Comparison of imatinib, nilotinib and silymarin in the treatment of carbon tetrachloride-induced hepatic oxidative stress, injury and fibrosis

Journal Article · Fri Apr 15 00:00:00 EDT 2011 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2011.02.004· OSTI ID:21535274

Zalata, Khaled R ^[1]; Mehal, Wajahat Z ^[2]; Shiha, Gamal E ^[3]; Ibrahim, Tarek M ^[4]

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1. Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura 35516 (Egypt)
2. Section of Digestive Diseases, Department of Internal Medicine, Yale University, New Haven, CT 06520-8019 (United States)
3. Department of Internal Medicine, Faculty of Medicine, Mansoura University, Mansoura 35516 (Egypt)
4. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516 (Egypt)

Effective and well-tolerated anti-fibrotic drugs are currently lacking. Therefore, this study was carried out to investigate the potential anti-fibrotic effects of imatinib, nilotinib and silymarin on established hepatic fibrosis in the carbon tetrachloride (CCl{sub 4}) rat model. Male Wistar rats received intraperitoneal injections of CCl{sub 4} twice weekly for 8 weeks, as well as daily intraperitoneal treatments of imatinib (10 and 20 mg/kg), nilotinib (10 and 20 mg/kg) and silymarin (100 mg/kg) during the last 4 weeks of CCl{sub 4}-intoxication. At the end of the study, hepatic damage was evaluated by analysis of liver function tests and hepatic oxidative stress parameters. Hepatic fibrosis was evaluated by histopathology and morphometry, as well as collagen and 4-hydroxyproline contents. Nilotinib (20 mg/kg) was the most effective treatment to counteract CCl{sub 4}-induced hepatic injury as indicated by liver function tests and histopathology. Nilotinib (10 mg/kg), nilotinib (20 mg/kg) and silymarin (100 mg/kg) treatments reduced the mean score of hepatic fibrosis by 31%, 68% and 47%, respectively, and hepatic collagen content by 47%, 49% and 18%, respectively in CCl{sub 4}-treated rats. Hepatic morphometric evaluation and 4-hydroxyproline content revealed that CCl{sub 4}-induced fibrosis was ameliorated significantly by nilotinib (20 mg/kg) and imatinib (20 mg/kg). Unlike nilotinib, imatinib (20 mg/kg) showed some sort of hepatic injury evidenced by elevation of serum aminotransferases and total bilirubin levels, and hepatic total nitrate/nitrite content, as well as characteristic anisonucleosis visualized with the hematoxylin-eosin staining. In conclusion, this study provides the evidence that nilotinib exerts anti-fibrotic activity and suggests that it may be valuable in the treatment of hepatic fibrosis in humans. - Graphical abstract: Display Omitted Research Highlights: > The anti-fibrotic effects of imatinib, nilotinib and silymarin were compared. > These effects were evaluated on CCl{sub 4}-induced hepatic fibrosis in rats. > Nilotinib was found to possess potent anti-fibrotic activity. > In addition, nilotinib did not show any signs of hepatotoxicity. > Thus, nilotinib may be valuable in the treatment of hepatic fibrosis in humans.

• OSTI ID: 21535274
• Journal Information: Toxicology and Applied Pharmacology, Vol. 252, Issue 2; Other Information: DOI: 10.1016/j.taap.2011.02.004; PII: S0041-008X(11)00050-0; Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
AMINOTRANSFERASES
BILIRUBIN
CARBON TETRACHLORIDE
COLLAGEN
FIBROSIS
HUMAN POPULATIONS
HYDROXYPROLINE
INTRAPERITONEAL INJECTION
LIVER
MALES
RATS
AMINES
AMINO ACIDS
ANIMALS
AZOLES
BODY
CARBOXYLIC ACIDS
CHLORINATED ALIPHATIC HYDROCARBONS
DIGESTIVE SYSTEM
ENZYMES
GLANDS
HALOGENATED ALIPHATIC HYDROCARBONS
HETEROCYCLIC ACIDS
HETEROCYCLIC COMPOUNDS
HYDROXY ACIDS
INJECTION
INTAKE
MAMMALS
NITROGEN TRANSFERASES
ORGANIC ACIDS
ORGANIC CHLORINE COMPOUNDS
ORGANIC COMPOUNDS
ORGANIC HALOGEN COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANS
PATHOLOGICAL CHANGES
PIGMENTS
POPULATIONS
PROTEINS
PYRROLES
PYRROLIDINES
RODENTS
SCLEROPROTEINS
TRANSFERASES
VERTEBRATES