Hepatoprotective effect of ketoconazole in chronic liver injury model.

Abstract

Ketoconazole is a first orally available anti-fungal drug which has been reported as a potent inhibitor of human cytochrome P-450. The present study was designed to examine the heptoprotective effect of ketoconazole in both in vitro and in vivo liver injury models. Hepatocyte injury was induced by 8mM CCl4 while hepatic fibrosis model was established by injecting 1 ml/kg CCl4 followed by treatment with ketoconazole. Effect of ketoconazole treatment on injured hepatocytes was determined by lactate dehydrogenase release and trypan blue assay. Analysis of ketoconazole treatment and prevention on liver fibrosis was assessed by sirius red staining, masson trichome staining, PCR and liver function tests for bilirubin and alanine transaminase (ALAT).A significant reduction (P<0.05) in LDH release and reduced number of dead cells was observed in hepatocytes treated with ketoconazole. Sirus red and masson trichome stainings showed reduced levels of collagen in both treated and preventive groups and down regulation of alpha smooth muscle actin was observed with up-regulations of MMP-2, CK-8 and CK-18. Hepatic functional assessment demonstrated reduced serum levels of bilirubin and ALAT. Treatment of fibrotic liver with ketoconazole improves hepatic microenvironment and enhanced reduction of liver injury after fibrosis. Cytochrome P-450 inhibitors seems a favored therapeutic option in attenuation of liver fibrosis.

• Authors: Usman Akhtar, Mobasher Ahmed, Asima Tayyeb, Umara Shehzad, Gibran Ali
• Journal: Pakistan journal of pharmaceutical sciences (Pak J Pharm Sci) Vol. 32 Issue 3 Pg. 1033-1042 (May 2019) ISSN: 1011-601X [Print] Pakistan
• PMID: 31278717 (Publication Type: Journal Article)

Chemical References

• Actins
• Protective Agents
• alpha-smooth muscle actin, mouse
• Carbon Tetrachloride
• L-Lactate Dehydrogenase
• Matrix Metalloproteinase 2
• Mmp2 protein, mouse
• Ketoconazole

Topics

• Actins (genetics)
• Animals
• Carbon Tetrachloride (toxicity)
• Cell Death (drug effects)
• Chemical and Drug Induced Liver Injury (metabolism, pathology, prevention & control)
• Disease Models, Animal
• Gene Expression Regulation (drug effects)
• Hepatocytes (drug effects, metabolism, pathology)
• Ketoconazole (pharmacology)
• L-Lactate Dehydrogenase (metabolism)
• Liver (drug effects, physiology)
• Liver Cirrhosis (chemically induced, pathology, prevention & control)
• Liver Function Tests
• Male
• Matrix Metalloproteinase 2 (genetics)
• Mice, Inbred C57BL
• Protective Agents (pharmacology)