Inhibition of CYP3A4 enhances aloe-emodin induced hepatocyte injury.

Aloe-emodin (AE) is a natural hydroxyanthraquinone derivative that was found in many medicinal plants and ethnic medicines. AE showed a wide array of pharmacological activities including anticancer, antifungal, laxative, antiviral, and antibacterial effects. However, increasing number of published studies have shown that AE may have some hepatotoxicity effects but the mechanism is not fully understood. Studies have shown that the liver injury induced by some free hydroxyanthraquinone compounds is associated with the inhibition of some metabolic enzymes. In this study, the CYP3A4 and CYP3A1 were found to be the main metabolic enzymes of AE in human and rat liver microsomes respectively. And AE was metabolized by liver microsomes to produce hydroxyl metabolites and rhein. When CYP3A4 was knocked down in L02 and HepaRG cells, the cytotoxicity of AE was increased significantly. Furthermore, AE increased the rates of apoptosis of L02 and HepaRG cells, accompanied by Ca2+ elevation, mitochondrial membrane potential (MMP) loss and reactive oxygen species (ROS) overproduction. The mRNA expression of heme oxygenase-1 in L02 and HepaRG cells increased significantly in the high-dose of AE (40 µmol/L) group, and the mRNA expression of quinone oxidoreductase-1 was activated by AE in all concentrations. Taken together, the inhibition of CYP3A4 enhances the hepatocyte injury of AE. AE can induce mitochondrial injury and the imbalance of oxidative stress of hepatocytes, which results in hepatocyte apoptosis.

[Risk analysis for cerebral hyperperfusion syndrome after carotid endarterectomy].

OBJECTIVE: To analyze risk factors for cerebral hyperperfusion syndrome (CHS) after carotid endarterectomy (CEA). METHODS: From September 2010 to September 2012, 183 consecutive patients with carotid artery stenosis who had indications for CEA entered the study. There were 149 male and 34 female patients, aged from 38 to 83 years with an average of (66 ± 9) years. Intracranial blood flow changes were monitored through transcranial Doppler routinely. Pre- and post-operative middle cerebral artery velocity (VMCA) were recorded. CHS was diagnosed by the combination of hyperperfusion syndrome and 100% increase of VMCA after operation compared with pre-operative baseline values. The patients who had CHS during hospitalization were recorded. Pre-operative and operative related factors were analyzed by univariate analysis, followed by Logistic regression model, to identify the risk factors of CHS. RESULTS: Overall, CHS occurred in 15 patients (8.2%) after CEA. The average onset time was (2.6 ± 0.2) days after surgery. By decreasing blood pressure and using dehydration medicine, all the patients with CHS recovered before discharge. None of them developed to intracranial hemorrhage. On univariate analysis, significant risk factors for CHS were history of stoke, symptomatic carotid artery stenosis and shunting during operation. On Logistic regression model, independent risk factor was symptomatic carotid artery stenosis (OR = 6.733, 95%CI: 1.455-31.155, P = 0.015), while shunting during operation (OR = 0.252, 95%CI: 0.067-0.945, P = 0.041) was a protective factor. CONCLUSIONS: Symptomatic carotid artery stenosis is an independent risk factor for CHS after CEA and shunting during operation is a protective factor. Using shunt may be an effective method of preventing CHS after CEA.