title: Protective Effects of Silymarin, Alone or in Combination with Chlorogenic Acid and/or Melatonin, Against Carbon Tetrachloride-induced Hepatotoxicity.
abstract: OBJECTIVE
  The aim of this study was to evaluate the hepatoprotective effects of silymarin (SIL), alone and combined with chlorogenic acid (CA) and/or melatonin (ME), using a rat model of carbon tetrachloride (CCl4)-induced injury.
  
  
  METHODS
  Hepatotoxicity was induced by a single dose of CCl4 (1 ml/kg, IP). One day after, rats were received SIL (200 mg/kg) alone or in combination with CA (60 mg/kg) and/or ME (20 mg/kg) for 21 days.
  
  
  RESULTS
  SIL significantly decreased serum alanine aminotransferase, inflammatory cytokines, and vascular endothelial growth factor levels. Histological alterations, fibrogenesis, oxidative DNA damage, inflammatory mediators, and caspase-3 activity were significantly attenuated in SIL treated CCl4-intoxicated rats. On the other hand, cytochrome P450 2E1 activity showed a significant decrease in the liver of CCl4-intoxicated rats, an effect that was reversed following treatment with SIL. All beneficial effects of SIL were markedly potentiated when combined with CA and/or ME.
  
  
  CONCLUSIONS
  These data indicate that SIL, alone and combined with CA and/or ME, protected the liver against CCl4-induced hepatotoxicity via attenuating inflammation, oxidative DNA damage, apoptosis, and fibrotic changes. The significantly intensified hepatoprotective effects of SIL when combined with both CA and ME suggest a possible synergism. These synergistic effects need to be further confirmed using detailed studies.
  
  
  CONCLUSIONS
  Silymarin, chlorogenic acid and melatonin possess in vivo hepatoprotective activitySilymarin, chlorogenic acid and melatonin attenuate fibrogenesis, oxidative DNA damage, inflammation and apoptosisChlorogenic acid and melatonin enhance the hepatoprotective effect of silymarin. Abbreviations used: SIL: silymarin, CA: chlorogenic acid, ME: melatonin, CCl4: carbon tetrachloride, CYP2E1, cytochrome P450 2E1, ALT: alanine aminotransferase, IL-6: interleukin 6, IFN-γ: interferon gamma, VEGF: vascular endothelial growth factor, TNF-α: tumor necrosis factor alpha, CRP: C-reactive protein, 8-OxodG: 8-Oxo-2'-deoxyguanosine, TGF-B1: transforming growth factor beta 1, HSCs: hepatic stellate cells.
authors: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors: Nouf
authors: N
authors: Al-Rasheed
authors: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors: Laila
authors: L
authors: Faddah
authors: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia; Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia.
authors: Nawal
authors: N
authors: Al-Rasheed
authors: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia; Department of Pharmacology, Faculty of Medicine, Alexandria University, Alexandria, Egypt.
authors: Yieldez A
authors: YA
authors: Bassiouni
authors: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors: Iman H
authors: IH
authors: Hasan
authors: Department of Zoology, Division of Physiology, Faculty of Science, Beni-Suef University, Beni-Suef, Egypt.
authors: Ayman M
authors: AM
authors: Mahmoud
authors: Department of Anatomy, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors: Raeesa A
authors: RA
authors: Mohamad
authors: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors: Hazar I
authors: HI
authors: Yacoub
keywords: Carbon tetrachloride; chlorogenic acid; inflammation; melatonin; silymarin