Protective Effects of CYP2E1 Inhibitors on Metabolic Syndrome-induced Liver Injury in Guinea Pigs

Abstract

The present work reports the effects of CYP2E1-inhibitors (quercetin, 4- methylpyrazole and disulfiram) on the indices characterizing state of the liver in guinea pigs with metabolic syndrome (MS) induced by protamine sulfate repeated administrations. The investigation of quercetin, 4-methylpyrazole and disulfiram effects on hepatic cytochrome P450 2E1 (CYP2E1) protein and activity changes was conducted.  Simultaneously, the content of reactive oxygen species (ROS) and markers of liver damage were determined in experimental animals’ blood. The link between increased hepatic expression of CYP2E1, prominent ROS generation and liver damage in animals with MS has been discovered. It has been demonstrated that CYP2E1 protein content and activity in guinea pigs with MS rose almost 3 times compared to intact animals. These events were accompanied by increase in ROS generation and metabolism and liver disturbances symptoms: increase in serum glucose and cholesterol contents (2 and 2.6 times respectively), alanine aminotransferase (2.8 times), aspartate aminotransferase (6.4 times), and alkaline phosphatase (1.8 times) elevations. Our investigation suggests that administration of quercetin, 4-methylpyrazole, and disulfiram in guinea pigs with MS caused decrease in this isoenzyme protein expression (2.5, 1.7 and 2.4 respectively) as well as its enzymatic activity in liver (6.6, 1.1, and 1.7 respectively). The content of blood ROS was partially restored or normalized by all three CYP2E1 inhibitors. In turn, suppression of CYP2E1 activity and ROS generation led to decrease in hepatic MS manifestation. It is apparent from the present observation that quercetin has the highest efficiency among the investigated substances. Further studies on various quercetin doses and administration regimens could provide relevant information for the development of MS-related nonalcoholic fatty liver disease treatment.