Boldine Supplementation Regulates Mitochondrial Function and Oxidative Stress in a Rat Model of Hepatotoxicity

Background: The xenobiotics-induced liver injury is a clinical complication. Hence, finding new hepatoprotective strategies has clinical value. Oxidative stress and its subsequent complications are major mechanisms involved in xenobiotics-induced hepatotoxicity. Boldine is one of the most potent antioxidant molecules widely investigated for its protective properties in different experimental models. In the current study, the hepatoprotective properties of boldine and its potential mechanisms of hepatoprotection have been investigated. Methods: Rats received thioacetamide (TAA; 200 mg/kg, i.p) as a model of acute liver injury. Boldine (5, 10, 1nd 20 mg/kg; 24 hours intervals; oral) was administered as the hepatoprotective agent. Results: Liver injury was evident in TAA-treated animals (48 hours after TAA exposure) as a severe increase in serum level of liver injury biomarkers and histopathological alterations. Moreover, markers of oxidative stress were increased in liver tissue of TAA-treated rats. Assessment of mitochondrial indices of functionality revealed a significant decrease in mitochondrial dehydrogenases activity, the collapse of mitochondrial membrane potential, mitochondrial swelling and depletion of ATP content. It was found that boldine supplementation mitigated liver tissue markers of oxidative stress and improved mitochondrial indices of functionality in TAA-treated animals. Conclusion: The hepatoprotective properties of boldine might primarily rely on antioxidant and mitochondria protecting effects of this alkaloid

Propylthiouracil-induced mitochondrial dysfunction in liver and its relevance to drug-induced hepatotoxicity

Background: Propylthiouracil (PTU) administration is associated with several cases of hepatotoxicity, especially in children. The mechanism(s) of PTU-induced hepatotoxicity is obscure. In the current study, we aimed to assess the effect of PTU on hepatocytes mitochondria in different experimental models. Methods: Mice were treated with PTU (10, 20, 40, 80, and 100 mg/kg, i.p) then, the liver mitochondria were isolated and evaluated. Moreover, liver mitochondria were isolated from normal mice and incubated with increasing concentrations of PTU (10 µM-1 mM). Mitochondrial dehydrogenases activity, mitochondrial membrane potential, mitochondrial swelling, and mitochondrial adenosine triphosphate (ATP) content were monitored. Results: PTU hepatotoxicity was biochemically evident in mice by increased serum biomarkers of liver injury. PTU also caused a decrease in mitochondrial dehydrogenases activity, increased mitochondrial swelling, depleted mitochondrial ATP, and caused mitochondrial depolarization both in vitro and in vivo. Conclusion: Our data suggest mitochondrial dysfunction as a mechanism for PTU-induced hepatotoxicit

Inhibition of CYP1A1 by pharmaceutical drugs, omeprazol and ketoconazole as a mechanism for activation of aryl hydrocarbon receptor (AHR)

Omeprazole (OMP) and ketoconazole (KTZ) have been shown to activate the AHR signaling pathway in spite of the fact that they bind to the receptor with low or no affinity. The aim of this study was to investigate whether KTZ and OMP can act as indirect activator of AHR. In order to evaluate the effects of KTZ and OMP on AHR signaling, we measured cytochromes p450 (CYP1A1) enzyme activity by ethoxyresorufin-O-deethylase (EROD) assay as endpoint. FICZ, at 1nM concentration, caused a transient elevation in the catalytic activity of CYP 1A1. KTZ and OMP were found to be inducer of CYP1A1 at concentrations above 50 µM. At early time of incubation (3hr), a dose-dependent inhibition of FICZ-induced EROD activity was seen. When OMP or KTZ were added together with FICZ, a prolonged activation of CYP1A1 was observed at later time of incubation (24h). Taken together, our findings support the earlier observation that we shown that CYP 1A1 inhibitors can act as an AHR activator though inhibition of metabolic degradation of FICZ. </p