Quercetin reduced the formation of N ‐acetyl‐ p ‐benzoquinoneimine, a toxic metabolite of paracetamol in rats and isolated rat hepatocytes

2019 ◽  
Vol 33 (7) ◽  
pp. 1770-1783 ◽  
Author(s):  
Ravindrababu Pingili ◽  
A. Krishnamanjari Pawar ◽  
Siva Reddy Challa
Keyword(s):  
Rat Hepatocytes ◽  
Toxic Metabolite ◽  
Isolated Rat Hepatocytes ◽  
Isolated Rat

Molecular cytotoxic mechanisms of chlorpromazine in isolated rat hepatocytes

2013 ◽  
Vol 91 (1) ◽  
pp. 56-63 ◽  
Author(s):  
Stephanie L. MacAllister ◽  
Cheryl Young ◽  
Anna Guzdek ◽  
Nickholas Zhidkov ◽  
Peter J. O'Brien
Keyword(s):  
First Generation ◽  
Rat Hepatocytes ◽  
Antipsychotic Agents ◽  
Toxic Metabolite ◽  
Quinone Oxidoreductase ◽  
Metabolite Formation ◽  
Isolated Rat Hepatocytes ◽  
Electron Reduction ◽  
Catalyzed Oxidation ◽  
Isolated Rat

Chlorpromazine (CPZ), a member of the largest class of first-generation antipsychotic agents, is known to cause hepatotoxicity in the form of cholestasis and hepatocellular necrosis in some patients. The mechanism of CPZ hepatotoxicity is unclear, but is thought to result from reactive metabolite formation. The goal of this research was to assess potential cytotoxic mechanisms of CPZ using the accelerated cytotoxicity mechanism screening (ACMS) technique with freshly isolated rat hepatocytes. This study identified CPZ cytotoxicity and inhibition of mitochondrial membrane potential (MMP) to be concentration-dependent. Furthermore, inhibition of cytochrome P450s (CYPs), including CYP2D1 and 1A2, delayed CPZ cytotoxicity, suggesting a role for CYP activation of CPZ to a toxic metabolite(s) in this model. Metabolism studies also demonstrated glucuronide and glutathione (GSH) requirement for CPZ detoxification in hepatocytes. Inactivating the 2-electron reduction pathway, NAD(P)H quinone oxidoreductase (NQO1), caused a significant increase in hepatocyte susceptibility to CPZ, indicating quinoneimine contribution to CPZ cytotoxicity. Nontoxic concentrations of peroxidase/H2O2 (inflammatory model) increased cytotoxicity in CPZ-treated hepatocytes and caused additional mitochondrial toxicity. Inflammation further depleted GSH and increased oxidized glutathione (GSSG) levels. Results suggest activation of CPZ to reactive metabolites by 2 pathways in hepatocytes: (i) a CYP-catalyzed quinoneimine pathway, and (ii) a peroxidase-catalyzed oxidation of CPZ to CPZ radicals.

scholarly journals Cytoprotective Effects of Taurine Against Toxicity Induced by Isoniazid and Hydrazine in Isolated Rat Hepatocytes

2013 ◽  
Vol 64 (2) ◽  
pp. 201-210 ◽  
Author(s):  
Reza Heidari ◽  
Hossein Babaei ◽  
Mohammad Ali Eghbal
Keyword(s):  
Lipid Peroxidation ◽  
Rat Hepatocytes ◽  
Toxic Metabolite ◽  
Protective Effects ◽  
Isolated Rat Hepatocytes ◽  
Intermediary Metabolite ◽  
Ros Formation ◽  
Membrane Depolarisation ◽  
Antioxidative Action ◽  
Isolated Rat

Isoniazid is one of the most commonly used drugs to treat tuberculosis. Its administration is associated with a high incidence of hepatotoxicity. The aim of this study was to establish the protective effects of taurine against cytotoxicity induced by isoniazid and its suspected toxic metabolite hydrazine in isolated rat hepatocytes by measuring reactive oxygen species (ROS) formation, lipid peroxidation, mitochondrial depolarisation, reduced glutathione (GSH), and oxidised glutathione (GSSG). Isoniazid caused no significant ROS formation in normal hepatocytes, but in glutathione-depleted cells it was considerable. Hydrazine caused ROS formation and lipid peroxidation in both intact and glutathione-depleted cells. Both isoniazid and hydrazine caused mitochondrial membrane depolarisation. Hydrazine lowered cellular GSH reserve and increased GSSG. Taurine (200 μmol L-1) and N-acetylcysteine (200 μmol L-1) effectively countered the toxic effects of isoniazid and/or hydrazine by decreasing ROS formation, lipid peroxidation, and mitochondrial damage. Taurine prevented depletion of GSH and lowered GSSG levels in hydrazine-treated cells. This study suggests that the protective effects of taurine against isoniazid and its intermediary metabolite hydrazine cytotoxicity in rat hepatocytes could be attributed to antioxidative action.

scholarly journals Lysosomal triacylglycerol lipase and lipolysis in isolated rat hepatocytes.

1979 ◽  
Vol 254 (18) ◽  
pp. 8841-8846
Author(s):  
L.J. Debeer ◽  
J. Thomas ◽  
P.J. De Schepper ◽  
G.P. Mannaerts
Keyword(s):  
Rat Hepatocytes ◽  
Isolated Rat Hepatocytes ◽  
Triacylglycerol Lipase ◽  
Isolated Rat
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