Publications by authors named "Sabariah Ismail"

19 Publications

  • Page 1 of 1

Inhibition of UGT2B7 Enzyme Activity in Human and Rat Liver Microsomes by Herbal Constituents.

Molecules 2018 Oct 19;23(10). Epub 2018 Oct 19.

Centre for Drug Research, Universiti Sains Malaysia, Gelugor 11800, Pulau Pinang, Malaysia.

The co-use of conventional drug and herbal medicines may lead to herb-drug interaction via modulation of drug-metabolizing enzymes (DMEs) by herbal constituents. UDP-glucuronosyltransferases (UGTs) catalyzing glucuronidation are the major metabolic enzymes of Phase II DMEs. The in vitro inhibitory effect of several herbal constituents on one of the most important UGT isoforms, UGT2B7, in human liver microsomes (HLM) and rat liver microsomes (RLM) was investigated. Zidovudine (ZDV) was used as the probe substrate to determine UGT2B7 activity. The intrinsic clearance (V/K) of ZDV in HLM is 1.65 µL/mg/min which is ten times greater than in RLM, which is 0.16 µL/mg/min. Andrographolide, kaempferol-3-rutinoside, mitragynine and zerumbone inhibited ZDV glucuronidation in HLM with IC values of 6.18 ± 1.27, 18.56 ± 8.62, 8.11 ± 4.48 and 4.57 ± 0.23 µM, respectively, hence, herb-drug interactions are possible if andrographolide, kaempferol-3-rutinoside, mitragynine and zerumbone are taken together with drugs that are highly metabolized by UGT2B7. Meanwhile, only mitragynine and zerumbone inhibited ZDV glucuronidation in RLM with IC values of 51.20 ± 5.95 μM and 8.14 ± 2.12 µM, respectively, indicating a difference between the human and rat microsomal model so caution must be exercised when extrapolating inhibitory metabolic data from rats to humans.
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http://dx.doi.org/10.3390/molecules23102696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222696PMC
October 2018

Mechanism of Action of Isolated Caffeic Acid and Epicatechin 3-gallate from against .

Pharmacogn Mag 2017 Jul 11;13(Suppl 2):S311-S315. Epub 2017 Jul 11.

Centre for Herbal Standardization, Penang, Malaysia.

Background: The escalating dominance of resistant strains as infectious pathogen had urged the researchers to look for alternative and complementary drugs.

Objective: The objective of this study is to address the biological targets and probable mechanisms of action underlying the potent antibacterial effect of the isolated compounds from (L.) against .

Materials And Methods: The action mechanisms of caffeic acid (CA) and epicatechin 3-gallate (ECG) on cells were investigated by several bacterial physiological manifestations involving outer membrane permeabilization, intracellular potassium ion efflux, and nucleotide leakage.

Results: The findings revealed that ECG and CA targeted both cell wall and cytoplasmic membrane of . The cellular membrane destruction and ensuing membrane permeability perturbation of had led to the ascending access of hydrophobic antibiotics, release of potassium ions, and leakages of nucleotides.

Conclusion: The overall study concludes that ECG and CA isolated from possess remarkable anti-infective potentials which can be exploited as drug template for the development of new antibacterial agent against resistant pathogen.

Summary: Epicatechin 3-gallate (ECG) and caffeic acid (CA) exhibited remarkable bactericidal abilities by increasing the outer membrane and plasma membrane permeability of pathogenECG and CA had facilitated the entry of hydrophobic antibiotics into by disintegrating the lipopolysaccharides layer of the outer membraneECG-induced potassium efflux with efficiency close to that obtained with cefepime suggesting mode of action through membrane disruptionBoth ECG and CA had caused consistent leakage of intracellular nucleotide content with the increase in time. ECG: Epicatechin 3-gallate; CA: Caffeic acid; : Euphoria hirta.
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http://dx.doi.org/10.4103/pm.pm_309_15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538172PMC
July 2017

Inhibitory Effects of , , , and Extracts and Constituents on Human Liver Glucuronidation Activity.

Pharmacogn Mag 2017 Jul 11;13(Suppl 2):S236-S243. Epub 2017 Jul 11.

Centre for Drug Research, Universiti Sains Malaysia, Pulau Pinang, Malaysia.

Background: , , and are commonly consumed as herbal medicines. However their effects on human liver glucuronidation activity are not yet evaluated.

Objective: In this study, we evaluate the inhibitory Effects of Andrographis paniculata, Gynura procumbens, Ficus deltoidea and Curcuma xanthorrhiza extracts and their constituents on human liver glucuronidation activity.

Materials And Methods: Herbal extracts (aqueous, methanolic and ethanolic extracts) and their constituents were incubated with human liver microsomes with the addition of UDPGA to initiate the reaction. Working concentrations of herbal extracts and their constituents ranged from 10 μg/mL to 1000 μg/mL and 10 μM to 300 μM respectively. IC50 was determined by monitoring the decrement of glucuronidation activity with the increment of herbal extracts or phytochemical constituent's concentrations.

Results: All herbal extracts inhibited human liver glucuronidation activity in range of 34.69 μg/mL to 398.10 μg/mL whereas for the constituents, only xanthorrhizol and curcumin (constituents of ) inhibited human liver glucuronidation activity with IC50 of 538.50 and 32.26 μM respectively.

Conclusion: In the present study, we have proved the capabilities of , , and to interfere with glucuronidation process in human liver microsomes.

Summary: This study documented the capabilities of , , and to inhibit human liver glucuronidation activity which may affect the metabolism of therapeutic drugs or hazardous toxicants that follow the same glucuronidation pathway. UGT: Uridine 5'-diphospho-glucuronosyltransferase; 4-MU: 4-methylumbelliferone; IC50: Half Maximal Inhibitory Concentration; Km: Michaelis constant; Vmax: Maximum velocity.
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http://dx.doi.org/10.4103/pm.pm_299_16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538160PMC
July 2017

The Inhibition of Hepatic and Renal Glucuronidation of -Nitrophenol and 4-Methylumbelliferone by Oil Palm Empty Fruit Bunch Lignin and Its Main Oxidation Compounds.

Pharmacogn Mag 2017 Jan 7;13(Suppl 1):S102-S114. Epub 2017 Apr 7.

School of Chemical Sciences, Universiti Sains Malaysia, Penang, Malaysia.

Background: In order to develop oil palm empty fruit bunch (EFB) lignin as a nutraceutical and health supplement, the investigation of its potential in interacting with other drugs via inhibition of drug-metabolizing enzymes (DMEs) would ensure product safety.

Objective: The study was aimed to investigate the effect of oil palm EFB lignin and its main oxidation compounds on phase II DME UDP-glucuronosyltransferases (UGTs) in rat liver and kidney microsomes.

Materials And Methods: The -nitrophenol (-NP) and 4-methylumbelliferone (4-MU) were employed as probe substrates in glucuronidation assays. The effect of soda oil palm EFB lignin on , , CL, , and mode of inhibition of 4-MU glucuronidation in RLM was also determined.

Results: The inhibitory potency of oil palm EFB lignin for both -NP and 4-MU glucuronidation in rat liver microsome (RLM) and rat kidneys microsomes (RKM) was found to be in the rank order of soda > kraft > organosolv. However, the inhibitory potency of its main oxidation compounds were in the rank order of vanillin > syringaldehyde > -hydroxybenzaldehyde. Soda oil palm EFB lignin exhibited mixed-type inhibition against 4-MU glucuronidation in RLM, showing the change in apparent and with only a minor effect on compared with control.

Conclusions: The findings showed that effect of oil palm EFB lignin on both -NP and 4-MU glucuronidation in RLM and RKM was enhanced by the presence of vanillin as well as flavonoids. Kinetic study showed that soda oil palm EFB lignin exhibited strong inhibition on UGT activity in RLM with mixed-type inhibition mode.

Summary: The inhibitory potential of oil palm EFB lignin extracts for -NP and 4-MU glucuronidation in RLM and RKM can be listed in the following rank order: soda > kraft > organosolvThe inhibitory potential of oil palm EFB lignin main oxidation compounds for -NP and 4-MU glucuronidation in RLM and RKM can be listed in the following rank order: vanillin > syringaldehyde > p-hydroxybenzaldehydeResults suggested that the effect of oil palm EFB lignin on -NP and 4-MU glucuronidation activity in both RLM and RKM was enhanced by the presence of vanillin as well as total flavonoid contentResults also suggested that oil palm EFB lignin may inhibit glucuronidation of substrate by UGT enzymes, especially UGT1A6, particularly in rat liver -NP: -Nitrophenol, 4-MU: 4-Methylumbelliferone, EFB: Empty fruit bunch, DME: Drug-metabolizing enzymes, UGT: UDPglucuronosyltransferase, : Maximal reaction velocity, : Michaelis-Menten constant, CLint: Intrinsic clearance, : Dissociation constant of an inhibitor enzyme complex, 4-MUG: 4-Methylumbelliferone glucuronide, DMSO: Dimethyl sulfoxide, IC50: Half maximal inhibitory concentration, -NPG: -Nitrophenol glucuronide, RKM: Rat kidneys microsomes, RLM: Rat liver microsome, UDPGA: UDPglucuronic acid, TCA: trichloroacetic acid, MPA: mycophenolic acid.
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http://dx.doi.org/10.4103/0973-1296.203990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5407101PMC
January 2017

Effects of Extracts and Their Constituents on Phase II Drug-metabolizing Enzymes Activity.

Pharmacognosy Res 2016 Oct-Dec;8(4):309-315

Centre for Drug Research, Universiti Sains, Penang, Malaysia.

Background: is a native Indonesian plant and traditionally utilized for a range of illness including liver damage, hypertension, diabetes, and cancer.

Objective: The study determined the effects of extracts (ethanol and aqueous) and their constituents (curcumene and xanthorrhizol) on UDP-glucuronosyltransferase (UGT) and glutathione transferase (GST) activities.

Materials And Methods: The inhibition studies were evaluated both in rat liver microsomes and in human recombinant UGT1A1 and UGT2B7 enzymes. p-nitrophenol and beetle luciferin were used as the probe substrates for UGT assay while 1-chloro-2,4-dinitrobenzene as the probe for GST assay. The concentrations of extracts studied ranged from 0.1 to 1000 μg/mL while for constituents ranged from 0.01 to 500 μM.

Results: In rat liver microsomes, UGT activity was inhibited by the ethanol extract (IC =279.74 ± 16.33 μg/mL). Both UGT1A1 and UGT2B7 were inhibited by the ethanol and aqueous extracts with IC values ranging between 9.59-22.76 μg/mL and 110.71-526.65 μg/Ml, respectively. Rat liver GST and human GST Pi-1 were inhibited by ethanol and aqueous extracts, respectively (IC =255.00 ± 13.06 μg/mL and 580.80 ± 18.56 μg/mL). Xanthorrhizol was the better inhibitor of UGT1A1 (IC 11.30 ± 0.27 μM) as compared to UGT2B7 while curcumene did not show any inhibition. For GST, both constituents did not show any inhibition.

Conclusion: These findings suggest that have the potential to cause herb-drug interaction with drugs that are primarily metabolized by UGT and GST enzymes.

Summary: Findings from this study would suggest which of extracts and constituents that would have potential interactions with drugs which are highly metabolized by UGT and GST enzymes. Further clinical studies can then be designed if needed to evaluate the pharmacokinetic relevance of these interactions : BSA: Bovine serum albumin, CAM: Complementary and alternative medicine, cDNA: Complementary deoxyribonucleic acid, CDNB: 1-Chloro-2,4-dinitrobenzene, CuSO4.5H2O: Copper(II) sulfate pentahydrate, CXEE: ethanol extract, CXAE: aqueous extract, GC-MS: Gas chromatography-mass spectroscopy, GSH: Glutathione, GST: Glutathione S-transferase, KCl: Potassium chloride, min: Minutes, MgCl: Magnesium chloride, mg/mL: Concentration (weight of test substance in milligrams per volume of test concentration), mM: Milimolar, NaCO: Sodium carbonate, NaOH: Sodium hydroxide, nmol: nanomol, NSAIDs: Non-steroidal antiinflammatory drug, p-NP: para-nitrophenol, RLU: Relative light unit, SEM: Standard error of mean, UDPGA: UDP-glucuronic acid, UGT: UDP-glucuronosyltransferase.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5004525PMC
http://dx.doi.org/10.4103/0974-8490.188873DOI Listing
October 2016

Effects of mitragynine and 7-hydroxymitragynine (the alkaloids of Mitragyna speciosa Korth) on 4-methylumbelliferone glucuronidation in rat and human liver microsomes and recombinant human uridine 5'-diphospho-glucuronosyltransferase isoforms.

Pharmacognosy Res 2014 Oct-Dec;7(4):341-9

Centre for Drug Research, Universiti Sains Malaysia, 11800 USM, Penang, Malaysia.

Background: Glucuronidation catalyzed by uridine 5'- diphospho-glucuronosyltransferase (UGT) is a major phase II drug metabolism reaction which facilitates drug elimination. Inhibition of UGT activity can cause drug-drug interaction. Therefore, it is important to determine the inhibitory potentials of drugs on glucuronidation.

Objective: The objective was to evaluate the inhibitory potentials of mitragynine, 7-hydroxymitragynine, ketamine and buprenorphine, respectively on 4-methylumbelliferone (4-MU) glucuronidation in rat liver microsomes, human liver microsomes and recombinant human UGT1A1 and UGT2B7 isoforms.

Materials And Methods: The effects of the above four compounds on the formation of 4-MU glucuronide from 4-MU by rat liver microsomes, human liver microsomes, recombinant human UGT1A1 and UGT2B7 isoforms were determined using high-performance liquid chromatography with ultraviolet detection.

Results: For rat liver microsomes, ketamine strongly inhibited 4-MU glucuronidation with an IC50 value of 6.21 ± 1.51 μM followed by buprenorphine with an IC50 value of 73.22 ± 1.63 μM. For human liver microsomes, buprenorphine strongly inhibited 4-MU glucuronidation with an IC50 value of 6.32 ± 1.39 μM. For human UGT1A1 isoform, 7-hydroxymitragynine strongly inhibited 4-MU glucuronidation with an IC50 value of 7.13 ± 1.16 μM. For human UGT2B7 isoform, buprenorphine strongly inhibited 4-MU glucuronidation followed by 7-hydroxymitragynine and ketamine with respective IC50 values of 5.14 ± 1.30, 26.44 ± 1.31, and 27.28 ± 1.18 μM.

Conclusions: These data indicate the possibility of drug-drug interaction if 7-hydroxymitragynine, ketamine, and buprenorphine are co-administered with drugs that are UGT2B7 substrates since these three compounds showed significant inhibition on UGT2B7 activity. In addition, if 7-hydroxymitragynine is to be taken with other drugs that are highly metabolized by UGT1A1, there is a possibility of drug-drug interaction to occur.
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http://dx.doi.org/10.4103/0974-8490.159580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4660513PMC
December 2015

Investigation of antioxidant and hepatoprotective activity of standardized Curcuma xanthorrhiza rhizome in carbon tetrachloride-induced hepatic damaged rats.

ScientificWorldJournal 2014 14;2014:353128. Epub 2014 Jul 14.

School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800 Minden, Pulau Pinang, Malaysia.

Curcuma xanthorrhiza (CX) has been used for centuries in traditional system of medicine to treat several diseases such as hepatitis, liver complaints, and diabetes. It has been consumed as food supplement and "jamu" as a remedy for hepatitis. Hence, CX was further explored for its potential as a functional food for liver related diseases. As such, initiative was taken to evaluate the antioxidant and hepatoprotective potential of CX rhizome. Antioxidant activity of the standardized CX fractions was determined using in vitro assays. Hepatoprotective assay was conducted against carbon tetrachloride- (CCl4-) induced hepatic damage in rats at doses of 125, 250, and 500 mg/kg of hexane fraction. Highest antioxidant activity was found in hexane fraction. In the case of hepatoprotective activity, CX hexane fraction showed significant improvement in terms of a biochemical liver function, antioxidative liver enzymes, and lipid peroxidation activity. Good recovery was observed in the treated hepatic tissues histologically. Hence, the results concluded that CX hexane fraction possessed prominent hepatoprotective activities which might be due to its in vitro antioxidant activity. These findings also support the use of CX as a functional food for hepatitis remedy in traditional medicinal system.
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http://dx.doi.org/10.1155/2014/353128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4122155PMC
May 2015

Mitragyna speciosa Korth leaves extracts induced the CYP450 catalyzed aminopyrine-N-demethylase (APND) and UDP-glucuronosyl transferase (UGT) activities in male Sprague-Dawley rat livers.

Drug Metabol Drug Interact 2013 ;28(2):95-105

Centre for Drug Research, Universiti Sains Malaysia, Penang, Malaysia.

Background: Mitragyna speciosa leaves have been abused by drug addicts as some of the alkaloids (mainly mitragynine) from the plant possess opiate and cocaine-like effects. These bring to its prohibition in Malaysia in 2004 as consumption of M. speciosa leaves has been perceived to lead to the abuse of other drugs such as cannabis and heroin.

Methods: In the current study, the in vitro and in vivo effects of M. speciosa methanolic, aqueous and total alkaloid leaves extracts on drug metabolizing enzymes, namely, cytochrome P450s (CYP450s) and UDP-glucuronosyl transferase (UGT) had been evaluated in rat liver cytosolic fraction and microsomes. Aminopyrine and p-nitrophenol (pNP) were employed as probe substrates in aminopyrine N-demethylase (APND) and UGT enzyme assays, respectively. Furthermore, mitragynine was also tested in vitro for its likelihood to inhibit APND and UGT activity. The assessment of the enzyme activity was conducted using spectrophotometric methods.

Results: In vitro, the IC50 value could only be obtained for the methanolic extract in APND study (595.30±30.78 µg/mL) and not in other studies due to the enzyme percentage inhibitions being <70%. In contrast to the in vitro study, the oral treatment of male Sprague-Dawley rats for 14 days with 50, 100 and 200 mg/kg of methanolic and aqueous extracts and with 5, 10 and 20 mg/kg of total alkaloid extract showed a profound increment on the APND and UGT activities.

Conclusions: The current findings showed that possibilities exist for herb-drug interaction with increased clearance of drugs, which are primarily metabolized by CYP450s and UGT1A6 among M. speciosa leaves extract users.
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http://dx.doi.org/10.1515/dmdi-2012-0039DOI Listing
September 2013

Review on pharmacological activities of Cinnamomum iners Reinw. ex Blume.

Nat Prod Res 2013 10;27(10):888-95. Epub 2012 May 10.

Centre for Drug Research, Universiti Sains Malaysia, 11800 Penang, Malaysia.

This review describes the morphological, phytochemical and pharmacological properties of Cinnamomum iners Reinw. ex Blume (Lauraceae). The plant grows wild in the lowland of Malaysia, India, Myanmar, Indonesia, Thailand, Singapore, Brunei and Philippines. This plant is commonly used for its carminative, analgesic and antipyretic properties, for postpartum treatment, rheumatism and digestive ailments. This article enumerates an overview of phytochemical and pharmacological aspects that is useful to researchers for further exploration necessary for the development of this potential herb.
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http://dx.doi.org/10.1080/14786419.2012.678347DOI Listing
January 2014

Chemical composition, antioxidant and cytotoxicity activities of the essential oils of Myristica fragrans and Morinda citrifolia.

J Sci Food Agric 2012 Feb;92(3):593-7

Background: In this study the chemical composition, antioxidant activities and cytotoxic effect of the essential oils of Myristica fragrans (nutmeg) and Morinda citrifolia (mengkudu) were determined.

Results: Thirty-eight compounds in nutmeg oil and six compounds in mengkudu oil were identified by gas chromatography–mass spectrometry. The free radical scavenging activity of nutmeg oil was superior of that mengkudu oil. The MTT assay of nutmeg oil on human colorectal carcinoma (HCT-116) and human breast carcinoma (MCF-7) cell lines showed IC₅₀ values of 78.61 and 66.45 µg mL⁻¹, respectively. The mengkudu oil exhibited IC₅₀ values of 91.46 and 78.15 µg mL⁻¹ for HCT-116 and MCF-7, respectively.

Conclusion: The results showed that nutmeg oil can be developed as potent anti-cancer and antioxidant drugs.
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http://dx.doi.org/10.1002/jsfa.4613DOI Listing
February 2012

Brine shrimp lethality and acute oral toxicity studies on Swietenia mahagoni (Linn.) Jacq. seed methanolic extract.

Pharmacognosy Res 2010 Jul;2(4):215-20

Center for Drug Research, Universiti Sains Malaysia, 11800 Penang, Malaysia.

Background: The seeds of Swietenia mahagoni have been applied in folk medicine for the treatment of hypertension, diabetes, malaria, amoebiasis, cough, chest pain, and intestinal parasitism. Here we are the first to report on the toxicity of the Swietenia mahagoni crude methanolic (SMCM) seed extract.

Methods: SMCM seed extract has been studied for its brine shrimp lethality and acute oral toxicity, in mice.

Results: The brine shrimp lethality bioassay shows a moderate cytotoxicity at high concentration. The LC50 for the extract is 0.68 mg/ml at 24 hours of exposure. The LD50 of the SMCM seed extract for acute oral toxicity in mice is greater than 5000 mg/kg.

Conclusion: This study demonstrates that Swietenia mahagoni crude methanolic seed extract may contain bioactive compounds of potential therapeutic significance which are relatively safe from toxic effects, and can compromise the medicinal use of this plant in folk medicine.
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http://dx.doi.org/10.4103/0974-8490.69107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3141130PMC
July 2010

An antimicrobial compound isolated from Cinnamomum iners leaves with activity against methicillin-resistant Staphylococcus aureus.

Molecules 2011 Apr 8;16(4):3037-47. Epub 2011 Apr 8.

Centre for Drug Research, Universiti Sains Malaysia, 11800 Penang, Malaysia.

This study was designed to investigate the antimicrobial activity of Cinnamomum iners standardized leave methanolic extract (CSLE), its fractions and isolated compounds. CSLE and fractions were subjected to disc diffusion, minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) tests using different Gram positive and Gram negative bacteria and yeast. Within the series of fractions tested, the ethyl acetate fraction was the most active, particularly against methicillin resistant Staphylococcus aureus (MRSA) and Escherichia coli, with MIC values of 100 and 200 µg/mL, respectively. The active compound in this fraction was isolated and identified as xanthorrhizol [5-(1, 5-dimethyl-4-hexenyl)-2-methylphenol] by various spectroscopic techniques. The overall results of this study provide evidence that Cinnamomum iners leaves extract as well as the isolated compound xanthorrhizol exhibit antimicrobial activity for both Gram negative and Gram positive pathogens, especially against MRSA strains.
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http://dx.doi.org/10.3390/molecules16043037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6260600PMC
April 2011

Effects of Andrographis paniculata and Orthosiphon stamineus extracts on the glucuronidation of 4-methylumbelliferone in human UGT isoforms.

Molecules 2010 May 14;15(5):3578-92. Epub 2010 May 14.

Centre for Drug Research, Universiti Sains Malaysia, 11800, Penang, Malaysia.

The effects of Andrographis paniculata and Orthosiphon stamineus extracts on the in vitro glucuronidation of 4-methylumbelliferone (4MU) by recombinant human UGTs, UGT1A1, UGT1A3, UGT1A6, UGT1A7, UGT1A8, UGT1A10, UGT2B7 and UGT2B15 were determined. The potential inhibitory effects of both of the extracts on the activity of each of the UGT isoforms were investigated using 4MU as the substrate. Incubations contained UDP-glucuronic acid (UDPGA) as the cofactor, MgCl(2), cell lysate of respective isoform, and 4MU at the approximate apparent K(m) or S(50) value of each isoform. Final concentrations of Andrographis paniculata and Orthosiphon stamineus extracts used were 0.025, 0.25, 2.5, 25 and 50 microg/mL and 0.01, 0.10, 1.0, 10 and 50 microg/mL respectively. Both extracts variably inhibited the activity of most of the isoforms in a concentration dependent manner. Andrographis paniculata extract was the better inhibitor of all the isoforms studied (IC(50) 1.70 microg/mL for UGT1A3, 2.57 microg/mL for UGT1A8, 2.82 microg/mL for UGT2B7, 5.00 micorg/mL for UGT1A1, 5.66 microg/mL for UGT1A6, 9.88 microg/mL for UGT1A7 and 15.66 microg/mL for UGT1A10). Both extracts showed less than 70% inhibition of UGT2B15, so the IC(50) values were >50 microg/mL. The inhibition of human UGTs by Andrographis paniculata and Orthosiphon stamineus extracts in vitro suggests a potential for drug-herbal extract interactions in the therapeutic setting.
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http://dx.doi.org/10.3390/molecules15053578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6263374PMC
May 2010

Determination of mitragynine in plasma with solid-phase extraction and rapid HPLC-UV analysis, and its application to a pharmacokinetic study in rat.

Anal Bioanal Chem 2010 Jul 8;397(5):2023-30. Epub 2010 May 8.

Centre for Drug Research, Universiti Sains Malaysia, 11800, Penang, Malaysia.

A new solid phase extraction method for rapid high performance liquid chromatography-UV determination of mitragynine in plasma has been developed. Optimal separation was achieved with an isocratic mobile phase consisting of acetonitrile-ammonium acetate buffer, 50 mM at pH 5.0 (50:50, v/v). The method had limits of detection and quantification of 0.025 and 0.050 microg/mL, respectively. The method was accurate and precise for the quantitative analysis of mitragynine in human and rat plasma with within-day and between-day accuracies between 84.0 and 109.6%, and their precision values were between 1.7 and 16.8%. Additional advantages over known methods are related to the solid phase extraction technique for sample preparation which yields a clean chromatogram, a short total analysis time, requires a smaller amount of plasma samples and has good assay sensitivity for bioanalytical application. The method was successfully applied in pharmacokinetic and stability studies of mitragynine. In the present study, mitragynine was found to be fairly stable during storage and sample preparation. The present study showed for the first time the detailed pharmacokinetic profiles of mitragynine. Following intravenous administration, mitragynine demonstrated a biphasic elimination from plasma. Oral absorption of the drug was slow, prolonged and was incomplete, with a calculated absolute oral bioavailability value of 3.03%. The variations observed in previous pharmacokinetic studies after oral administration of mitragynine could be attributed to its poor bioavailability rather than to the differences in assay method, metabolic saturation or mitragynine dose.
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http://dx.doi.org/10.1007/s00216-010-3707-7DOI Listing
July 2010

Evaluation of the antinociceptive activity and acute oral toxicity of standardized ethanolic extract of the rhizome of Curcuma xanthorrhiza Roxb.

Molecules 2010 Apr 22;15(4):2925-34. Epub 2010 Apr 22.

Centre for Drug Research, Universiti Sains Malaysia, Pulau Pinang, Malaysia.

Ethanolic extract of Curcuma xanthorrhiza was used to evaluate the analgesic and toxicity effects in vivo. The extract was standardized using GC-MS, which showed that 1 mg of Curcuma xanthorrhiza ethanolic extract contains 0.1238 mg of xanthorrhizol. The analgesic activity was studied in rats using three different models, namely the hot plate test, tail flick test and formalin-induced pain test. The acute oral toxicity was examined by the oral administration of standardized Curcuma xanthorrhiza ethanolic extract in mice at doses ranging from 300-5,000 mg/kg and observation for 14 days. Standardized Curcuma xanthorrhiza ethanolic extract did not show significant analgesic effect in the hot plate and tail flick tests. However, in the formalin-induced pain test, Curcuma xanthorrhiza ethanolic extract significantly (P < 0.05) suppressed the paw licking time of rats in both early and late phases at doses 200 and 400 mg/kg of the extract, respectively. In the acute oral toxicity study, Curcuma xanthorrhiza ethanolic extract did not show any toxic effects in mice at 5 g/kg. These experimental results suggest that the standardized Curcuma xanthorrhiza ethanolic extract showed peripheral and central antinociceptive activity associated with neurogenic pain as well as a relative absence of toxic effects which could compromise the medicinal use of this plant in folk medicine.
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http://dx.doi.org/10.3390/molecules15042925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6257229PMC
April 2010

In vitro and in vivo effects of three different Mitragyna speciosa korth leaf extracts on phase II drug metabolizing enzymes--glutathione transferases (GSTs).

Molecules 2010 Jan 20;15(1):432-41. Epub 2010 Jan 20.

Centre for Drug Research, Universiti Sains Malaysia, 11800 USM Penang, Malaysia.

In the present study, we investigate the effects of three different Mitragyna speciosa extracts, namely methanolic, aqueous and total alkaloid extracts, on glutathione transferase-specific activity in male Sprague Dawley rat liver cytosol in vitro and in vivo. In the in vitro study, the effect of Mitragyna speciosa extracts (0.01 to 750 microg/mL) against the specific activity of glutathione transferases was examined in rat liver cytosolic fraction from untreated rats. Our data show concentration dependent inhibition of cytosolic GSTs when Mitragyna speciosa extract was added into the reaction mixture. At the highest concentration used, the methanolic extract showed the highest GSTs specific activity inhibition (61%), followed by aqueous (50%) and total alkaloid extract (43%), respectively. In in vivo study, three different dosages; 50, 100 and 200 mg/kg for methanolic and aqueous extracts and 5, 10 and 20 mg/kg for total alkaloid extract were given orally for 14 days. An increase in GST specific activity was generally observed. However, only Mitragyna speciosa aqueous extract with a dosage of 100 mg/kg showed significant results: 129% compared to control.
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http://dx.doi.org/10.3390/molecules15010432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6256986PMC
January 2010

Activity of Eurycoma longifolia root extract against Plasmodium falciparum in vitro.

Wien Klin Wochenschr 2009 Oct;121 Suppl 3:23-6

Institute of Specific Prophylaxis and Tropical Medicine, Medical University of Vienna, Vienna, Austria.

The habitats of Eurycoma longifolia Jack, a slender tree, are jungles in Malaysia and Indonesia. It belongs to the family Simaroubaceae and is a source of quassinoids with anabolic, antimalarial and cytostatic activity. In this study, conducted during 2008 in Mae Sot, Thailand, a standardized extract of E. longifolia containing three major quassinoids, eurycomanone (1), 13,21-dihydroeurycomanone (2) and 13alpha(21)-epoxyeurycomanone (3) was evaluated for antiplasmodial activity against Plasmodium falciparum and its activity has been compared with that of artemisinin, using 38 fresh parasite isolates and assessment of inhibition of schizont maturation. The IC(50), IC(90) and IC(99) values for artemisinin were 4.30, 45.48 and 310.97 microg/l, and those for the root extract from E. longifolia 14.72, 139.65 and 874.15 microg/l respectively. The GMCOC for artemisinin was 337.81 mug/l, and for the plant extract it was 807.41 microg/l. The log-concentration probit regressions were parallel. The inhibitory activity of the E. longifolia extract was higher than that expected from the three quassinoids isolated from the plant, suggesting synergism between the quassinoids or the presence of other unidentified compounds.
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http://dx.doi.org/10.1007/s00508-009-1230-7DOI Listing
October 2009

In Vitro antioxidant and xanthine oxidase inhibitory activities of methanolic Swietenia mahagoni seed extracts.

Molecules 2009 Nov 6;14(11):4476-85. Epub 2009 Nov 6.

Centre for Drug Research, Universiti Sains Malaysia, 11800 Penang, Malaysia.

This study examines the in vitro antioxidant activities of the methanol extract of Swietenia mahagoni seeds (SMCM seed extract). The extract was screened for possible antioxidant activities by free radical scavenging activity (DPPH), xanthine oxidase inhibition (XOI), hydrogen peroxide scavenging activity (HPSA) and ferric-reducing antioxidant power (FRAP) assays. The total phenolic and flavonoid contents were also determined. The extract exhibits antioxidant activity of 23.29% with an IC(50 )value of 2.3 mg/mL in the DPPH radical scavenging method, 47.2% in the XOI assay, 49.5% by the HPSA method, and 0.728 mmol/Fe(II)g in the FRAP method at the concentration tested. The amount of total phenolics and flavonoid contents was 70.83 mg gallic acid equivalent (GAE) and 2.5 +/- 0.15 mg of catechin equivalent per gram of dry extract, respectively. High Performance Thin Layer Chromatography (HPTLC) screening indicates the presence of phenolic compounds in the SMCM seed extract. The results indicate that the extract has both high free radical scavenging and xanthine oxidase inhibition activity. The antioxidant activity of SMCM seed extract is comparable with that of other Malaysian tropical fruits and herbal plants.
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http://dx.doi.org/10.3390/molecules14114476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6254912PMC
November 2009

Evaluation of antioxidant and antibacterial activities of aqueous, methanolic and alkaloid extracts from Mitragyna speciosa (Rubiaceae family) leaves.

Molecules 2009 Oct 9;14(10):3964-74. Epub 2009 Oct 9.

Centre for Drug Research, Universiti Sains Malaysia, 11800 Minden, Penang, Malaysia.

Studies on the antioxidant and antimicrobial activities of Mitragyna speciosa leaf extracts are lacking. In this study the antioxidant properties of water, methanolic and alkaloid M. speciosa leaf extracts were evaluated using the DPPH (2,2-diphenyl-1- picrylhydrazyl) radical scavenging method. The amount of total phenolics and flavanoid contents were also estimated. The DPPH IC(50) values of the aqueous, alkaloid and methanolic extracts were 213.4, 104.81 and 37.08 microg/mL, respectively. The total phenolic content of the aqueous, alkaloid and methanolic extracts were 66.0 mg, 88.4, 105.6 mg GAE/g, respectively, while the total flavanoid were 28.2, 20.0 and 91.1 mg CAE/g respectively. The antioxidant activities were correlated with the total phenolic content. This result suggests that the relatively high antioxidant activity of the methanolic extract compared to aqueous and alkaloid extract could be possibly be due to its high phenolic content. The aqueous, alkaloid and methanolic extracts were screened for antimicrobial activity. The extracts showed antimicrobial activity against Salmonella typhi and Bacillus subtilis. The minimum inhibitory concentrations (MICs) of extracts determined by the broth dilution method ranged from 3.12 to 6.25 mg/mL. The alkaloid extract was found to be most effective against all of the tested organisms.
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http://dx.doi.org/10.3390/molecules14103964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6255380PMC
October 2009