Anisimova S. Role of the cytochrome P-450 in the antituberculosis drugs hepatotoxicity mechanisms and experimental substantiation of composition "Metovitan" corrective action

The dissertation is devoted to the role of the cytochrome P-450 isoforms in the antituberculosis drugs hepatotoxicity and experimental substantiation of hepatoprotective properties of "Metovitan"'s metabolic action. ET, RF, ISO or PA administration modulated CYP3A2, CYP2C23, CYP2E1 mRNA expression and their enzymatic activity in liver microsomes, along with an increase in the cytochrome P-450 total content indicates a violation of metabolic processes. This effect was accompanied by an imbalance of liver pro-and antioxidant status, increased levels of nuclear DNA fragmentation and chronic inflammation of the liver. Application of composition "Metovitan" greatly helped to preserve mRNA expression and enzymatic activity changes of the above mentioned isoforms. Corrective action has been shown "Metovitan" on blood serum biochemical parameters and state of pro-/ antioxidant status in rat liver. The "Metovitan" prevented degenerative changes and inflammation in the liver. Thus, results suggest that the modulation of CYP3A2, CYP2C23 and CYP2E1 expression and activity is a key mechanism of antituberculosis drugs hepatotoxic action at their combined use. "Metovitan"'s ability to normalize these parameters determines it's hepatoprotective properties.