Effects of Andrographis paniculata crude extract and Andrographolide on hepatic cytochrome P450 mRNA expression and monooxygenase activities

The effects of Andrographolide (AND), the major diterpenoid constituent of Andrographis paniculata (Burn. f. Wall. ex Nees., Acanthaceae) and of the crude extract (APE) on activity of hepatic CYP was examined in vivo in rats and in vitro in rat and human liver microsomes and hepatocytes. In vitro in rat and human liver microsomes APE inhibited CYP2C-dependent tolbutamide hydroxylation with an apparent Ki values of 8.21 and 7.51µM, respectively and the mode of inhibition was of mixed type. There was no evidence of metabolism-dependent inhibition. After in vivo administration to rats, APE and AND significantly affected CYP2C11 expression and activity. A 30% decrease of CYP2C11-dependent activity was obtained at 0.5 and 2.5g APE/kg rat/day (corresponding respectively to 5 and 25mg AND/kg/day), as compared to control group, and was accompanied by a decrease in CYP2C11 apoprotein expression. At 5 and 25mg/kg/day, AND also decreased CYP2C11-dependent activity by 50%, as compared to control group, and CYP2C11 protein expression was decreased. In vitro incubation of primary cultures of rat and human hepatocytes with 50µM APE or AND resulted in significant decreases in CYP2C and CYP3A activity levels in both species. In addition, CYP2C9 and 3A4 mRNA were decreased after AND and APE treatment of human hepatocytes. In conclusion, it cannot be excluded from the present study that APE could cause herb-drug interactions in humans through CYP2C9 and CYP3A4 inhibition.