J Ethnopharmacol. 2010 Nov 17. [Epub ahead of print]
In vitro modulatory effects of Andrographis paniculata; Centella asiatica and Ortho siphon stamineus on cytochrome P450 2C19 (CYP2C19).
Pan Y, Abd-Rashid BA, Ismail Z, Ismail R, Mak JW, Pook PC, Er HM, Ong CE.
School of Pharmacy and Health Sciences, International Medical University, 126, Jalan 19/155B, Bukit Jalil, 57000 Kuala Lumpur, Malaysia.
Abstract
ETHNO PHARMACOLOGICAL
RELEVANCE: Andrographils paniculata (AP), Centella asiatica (CA) and Orthosiphon stamineus (OS) are three popular herbs tradtionally used worldwide. AP is known for the treatment of infections and diabetes and CA is good for wound healing and heathy skin while OS is usually consumed as tea to treat kidney and urinary disorders. Interaction of these herbs with human cytochrome P450 2C19 (CYP2C19), a major hepatic CYP isoform involved in metabolism of many clinical drugs have not been investigated to date.
AIM OF THE STUDY: In this study, the modulatory effects of various extracts and major active constituents of AP, CA and OS on CYP2C19 acitvities were evaluated.
MATERIALS AND METHODS: S-mephenytoin, the CYP2C19 substrate probe, was incubated in the presence or absence of AP, CA and OS components. The changes in the rate of metabolite (hydroxymephenytoin) formation was subsequently determined by a high-performance liquid chromatography (HPLC)-based enzyme assay to characterize the modulatory effects.
RESULTS: Among the herbal extacts studied, AP ethanol extract and CA dichloromethane extract exhibited mixed type inhibition towards CYP2C19 with K(i) values of 67.1 and 16.4μg/ml respectively; CA ethanol extract and OS petroleum ether extract competitively inhibited CYP2C19 activity (K(i)=39.6 and 41.5μg/ml respectively). Eupatorin (a major active constituent of OS) was found to significantly inhibit CYP2C19 by mixed type inhibition (K(i)=7.1μg/ml or 20.6μM).
CONCLUSIONS: It was observed that AP, CA and OS inhibited CYP2C19 activity with varying potency. While weak inhibitory effect was observed with AP, moderate to strong inhibition was observed with CA dichloromethane extract and eupatorin, the major OS constituent. Therefore care should be taken when these CA and OS components are co-administered with CYP2C19 substrates (such as omeprazole, proguanil, barbiturates, citalopram, and diazepam).
Copyright © 2010. Published by Elsevier Ireland Ltd.
PMID: 21093571 [PubMed - as supplied by publisher]
Cellular glutathione content modulates the effect of andrographolide on β-naphthoflavone-induced CYP1A1 mRNA expression in mouse hepatocytes
Toxicology. 2010 Nov 18. [Epub ahead of print]
Cellular glutathione content modulates the effect of andrographolide on β-naphthoflavone-induced CYP1A1 mRNA expression in mouse hepatocytes.
Kondo S, Chatuphonprasert W, Jaruchotikamol A, Sakuma T, Nemoto N.
Department of Toxicology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
Abstract
We previously reported that andrographolide (Andro), a major bioactive constituent of Andrographis paniculata, synergistically enhanced the inducible expression of CYP1A1 mRNA. In this study, although the synergism was confirmed at 24h after the start of treatment with Andro and β-naphthoflavone (βNF), a CYP1A inducer, the expression was profoundly suppressed at an earlier phase, namely at 6 -12h, when the βNF-induced expression peaked. Although oxidized glutathione (GSSG) levels were higher in co-treated cells at 6 and 24h, levels of reactive oxygen species varied depending on the treatment period and species, indicating no relation to the synergistic expression of CYP1A1 mRNA. Glutathione (GSH) and N-acetyl-L-cysteine (NAC) significantly enhanced the βNF-induced expression, and partly reversed the suppressive effect of Andro in the early phase. At 24h, the addition of GSH or NAC had no effect on βNF-induced CYP1A1 mRNA expression, but significantly reduced the synergistic effect of Andro. The synergistic effect was enhanced by L-buthionine-(S,R)-sulfoximine, a GSH depleter. Furthermore, H(2)O(2) and ascorbic acid further modified the profile of synergism of Andro on βNF-inducible CYP1A1 mRNA expression. These results suggest that GSH status might be involved in βNF-induced CYP1A1 mRNA expression, and the interaction of Andro with GSH might modulate the expression.
Copyright © 2010. Published by Elsevier Ireland Ltd.
PMID: 21094198 [PubMed - as supplied by publisher]
Cellular glutathione content modulates the effect of andrographolide on β-naphthoflavone-induced CYP1A1 mRNA expression in mouse hepatocytes.
Kondo S, Chatuphonprasert W, Jaruchotikamol A, Sakuma T, Nemoto N.
Department of Toxicology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
Abstract
We previously reported that andrographolide (Andro), a major bioactive constituent of Andrographis paniculata, synergistically enhanced the inducible expression of CYP1A1 mRNA. In this study, although the synergism was confirmed at 24h after the start of treatment with Andro and β-naphthoflavone (βNF), a CYP1A inducer, the expression was profoundly suppressed at an earlier phase, namely at 6 -12h, when the βNF-induced expression peaked. Although oxidized glutathione (GSSG) levels were higher in co-treated cells at 6 and 24h, levels of reactive oxygen species varied depending on the treatment period and species, indicating no relation to the synergistic expression of CYP1A1 mRNA. Glutathione (GSH) and N-acetyl-L-cysteine (NAC) significantly enhanced the βNF-induced expression, and partly reversed the suppressive effect of Andro in the early phase. At 24h, the addition of GSH or NAC had no effect on βNF-induced CYP1A1 mRNA expression, but significantly reduced the synergistic effect of Andro. The synergistic effect was enhanced by L-buthionine-(S,R)-sulfoximine, a GSH depleter. Furthermore, H(2)O(2) and ascorbic acid further modified the profile of synergism of Andro on βNF-inducible CYP1A1 mRNA expression. These results suggest that GSH status might be involved in βNF-induced CYP1A1 mRNA expression, and the interaction of Andro with GSH might modulate the expression.
Copyright © 2010. Published by Elsevier Ireland Ltd.
PMID: 21094198 [PubMed - as supplied by publisher]
Andrographolide-induced pi class of glutathione S-transferase gene expression via PI3K/Akt pathway in rat primary hepatocytes
Food Chem Toxicol. 2010 Nov 4. [Epub ahead of print]
Andrographolide-induced pi class of glutathione S-transferase gene expression via PI3K/Akt pathway in rat primary hepatocytes.
Lu CY, Li CC, Yao HT, Liu KL, Tsai CW, Lii CK, Chen HW.
Department of Nutrition, Chung Shan Medical University, Taichung, Taiwan.
Abstract
Andrographis paniculata is an herb widely used in China, Korea, and India for its anti-hepatotoxic, anti-viral, and anti-inflammatory effects. Andrographolide is the major bioactive diterpene lactone in A. paniculata. The pi class of glutathione S-transferase (GSTP) is one of the phase II biotransformation enzymes. Our previous study indicated that andrographolide upregulates the expression of GSTP. The aim of this study was to investigate the mechanism by which andrographolide induces GSTP gene expression in rat primary hepatocytes. In hepatocytes treated with 40 μM andrographolide, immunoblots showed maximal Akt phosphorylation at 0.5 h and maximal c-jun phosphorylation at 3 h. However, pretreatment with PI3K inhibitors, wortmannin and LY294002, or siPI3K inhibited the andrographolide-induced phosphorylation of c-jun and GSTP protein expression. EMSA showed that pretreatment with wortmannin, LY294002, or siPI3K attenuated the AP-1-DNA binding activity caused by andrographolide. Results of immunoprecipitation indicated that nuclear c-fos/c-jun heterodimer increases with andrographolide treatment. Addition of antibodies against c-jun and c-fos decreased nuclear protein bound to the AP-1 consensus DNA sequence. In summary, andrographolide induces GSTP gene expression in rat primary hepatocytes through activation of the PI3K/Akt, phosphorylation of c-jun, nuclear accumulation of AP-1, and subsequent binding to the response element in the gene promoter region.
Copyright © 2010. Published by Elsevier Ltd.
PMID: 21056613 [PubMed - as supplied by publisher]
Andrographolide-induced pi class of glutathione S-transferase gene expression via PI3K/Akt pathway in rat primary hepatocytes.
Lu CY, Li CC, Yao HT, Liu KL, Tsai CW, Lii CK, Chen HW.
Department of Nutrition, Chung Shan Medical University, Taichung, Taiwan.
Abstract
Andrographis paniculata is an herb widely used in China, Korea, and India for its anti-hepatotoxic, anti-viral, and anti-inflammatory effects. Andrographolide is the major bioactive diterpene lactone in A. paniculata. The pi class of glutathione S-transferase (GSTP) is one of the phase II biotransformation enzymes. Our previous study indicated that andrographolide upregulates the expression of GSTP. The aim of this study was to investigate the mechanism by which andrographolide induces GSTP gene expression in rat primary hepatocytes. In hepatocytes treated with 40 μM andrographolide, immunoblots showed maximal Akt phosphorylation at 0.5 h and maximal c-jun phosphorylation at 3 h. However, pretreatment with PI3K inhibitors, wortmannin and LY294002, or siPI3K inhibited the andrographolide-induced phosphorylation of c-jun and GSTP protein expression. EMSA showed that pretreatment with wortmannin, LY294002, or siPI3K attenuated the AP-1-DNA binding activity caused by andrographolide. Results of immunoprecipitation indicated that nuclear c-fos/c-jun heterodimer increases with andrographolide treatment. Addition of antibodies against c-jun and c-fos decreased nuclear protein bound to the AP-1 consensus DNA sequence. In summary, andrographolide induces GSTP gene expression in rat primary hepatocytes through activation of the PI3K/Akt, phosphorylation of c-jun, nuclear accumulation of AP-1, and subsequent binding to the response element in the gene promoter region.
Copyright © 2010. Published by Elsevier Ltd.
PMID: 21056613 [PubMed - as supplied by publisher]
In vitro modulation of LPS/calcimycin induced inflammatory and allergic mediators by pure compounds of Andrographis paniculata (King of bitters) extract
Int Immunopharmacol. 2010 Oct 26. [Epub ahead of print]
In vitro modulation of LPS/calcimycin induced inflammatory and allergic mediators by pure compounds of Andrographis paniculata (King of bitters) extract.
Chandrasekaran CV, Thiyagarajan P, Deepak HB, Agarwal A.
Abstract
The aim of the current study was to probe the anti-inflammatory/anti-allergic potential of seven phytoconstituents (andrographolide, neoandrographolide, isoandrographolide, andrograpanin, 14-deoxy-11,12-didehydroandrographolide, 7-O-methylwogonin and skullcapflavone-I) isolated from Andrographis paniculata (King of bitters) on the production of key inflammatory/allergic mediators (NO, PGE(2), IL-1 beta, IL-6, LTB(4), TXB(2) and histamine). The results demonstrated that andrographolide, isoandrographolide, 7-O-methylwogonin and skullcapflavone-I significantly inhibited LPS stimulated NO and PGE(2) release in J774A.1 macrophages. Andrographolide, isoandrographolide and 7-O-methylwogonin showed considerable inhibition of IL-1 beta production in LPS elicited macrophages. LPS induced IL-6 production was significantly inhibited by andrographolide, isoandrographolide and skullcapflavone-I in a concentration dependent manner. The results revealed that andrographolide, isoandrographolide and skullcapflavone-I significantly decreased TXB(2) release in A23187 activated HL-60 promyelocytic cells. Furthermore, the anti-allergic properties of the phytoconstituents was investigated on A23187 induced LTB(4) production (HL-60 cells) and histamine release (RBL-2H3 basophilic cells). The results showed that only skullcapflavone-I and 7-O-methylwogonin showed marked inhibitory effect on LTB(4) production, however, only 7-O-methylwogonin exerted dose-dependent inhibition towards histamine release. Therefore, this study indicates that some of these phytoconstituents exhibit potent anti-inflammatory/anti-allergic effects by modulating different inflammatory/allergic mediators. Hence, these phytoconstituents might provide useful phytomedical treatment against variety of inflammatory and allergic disorders.
Copyright © 2010. Published by Elsevier B.V.
PMID: 21034865 [PubMed - as supplied by publisher]
In vitro modulation of LPS/calcimycin induced inflammatory and allergic mediators by pure compounds of Andrographis paniculata (King of bitters) extract.
Chandrasekaran CV, Thiyagarajan P, Deepak HB, Agarwal A.
Abstract
The aim of the current study was to probe the anti-inflammatory/anti-allergic potential of seven phytoconstituents (andrographolide, neoandrographolide, isoandrographolide, andrograpanin, 14-deoxy-11,12-didehydroandrographolide, 7-O-methylwogonin and skullcapflavone-I) isolated from Andrographis paniculata (King of bitters) on the production of key inflammatory/allergic mediators (NO, PGE(2), IL-1 beta, IL-6, LTB(4), TXB(2) and histamine). The results demonstrated that andrographolide, isoandrographolide, 7-O-methylwogonin and skullcapflavone-I significantly inhibited LPS stimulated NO and PGE(2) release in J774A.1 macrophages. Andrographolide, isoandrographolide and 7-O-methylwogonin showed considerable inhibition of IL-1 beta production in LPS elicited macrophages. LPS induced IL-6 production was significantly inhibited by andrographolide, isoandrographolide and skullcapflavone-I in a concentration dependent manner. The results revealed that andrographolide, isoandrographolide and skullcapflavone-I significantly decreased TXB(2) release in A23187 activated HL-60 promyelocytic cells. Furthermore, the anti-allergic properties of the phytoconstituents was investigated on A23187 induced LTB(4) production (HL-60 cells) and histamine release (RBL-2H3 basophilic cells). The results showed that only skullcapflavone-I and 7-O-methylwogonin showed marked inhibitory effect on LTB(4) production, however, only 7-O-methylwogonin exerted dose-dependent inhibition towards histamine release. Therefore, this study indicates that some of these phytoconstituents exhibit potent anti-inflammatory/anti-allergic effects by modulating different inflammatory/allergic mediators. Hence, these phytoconstituents might provide useful phytomedical treatment against variety of inflammatory and allergic disorders.
Copyright © 2010. Published by Elsevier B.V.
PMID: 21034865 [PubMed - as supplied by publisher]
Andrographis paniculata Downregulates Proinflammatory Cytokine Production and Augments Cell Mediated Immune Response in Metastatic Tumor-Bearing Mice
Asian Pac J Cancer Prev. 2010;11(3):723-9
Andrographis paniculata Downregulates Proinflammatory Cytokine Production and Augments Cell Mediated Immune Response in Metastatic Tumor-Bearing Mice
Sheeja K, Kuttan G.
Department of Immunology, Amala Cancer Research Centre, Amala Nagar, Thrissur, Kerala, India. E-mail : amalacancerresearch@gmail.com
Abstract
Effects of Andrographis paniculata extract and its major component, andrographolide, on cell-mediated immune responses in metastatic tumor bearing animals were studied. NK cell mediated target cell lysis was enhanced by the administration of Andrographis paniculata extract (45.0% cell lysis) and andrographolide (40.2% cell lysis) on the 5th day after tumor induction when compared to untreated metastatic tumor bearing animals in which maximum target cell lysis was observed on 11th day (11.4%). Antibody dependent cell-mediated cytotoxicity (ADCC) was also enhanced by treatment with the extract (42.0% cell lysis) and andrographolide (40.2%) in comparison with the untreated case (11.0%). Similarly, the extract (25%) and andrographolide (22%) showed higher ACC activity than the control (14%) and treatment of extract and andrographolide resulted in significant increase in serum IL-2 and TIMP-1 levels. Furthermore, the levels of proinflammatory cytokines such as IL-1?, IL-6, GM-CSF and TNF-? were effectively reduced by the administration of extract and andrographolide in metastatic tumor bearing animals.
PMID: 21039043 [PubMed - in process]
Andrographis paniculata Downregulates Proinflammatory Cytokine Production and Augments Cell Mediated Immune Response in Metastatic Tumor-Bearing Mice
Sheeja K, Kuttan G.
Department of Immunology, Amala Cancer Research Centre, Amala Nagar, Thrissur, Kerala, India. E-mail : amalacancerresearch@gmail.com
Abstract
Effects of Andrographis paniculata extract and its major component, andrographolide, on cell-mediated immune responses in metastatic tumor bearing animals were studied. NK cell mediated target cell lysis was enhanced by the administration of Andrographis paniculata extract (45.0% cell lysis) and andrographolide (40.2% cell lysis) on the 5th day after tumor induction when compared to untreated metastatic tumor bearing animals in which maximum target cell lysis was observed on 11th day (11.4%). Antibody dependent cell-mediated cytotoxicity (ADCC) was also enhanced by treatment with the extract (42.0% cell lysis) and andrographolide (40.2%) in comparison with the untreated case (11.0%). Similarly, the extract (25%) and andrographolide (22%) showed higher ACC activity than the control (14%) and treatment of extract and andrographolide resulted in significant increase in serum IL-2 and TIMP-1 levels. Furthermore, the levels of proinflammatory cytokines such as IL-1?, IL-6, GM-CSF and TNF-? were effectively reduced by the administration of extract and andrographolide in metastatic tumor bearing animals.
PMID: 21039043 [PubMed - in process]
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