Polymorphisms in cytochrome P450 genes encoding enzymes of critical importance for drug metabolism have the highest genetic influence on interindividual variations in drug bioavailability. Human CYP2D6 enzyme is claimed to be polymorphically expressed among different ethnic groups. It has been suggested to account for a large part of the interindividual differences in drug metabolism and pharmacokinetics. In the current investigation, 100 healthy unrelated subjects living in Tabriz, Iran, were randomly selected. Genotyping was designed to determine the frequencies of five major and important alleles: CYP2D6*2, CYP2D6*4, CYP2D6*5, CYP2D6*10, and CYP2D6*17. After collecting venous blood samples, polymerase chain reaction-restriction fragment length polymorphism methodology was performed for detection of the alleles (except CYP2D6*5, which has been detected using an allele-specific polymerase chain reaction procedure). Finally, the obtained data were used to determine the allele frequencies. The frequencies for CYP2D6 alleles *2, *4, *5, and *10 were 32%, 12.5%, 3%, and 9%, respectively. CYP2D6*17 was completely absent in this study group. Poor metabolizer phenotype can be related to *4/*4 and *4/*5 genotypes with a total frequency of 4%. This is the first study of the CYP2D6 genetic polymorphism in an Iranian population. The frequencies of the studied alleles resulted in degrees of differences between this population and Orientals, Saudi Arabians, and Caucasians, while similarities to the reported results obtained from the studies among Mediterraneans and South Indians are noticeable.
Triptans are used as antimigraine agents. Some cases of hepatotoxicity by triptans have been reported. However, the exact mechanism of triptan-induced hepatotoxicity is not clear yet. In this study, the cytotoxic effects of rizatriptan were investigated in freshly isolated rat hepatocytes using accelerated cytotoxicity mechanism screening. We designed experiments to evaluate toxicity markers, such as cell death, reactive oxygen species (ROS) formation, lipid peroxidation, mitochondrial membrane potential, lysosomal membrane integrity and the amount of reduced and oxidized glutathione in the rizatriptan-treated hepatocytes. Cytotoxicity caused by rizatriptan in rat hepatocytes was concentration-dependent. An increase in ROS formation accompanied by a significant rise in lipid peroxidation, mitochondrial depolarization and loss of lysosomal membrane integrity was observed. Cellular glutathione reservoirs were decreased and a significant amount of oxidized glutathione was formed. All the aforementioned rizatriptan-induced cellular events were significantly (p<0.05) prevented by ROS scavengers, antioxidants, endocytosis inhibitors and adenosine triphosphate (ATP) generators. Also, the present results demonstrated that CYP450 is involved in rizatriptan-induced oxidative stress and cytotoxicity mechanism and different CYP450 inducers had different effects on the toxicity. It is suggested that the adverse effect of rizatriptan towards hepatocytes is mediated by oxidative stress and the hepatocytes lysosomes and mitochondria play an important role in rizatriptan-induced cell injury.
Methylsulfonylmethane (MSM) is naturally occurring organic sulfur that is known as a potent antioxidant/anti-inflammatory compound. The aim of this study was to investigate the effect of MSM on hemodynamics functions and oxidative stress in rats with monocrotaline- (MCT-) induced pulmonary arterial hypertension (PAH). Wistar rats were randomly assigned to 38-days treatment. MSM was administered to rats at 100, 200, and 400 mg/kg/day doses 10 days before a single dose of 60 mg/kg, IP, MCT. Hemodynamics of ventricles were determined by Powerlab AD instrument. Blood samples were obtained to evaluate changes in the antioxidative system including activities of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), and the level of reduced glutathione (GSH) and malondialdehyde (MDA). Improvements in cardiopulmonary hemodynamics were observed in the MSM-treated pulmonary arterial hypertensive rats, with a significant reduction in right ventricular systolic pressure (RSVP) and an increase in the mean arterial pressure (MAP). The values of CAT, SOD, GSH-px activities, and GSH were significantly lower in MCT-induced PAH (P < 0.01), but they were recovered to control levels of MSM-treated groups. Our present results suggest that long-term administration of the MSM attenuates MCT-induced PAH in rats through modulation of oxidative stress and antioxidant defense.
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