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Evaluation of memory enhancing clinically available standardized extract of Bacopa monniera on P-glycoprotein and cytochrome P450 3A in Sprague-Dawley rats.

Singh R, Panduri J, Kumar D, Kumar D, Chandsana H, Ramakrishna R, Bhatta RS - PLoS ONE (2013)

Bottom Line: The BM treatment decreased the cytochrome P450 3A (CYP3A) mediated testosterone 6β-hydroxylation activity of the liver and intestine by 2 and 1.5 fold, respectively compared to vehicle treated control.Similarly pretreatment with BM extract decreased the expression of intestinal P-glycoprotein (Pgp) as confirmed by Western blot analysis but did not alter the expression of hepatic Pgp.Significant increase in AUC and Cmax of carbamazepine (4 and 1.8 fold) and digoxin (1.3 and 1.2 fold), respectively following the BM pre-treatment confirmed the down regulation of CYP3A and Pgp.

View Article: PubMed Central - PubMed

Affiliation: Pharmacokinetics and Metabolism Division. CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India.

ABSTRACT
Bacopa monniera is a traditional Ayurvedic herbal medicine used to treat various mental ailments from ancient times. Recently, chemically standardized alcoholic extract of Bacopa monniera (BM) has been developed and currently available as over the counter herbal remedy for memory enhancement in children and adults. However, the consumption of herbal drugs has been reported to alter the expression of drug metabolizing enzymes and membrane transporters. Present study in male Sprague-Dawley rat was performed to evaluate the effect of memory enhancing standardized extract of BM on hepatic and intestinal cytochrome P450 3A and P-glycoprotein expression and activity. The BM (31 mg/kg/day) was orally administered for one week in BM pre-treated group while the control group received the same amount of vehicle for the same time period. The BM treatment decreased the cytochrome P450 3A (CYP3A) mediated testosterone 6β-hydroxylation activity of the liver and intestine by 2 and 1.5 fold, respectively compared to vehicle treated control. Similarly pretreatment with BM extract decreased the expression of intestinal P-glycoprotein (Pgp) as confirmed by Western blot analysis but did not alter the expression of hepatic Pgp. To investigate whether this BM pretreatment mediated decrease in activity of CYP3A and Pgp would account for the alteration of respective substrate or not, pharmacokinetic study with carbamazepine and digoxin was performed in BM pre-treated rats and vehicle treated rats. Carbamazepine and digoxin were used as CYP3A and Pgp probe drugs, respectively. Significant increase in AUC and Cmax of carbamazepine (4 and 1.8 fold) and digoxin (1.3 and 1.2 fold), respectively following the BM pre-treatment confirmed the down regulation of CYP3A and Pgp.

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Effect of BM pretreatment on P-gp level.(A) Effect of BM pretreatment on intestine and liver MDR1 expression. BM treatment decreases the MDR1 level in intestine. Fold changes in mRNA level are derived after normalizing with GAPDH mRNA level used as internal loading control (n = 3 in each group) and are indicated by numbers. BM represent rats pretreated with BM (31 mg/kg/day) for 7 days and control represents rats received same volume of vehicle Values are expressed as mean ± S.D. all results are from 3 independent experiments with similar results; * indicates significant difference in BM pretreated rats compared to vehicle treated rats with P value <0.05. (B) Effect of BM pretreatment on P-gp protein expression. Expression of P-gp protein in intestine, liver and kidney in rats pretreated with BM (31 mg/kg/day) for 7 days and control rats treated with vehicle for same time period. Membrane for western blotting was prepared as described in Material and Methods. 50 µg of protein was separated on 7.5% SDS-PAGE. Proteins were electrotransferred to PVDF membrane and probed with anti P-gp antibody and blot was developed with ECL kit. BM represent rats pre-treated with BM (31 mg/kg/day) for 7 days and control represents rats received same volume of vehicle.
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pone-0072517-g002: Effect of BM pretreatment on P-gp level.(A) Effect of BM pretreatment on intestine and liver MDR1 expression. BM treatment decreases the MDR1 level in intestine. Fold changes in mRNA level are derived after normalizing with GAPDH mRNA level used as internal loading control (n = 3 in each group) and are indicated by numbers. BM represent rats pretreated with BM (31 mg/kg/day) for 7 days and control represents rats received same volume of vehicle Values are expressed as mean ± S.D. all results are from 3 independent experiments with similar results; * indicates significant difference in BM pretreated rats compared to vehicle treated rats with P value <0.05. (B) Effect of BM pretreatment on P-gp protein expression. Expression of P-gp protein in intestine, liver and kidney in rats pretreated with BM (31 mg/kg/day) for 7 days and control rats treated with vehicle for same time period. Membrane for western blotting was prepared as described in Material and Methods. 50 µg of protein was separated on 7.5% SDS-PAGE. Proteins were electrotransferred to PVDF membrane and probed with anti P-gp antibody and blot was developed with ECL kit. BM represent rats pre-treated with BM (31 mg/kg/day) for 7 days and control represents rats received same volume of vehicle.

Mentions: The mRNA expression profile of intestinal MDR1 of BM pre-treated and the vehicle pre-treated group was compared. In BM pre-treated group mRNA level of intestinal MDR1 was decreased by 2.5 fold compared to vehicle pre-treated group (Figure 2A). No significant difference in hepatic MDR1 mRNA was observed. Similarly weaker intensity of the bands revealed by Western blot after normalizing with beta-actin bands in the intestine of rats pre-treated with BM corresponds to a decrease in Pgp protein expression (Figure 2B). However no difference in hepatic and kidney Pgp expression was observed (data not shown).


Evaluation of memory enhancing clinically available standardized extract of Bacopa monniera on P-glycoprotein and cytochrome P450 3A in Sprague-Dawley rats.

Singh R, Panduri J, Kumar D, Kumar D, Chandsana H, Ramakrishna R, Bhatta RS - PLoS ONE (2013)

Effect of BM pretreatment on P-gp level.(A) Effect of BM pretreatment on intestine and liver MDR1 expression. BM treatment decreases the MDR1 level in intestine. Fold changes in mRNA level are derived after normalizing with GAPDH mRNA level used as internal loading control (n = 3 in each group) and are indicated by numbers. BM represent rats pretreated with BM (31 mg/kg/day) for 7 days and control represents rats received same volume of vehicle Values are expressed as mean ± S.D. all results are from 3 independent experiments with similar results; * indicates significant difference in BM pretreated rats compared to vehicle treated rats with P value <0.05. (B) Effect of BM pretreatment on P-gp protein expression. Expression of P-gp protein in intestine, liver and kidney in rats pretreated with BM (31 mg/kg/day) for 7 days and control rats treated with vehicle for same time period. Membrane for western blotting was prepared as described in Material and Methods. 50 µg of protein was separated on 7.5% SDS-PAGE. Proteins were electrotransferred to PVDF membrane and probed with anti P-gp antibody and blot was developed with ECL kit. BM represent rats pre-treated with BM (31 mg/kg/day) for 7 days and control represents rats received same volume of vehicle.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3756011&req=5

pone-0072517-g002: Effect of BM pretreatment on P-gp level.(A) Effect of BM pretreatment on intestine and liver MDR1 expression. BM treatment decreases the MDR1 level in intestine. Fold changes in mRNA level are derived after normalizing with GAPDH mRNA level used as internal loading control (n = 3 in each group) and are indicated by numbers. BM represent rats pretreated with BM (31 mg/kg/day) for 7 days and control represents rats received same volume of vehicle Values are expressed as mean ± S.D. all results are from 3 independent experiments with similar results; * indicates significant difference in BM pretreated rats compared to vehicle treated rats with P value <0.05. (B) Effect of BM pretreatment on P-gp protein expression. Expression of P-gp protein in intestine, liver and kidney in rats pretreated with BM (31 mg/kg/day) for 7 days and control rats treated with vehicle for same time period. Membrane for western blotting was prepared as described in Material and Methods. 50 µg of protein was separated on 7.5% SDS-PAGE. Proteins were electrotransferred to PVDF membrane and probed with anti P-gp antibody and blot was developed with ECL kit. BM represent rats pre-treated with BM (31 mg/kg/day) for 7 days and control represents rats received same volume of vehicle.
Mentions: The mRNA expression profile of intestinal MDR1 of BM pre-treated and the vehicle pre-treated group was compared. In BM pre-treated group mRNA level of intestinal MDR1 was decreased by 2.5 fold compared to vehicle pre-treated group (Figure 2A). No significant difference in hepatic MDR1 mRNA was observed. Similarly weaker intensity of the bands revealed by Western blot after normalizing with beta-actin bands in the intestine of rats pre-treated with BM corresponds to a decrease in Pgp protein expression (Figure 2B). However no difference in hepatic and kidney Pgp expression was observed (data not shown).

Bottom Line: The BM treatment decreased the cytochrome P450 3A (CYP3A) mediated testosterone 6β-hydroxylation activity of the liver and intestine by 2 and 1.5 fold, respectively compared to vehicle treated control.Similarly pretreatment with BM extract decreased the expression of intestinal P-glycoprotein (Pgp) as confirmed by Western blot analysis but did not alter the expression of hepatic Pgp.Significant increase in AUC and Cmax of carbamazepine (4 and 1.8 fold) and digoxin (1.3 and 1.2 fold), respectively following the BM pre-treatment confirmed the down regulation of CYP3A and Pgp.

View Article: PubMed Central - PubMed

Affiliation: Pharmacokinetics and Metabolism Division. CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India.

ABSTRACT
Bacopa monniera is a traditional Ayurvedic herbal medicine used to treat various mental ailments from ancient times. Recently, chemically standardized alcoholic extract of Bacopa monniera (BM) has been developed and currently available as over the counter herbal remedy for memory enhancement in children and adults. However, the consumption of herbal drugs has been reported to alter the expression of drug metabolizing enzymes and membrane transporters. Present study in male Sprague-Dawley rat was performed to evaluate the effect of memory enhancing standardized extract of BM on hepatic and intestinal cytochrome P450 3A and P-glycoprotein expression and activity. The BM (31 mg/kg/day) was orally administered for one week in BM pre-treated group while the control group received the same amount of vehicle for the same time period. The BM treatment decreased the cytochrome P450 3A (CYP3A) mediated testosterone 6β-hydroxylation activity of the liver and intestine by 2 and 1.5 fold, respectively compared to vehicle treated control. Similarly pretreatment with BM extract decreased the expression of intestinal P-glycoprotein (Pgp) as confirmed by Western blot analysis but did not alter the expression of hepatic Pgp. To investigate whether this BM pretreatment mediated decrease in activity of CYP3A and Pgp would account for the alteration of respective substrate or not, pharmacokinetic study with carbamazepine and digoxin was performed in BM pre-treated rats and vehicle treated rats. Carbamazepine and digoxin were used as CYP3A and Pgp probe drugs, respectively. Significant increase in AUC and Cmax of carbamazepine (4 and 1.8 fold) and digoxin (1.3 and 1.2 fold), respectively following the BM pre-treatment confirmed the down regulation of CYP3A and Pgp.

Show MeSH
Related in: MedlinePlus