Effect Of Hepatic Drug Metabolizing Enzymes In Mice Treated With Extract Of Scutellariae Barbatae

Part I Modulation of hepatic drug metabolizing enzymes in mice treated with extract of Scutellariae BarbataeAIMS: To investigate the effects of aqueous extract and ethanol extract of Scutellariae Barbatae on the activities of hepatic cytochrome P450 and glutathione S-transferase in KunMing mice.METHODS: Male KM mice were administered by gastrogavage with different doses (1gkg^-1·day^-1 , 2gkg^-1·day^-1 and 5g·kg^-1·day^-1, respectively) of aqueous extract and ethanol extract of Scutellariae Barbatae for five consecutive days, liver microsomes and cytosolic fractions were extracted. Probe drugs including tolbutamide, metoprolol, chlorzoxazone and midazolam were used to estimate Cyp2c, Cyp2d, Cyp2el and Cyp3a activities, respectively. Concentrations of the probe drugs and their metabolites in the incubated system were determined by HPLC and the cytochrome P450 activities were measured by the production of metabolites. GST activity were detected by the spectrophotometric method.RESULTS : (1) Aqueous extract of Scutellariae Barbatae of 2gkg^-1·day^-1 for five consecutive days led to 18% decrease in liver microsomal midazolam 1-hydroxylation activity, and 31% in liver microsomal tolbutamide 4-hydroxylation activities, respectively. Aqueous extract of Scutellariae Barbatae of 5g·kg^-1·day^-1 for five consecutive days led to 33% decrease in liver microsomal midazolam 1-hydroxylation activity, and 52% decrease in liver microsomal tolbutamide 4-hydroxylation activities, respectively. Aqueous extract or ethanolextract of Scutellariae Barbatae of 1g·kg^-1·day^-1 showed no significant differences compared with the control group on CYPs activity. Aqueous extract of Scutellariae Barbatae of 5g·kg^-1·day^-1 for five consecutive days led to 17% decrease in hepatic cytosolic GST activity. No effects on Cyp2d and Cyp2el activities observed between the control group and aqueous extract of Scutellariae Barbatae treated groups.(2) Ethanol extract of Scutellariae Barbatae of 2g·kg^-1·day^-1 for five consecutive days led to 23% decrease in liver microsomal midazolam 1-hydroxylation activity, and 21% in liver microsomal tolbutamide 4-hydroxylation activities, respectively. Ethanol extract of Scutellariae Barbatae of 5g·kg^-1·day^-1 for five consecutive days led to 34% decrease in liver microsomal midazolam 1-hydroxylation activity, and 47% decrease in liver microsomal tolbutamide 4-hydroxylation activities, respectively. Ethanol extract of Scutellariae Barbatae of 1g·kg^-1·day^-1 showed no significant differences compared with the control group on CYPs activity. No effects on Cyp2d and Cyp2el activities observed between the control group and ethanol extract of Scutellariae Barbatae treated groups.(3) The activities of CYPs and GST between aqueous extract and ethanol extract of Scutellariae Barbatae groups were no difference.CONCLUSIONS : Aqueous extract and ethanol extract of Scutellariae Barbatae have the potential ability to inhibit the activities of drug metabolism enzymes in mice liver , including Cyp2c, Cyp3a and GST .The effects of extract of Scutellariae Barbatae on CYPs activities showed dose-dependence. Thus, caution should be paid to the possible drug interactions of Scutellariae Barbatae and CYP substrates. AIMS: To investigate the recovery of hepatic CYPs activities in mice influenced by aqueous extract and ethanol extract of Scutellariae Barbatae.METHODS: Male KM mice were administered by gastrogavage with 2g·kg^-1·day^-1 of aqueous extract and ethanol extract of Scutellariae Barbatae for five consecutive days. After the extract of Scutellariae Barbatae treatment, mice were fed normal diet without extract of Scutellariae Barbatae for another 5 or 10 days. After a predetermined period, mice were sacrificed and liver microsomes were extracted. Probe drugs including tolbutamide and midazolam were used to estimate Cyp2c and Cyp3a activities, respectively. Concentrations of the probe drugs and their metabolites in the incubated system were determined by HPLC and the cytochrome P450 activities were measured by the production of metabolites.RESULTS: Feeding with 2g·kg^-1·day^-1 of aqueous extract of Scutellariae Barbatae for five consecutive days significantly decreased the activity of Cyp2c and Cyp3a in the liver by 32% and 22%, respectively, with 2g·kg^-1·day^-1 of ethanol extract of Scutellariae Barbatae showed 20% and 27% of Cyp2c and Cyp3a activity decrease, respectively . The activities of Cyp2c and Cyp3a were recovered almost at the control level at 5 days after the discontinuation of extract of Scutellariae Barbatae treatment. At 10 days after the discontinuation, Cyp2c and Cyp3a activities were similar to the untreated control values.CONCLUSIONS: The inhibition in hepatic CYP activity in mice by repeated extract of Scutellariae Barbatae ingestion and relatively rapid recovery of these enzymes after the discontinuation of extract of Scutellariae Barbatae ingestion. These results suggest that a potential CYP-mediated interaction of extract of Scutellariae Barbatae with other drugs could be avoided by discontinuation of extract of ScutellariaeBarbatae ingestion.