syndromes. J Child Neurol 10(Suppl. 2):S8–S24

    PubMed  Google Scholar 

  • Potter WZ, Davis DC, Mitchell JR, Jollow DJ, Gillette JR, Brodie BB (1973) Acetaminophen-induced hepatic necrosis. 3. Cytochrome P-450-mediated covalent binding in vitro. J Pharmacol Exp Ther 187(1):203–210

    PubMed  CAS  Google Scholar 

  • Prieto JA, Andrade F, Aldámiz-Echevarría L, Sanjurjo P (2006) Determination of free and total carnitine in plasma by an enzymatic reaction and spectrophotometric quantitation spectrophotometric determination of carnitine. Clin Biochem 39(10):1022–1027

    Article  PubMed  CAS  Google Scholar 

  • Raghavendran HB, Sathivel A, Devaki T (2006) Defensive nature of Sargassum polycystum (Brown alga) against acetaminophen-induced toxic hepatitis in rats: role of drug metabolizing microsomal enzyme system, tumor necrosis factor-alpha and fate of liver cell structural integrity. World J Gastroenterol 12(24):3829–3834

    PubMed  CAS  Google Scholar 

  • Reitman A, Frankel S (1957) The determination of serum glutamic oxaloacetic and glutamic pyruvic transaminases. Am J Clin Pathol 28:56–63

    PubMed  CAS  Google Scholar 

  • Rinaldo P, Matern D (2002) Fatty acid oxidation disorders. Annu Rev Physiol 64:477–502

    Article  PubMed  CAS  Google Scholar 

  • Roberts RA, Ganey PE, Ju C, Kamendulis LM, Rusyn I, Klaunig JE (2007) Role of the Kupffer Cell in Mediating Hepatic Toxicity and Carcinogenesis. Tox Sci 96(1):2–15

    Article  CAS  Google Scholar 

  • Rubio-Gozalbo ME, Bakker JA, Waterham HR, Wanders RJ (2004) Carnitine-acylcarnitine translocase deficiency, clinical, biochemical and genetic aspects. Mol Aspects Med 25(5–6):521–532

    Article  PubMed  CAS  Google Scholar 

  • Rumack BH (2004) Acetaminophen misconceptions. Hepatology. 40(1):10–15

    Article  PubMed  CAS  Google Scholar 

  • Sayed-Ahmed MM, Eissa MA, Kenawy SA, Mostafa N, Calvani M, Osman AM (2004) Progression of cisplatin-induced nephrotoxicity in a carnitine-depleted rat model. Chemotherapy 50(4):162–170

    Article  PubMed  CAS  Google Scholar 

  • Sener G, Ekşioğlu-Demiralp E, Cetiner M, Ercan F, Sirvanci S, Gedik N, Yeğen BC (2006) L-Carnitine ameliorates methotrexate-induced oxidative organ injury and inhibits leukocyte death. Cell Biol Toxicol 22(1):47–60

    Article  PubMed  CAS  Google Scholar 

  • Spasov AA, Iezhitsa IN (2005) Stereopharmacology of carnitine. Ross Fiziol Zh Im I M Sechenova 91(12):1469–1480

    PubMed  CAS  Google Scholar 

  • Spasov AA, Iezhitsa IN, Pisarev VB, Snigur GL, Kravchenko MS (2006) Changes in myocardium, skeletal muscle and liver of rats fed carnitine-deficient diet and treated with carnitine optical isomers. Morfologiia 129(3):48–52

    PubMed  CAS  Google Scholar 

  • Stanley CA (2004) Carnitine deficiency disorders in children, Ann NY Acad Sci 1033:42–51

    Article  PubMed  CAS  Google Scholar 

  • Toklu HZ, Sehirli AO, Velioğlu-Oğünç A, Cetinel S, Sener G (2006) Acetaminophen-induced toxicity is prevented by beta-D-glucan treatment in mice. Eur J Pharmacol 543(1–3):133–140

    Article  PubMed  CAS  Google Scholar 

  • Túnez I, Muñoz MC, Medina FJ, Salcedo M, Feijóo M, Montilla P (2007) Comparison of melatonin, vitamin E and l-carnitine in the treatment of neuro- and hepatotoxicity induced by thioacetamide. Cell Biochem Funct 25(2):119–127

    Article  PubMed  Google Scholar 

  • Uchiyama M, Mihara K (1978) Determination of malondialdehyde precursor in tissue by thiobarbituric acid test. Anal Biochem 86:271–278

    Article  PubMed  CAS  Google Scholar 

  • Winterbourn CC, Brennan SO (1997) Characterization of the oxidation products of the reaction between reduced glutathione and hypochlorous acid. Biochem J 326:87–92

    PubMed  CAS  Google Scholar 

  • Woldseth B, Rootwelt T (2006) Mitochondrial beta-oxidation defects. Tidsskr Nor Laegeforen 126(6):756–759

    PubMed  Google Scholar 

  • Wolters G, Kuijpers LP, Kacaki J, Shuurs AH (1977) Enzyme-linked immunosorbent assay for hepatitis B surface antigen. J Infect Dis 136:S311–S317

    Google Scholar 

  • Yapar K, Kart A, Karapehlivan M, Atakisi O, Tunca R, Erginsoy S, Citil M (2007) Hepatoprotective effect of l-carnitine against acute acetaminophen toxicity in mice. Exp Toxicol Pathol 59(2):121–128

    Article  PubMed  CAS  Google Scholar 

  • Yemitan OK, Izegbu MC (2006) Protective effects of Zingiber officinale (Zingiberaceae) against carbon tetrachloride and acetaminophen-induced hepatotoxicity in rats. Phytother Res 20(11):997–1002

    Article  PubMed  Google Scholar 

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  1. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Nasr City, Cairo, Egypt

    Hossam M. M. Arafa

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Arafa, H.M.M. Carnitine deficiency: a possible risk factor in paracetamol hepatotoxicity. Arch Toxicol 83, 139–150 (2009). https://doi.org/10.1007/s00204-008-0330-x

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