The protective role of l-carnitine against 1st- and 2nd-generation antihistamine-induced liver injury in mice
- 1 Downloads
H1 antihistamines are the most widely used drugs for relieving symptoms of histamine-mediated disease. Although chlorpheniramine maleate and cetirizine hydrochloride have tolerable side effects, they induce severe side effects on chronic use such as hepatitis and cholestatic jaundice. Oxidative stress has been implicated as a mechanism of drug-induced hepatotoxicity. l-Carnitine is an effective biological active compound that is involved in oxidation of fatty acids in the liver through transportation of fatty acids into the mitochondria for energy production from fat. l-Carnitine has well-known antioxidant properties, improves hepatic function, and improves mitochondrial function in hepatic cells. In the present study, we evaluated the possible role of oxidative stress and the therapeutic and hepatoprotective effect of l-carnitine on chlorpheniramine maleate– and cetirizine hydrochloride–induced liver damage during chronic use. Methods are measurement of ALT, AST, ALP and albumin serum levels and measurement of hepatic oxidative stress biomarkers MDA and GSH in groups with and without combination with l-carnitine. Histopathological examination of changes in hepatic tissue and scoring of the induced hepatic damage was conducted in all treatment groups. Co-treatment of l-carnitine with chlorpheniramine maleate and cetirizine hydrochloride significantly improved the deteriorated hepatic function as indicated by reduction in the serum levels of ALT, AST, ALP, and elevation in serum albumin levels compared with control and untreated groups. Moreover, co-administration of l-carnitine with chlorpheniramine maleate and cetirizine hydrochloride decreased hepatic MDA and elevated hepatic GSH levels compared with control and untreated groups. Ultrastructure examination of hepatic tissue found that co-treatment with l-carnitine decreased hepatic necrosis and damage. In conclusion, oxidative stress can be a possible explanation of hepatic damage induced by chronic therapy with chlorpheniramine maleate and cetirizine hydrochloride. l-Carnitine has prominent hepatoprotective effects on chlorpheniramine maleate– and cetirizine hydrochloride–induced hepatic damage possibly through improvement of hepatic function and decreasing oxidative stress.
KeywordsAntihistamine Chlorpheniramine maleate Cetirizine hydrochloride Liver Hepatotoxicity Oxidative stress l-Carnitine
The authors acknowledge the animal house of Assuit University for providing the experimental animals and every kind hand which helped and participated in the accomplishment of this work is deeply acknowledged.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.
- Arendt C, Bernheim J (1989) Double-blind comparison of maintenance treatment of chronic idiopathic urticaria by cetirizine and terfenadine. Curr Ther Res 46:724–734Google Scholar
- Bera F, Sipruhis JP, Jonville-Bera AP et al (1993) Cytolytic hepatic involvement after administration of cetirizine (Zyrtec) (in French). Gastroenterol Clin Biol 17:770–771Google Scholar
- Bertelli A, Cerrati A, Giovannini L, Mian M, Spaggiari P, Bertelli AE (1993) Protective action of L-carnitine and coenzyme Q10 against hepatic triglyceride infiltration induced by hyperbaric oxygen and ethanol. Drugs Exp Clin Res 2:65–68Google Scholar
- Coskun A, Yavasoglu I, Yasa MH, Culhaci N, Yukselen V (2018) Cetirizine-induced hepatotoxicity: case series and review of the literature. Gastroenterol Rep 6(3):228–230Google Scholar
- el-Sadek SE, Ibrahim SS, Abdel-Salam SA (1989) Effect of chloropheniramine maleate on liver and kidney functions as well as blood count of guinea pigs. Arch Exp Vet 43(2):249–253Google Scholar
- Ishikawa H, Takaki A, Tsuzaki R, Yasunaka T, Koike K, Shimomura Y, Seki H, Matsushita H, Miyake Y, Ikeda F, Shiraha H, Nouso K, Yamamoto K (2014) L-Carnitine prevents progression of non-alcoholic steatohepatitis in a mouse model with upregulation of mitochondrial pathway. PLos One 9(7):e100627CrossRefGoogle Scholar
- Jun DW, Kim BI, Cho YK, Kim HJ, Kwon YO, Park SY, Han SY et al (2013) Efficacy and safety of entecavir plus carnitine complex (GODEX(R)) compared to entecavirmonotherapy in patient with ALT elevated chronic hepatitis B: randomized, multicenter open-label trials. The GOAL study. Clin Mol Hepatol 19(2):165–172CrossRefGoogle Scholar
- Kesiova M, Alexandrova A, Yordanova N, Kirkova M, Todorov S (2006) Effects of diphenhydramine and famotidine on lipid peroxidation and activities of antioxidant enzymes in different rat tissues. Pharmacol Rep 58(2):221–228Google Scholar
- Krahenbuhl S, Reichen J (1997) Carnitine metabolism in patients with chronic liver disease. Hepatology. 25(1):148–153Google Scholar
- Malaguarnera M, Vacante M, Giordano M, Motta M, Bertino G, Pennisi M, Neri S, Malaguarnera M, Li Volti G, Galvano F (2011a) L-carnitine supplementation improves hematological pattern in patients affected by HCV treated with Peg interferon-alpha 2b plus ribavirin. World J Gastroenterol 17(39):4414–4420CrossRefGoogle Scholar
- Namn Y, Schneider Y, Cui IH, Jesudian A (2017) Diphenhydramine as a cause of drug-induced liver injury. Case Rep Hepatol 3864236. 4 pagesGoogle Scholar
- National Toxicology Program (1986) NTP toxicology and carcinogenesis studies of chlorpheniramine maleate (CAS No. 113-92-8) in F344/N rats and B6C3F1 mice (Gavage Studies). Natl Toxicol Program Tech Rep Ser 317:1–198Google Scholar
- Raveendran VV, Kassel KM, Smith DD, Luyendyk J, Williams KJ, Cherian R, Pratt-Hyatt MJ (2014a) H1-antihistamines exacerbate high fat diet-induced hepatic steatosis in wild-type but not in apolipoprotein E-knockout mice. Am J Physiol Heart Circ PhysiolGoogle Scholar
- Raveendran VV, Kassel KM, Smith DD, Luyendyk JP, Williams KJ, Cherian R, Reed GA, Flynn CA, Csanaky IL, Lickteig AL, Pratt-Hyatt MJ, Klaassen CD, Dileepan KN (2014b) H1-antihistamines exacerbate high-fat diet-induced hepatic steatosis in wild-type but not in apolipoprotein E knockout mice. Am J Physiol Gastrointest Liver Physiol 307(2):G219–G228CrossRefGoogle Scholar
- Schumann G, Bonora R, Ceriotti F, Férard G, Ferrero CA, Franck PFH, Gella FG, Hoelzel W, Jørgensen PJ, Kanno T, Kessner A, Klauke R, Kristiansen N, Lessinger JM, Linsinger TPJ, Misaki H, Panteghini M, Pauwels J, Schiele F, Schimmel HG, Weidemann G, Siekmann L (2002) IFCC primary reference procedures for the measurement of catalytic activity concentrations of enzymes at 37°C. Clin Chem Lab Med 40(7):725–733Google Scholar
- Sherwin JE, Sobenes JR (1996) Liver function. In: Kaplan LA, Pesce AJ (eds) Clinical chemistry: theory, analysis and correlation, 3rd edn. Mosby, St. Louis, pp 505–527Google Scholar
- Yao H, Gong J, Peterson AL, Lu X, Zhang P, Dennery PA (2018) Fatty acid oxidation protects against hyperoxia-induced endothelial cell apoptosis and lung injury in neonatal mice. Am J Respir Cell Mol Biol. https://doi.org/10.1165/rcmb.2018-0335OC
- Yuan L, Kaplowitz N (2008) Glutathione in liver diseases and hepatotoxicity. Mol Asp Med 30(1-2):29–41Google Scholar