Original Papers
459
NAD(P)H : Quinone Oxidoreductase 1 Inducer Activity of Some Saudi Arabian Medicinal Plants
Authors
Abdelaaty A. Shahat 1, 2, Mansour S. Alsaid 1, Muhammad A. Alyahya 1, Maureen Higgins 3, Albena T. Dinkova-Kostova 3, 4
Affiliations
1
3
4
Key words " NQO1 l " traditional healers l " Saudi Arabian medicinal l plants " chemoprotection l
received revised accepted
Dec. 29, 2012 January 31, 2013 February 8, 2013
Bibliography DOI http://dx.doi.org/ 10.1055/s-0032-1328322 Published online March 19, 2013 Planta Med 2013; 79: 459–464 © Georg Thieme Verlag KG Stuttgart · New York · ISSN 0032‑0943 Correspondence Dr. Abdelaaty A. Shahat Medicinal, Aromatic & Poisonous Plants Research Center College of Pharmacy, King Saud University King Khaled street Riyadh 11451 Saudi Arabia Phone: + 96 65 37 50 73 20 Fax: + 96 6 14 67 62 20
[email protected]
Medicinal, Aromatic & Poisonous Plants Research Center, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia Phytochemistry Department, National Research Centre, Dokki, Cairo, Egypt Jacqui Wood Cancer Centre, Division of Cancer Research, Medical Research Institute, University of Dundee, Dundee, Scotland, United Kingdom Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Abstract !
Medicinal plants are a rich source of biologicallyactive phytochemicals and have been used in traditional medicine for centuries. Specific phytochemicals and extracts of their plant sources have the ability to reduce the risk for chronic degenerative diseases by induction of enzymes involved in xenobiotic metabolism, many of which also have antioxidant and anti-inflammatory functions. One such multifunctional cytoprotective enzyme is NAD(P)H : quinone oxidoreductase. In this study, we prepared extracts of 27 Saudi Arabian medicinal plants which belong to 18 different plant families and tested their ability to induce NAD(P)H : quinone oxidoreductase in murine hepatoma cells grown in microtiter plate wells. In addition to the Brassicaceae, a known source of NAD(P)H : quinone oxidoreductase in-
Introduction !
Plants have an enormous potential for the development of new drugs which has not been fully explored yet. There are many approaches to search for biologically active principles in plants [1]. Many medicinal plants have been used as dietary supplements and in the treatment of numerous diseases without proper knowledge of their function. Although phytotherapy continues to be used in several countries, few plants have received scientific or medical scrutiny. Moreover, a large number of medicinal plants possess some degree of toxicity [2]. According to the World Health Organization (WHO), more than 4000 million people in developing countries believe in the efficacy of plant remedies and use them regularly [3]. However, the principal chemical compounds, active ingredients, mode of action and safety of many of these plants have not yet been explored appropriately and require further research. In
ducer activity, we found substantial inducer activity in extracts from the Apiaceae, Apocynaceae, and the Asteraceae families. Five out of a total of eight active extracts are from plants which belong to the Asteraceae family. We further show that artemisinin, an agent which is used clinically for the treatment of malaria, contributes but does not fully account for the inducer activity of the extract of Artemisia monosperma. In contrast to artemisinin, deoxyartemisinin is inactive in this assay, demonstrating the critical role of the endoperoxide moiety of artemisinin for inducer activity. Thus, the NAD(P)H : quinone oxidoreductase inducer activity of extracts of some Saudi Arabian medicinal plants indicates the presence of specific phytochemicals which have the potential to protect against chronic degenerative diseases.
terms of biodiversity, the flora of Saudi Arabia represents one of the richest areas in the Arabian Peninsula and comprises a very important genetic resource of crop and medicinal plants. It is estimated that the flora of Saudi Arabia has a large medicinal species diversity, greater than 1200 (more than 50 %) out of its 2250 species. In addition to its large number of endemic species, components of the flora of Saudi Arabia have elements from Asia, Africa, and the Mediterranean region [4]. NAD(P)H : quinone oxidoreductase (NQO1, EC 1.6.99.2) is an enzyme with multiple cytoprotective functions [5]. It is a widely distributed FADdependent flavoprotein that catalyzes the obligatory two-electron reduction of quinones, quinone imines, nitroaromatics, and azo dyes by using either NADPH or NADH as the hydride donor. This catalytic function of NQO1 plays an important cytoprotective role as it diverts its electrophilic quinone substrates from participating in one-elec-
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tron reductions that can generate semiquinones and various reactive oxygen species as a result of redox cycling, as well as from participating in reactions with nucleophiles that could lead to sulfhydryl depletion. The gene encoding NQO1 is highly inducible [6] through transcription factor nuclear factor-erythroid 2related factor 2 (Nrf2) [7]. Importantly, induction of NQO1 correlates with protection against oxidative stress and against the toxic and neoplastic effects of carcinogens in numerous biological systems [8]. This finding has led to the development of a highly quantitative and robust bioassay to screen pure compounds as well as complex mixtures, such as plant extracts, for their ability to induce NQO1 [9, 10]. Moreover, the NQO1 bioassay has reliably predicted the ability of numerous new agents to not only induce the enzyme in various tissues in vivo but also to protect experimental animals against a range of chronic diseases such as cardiovascular disease, cancer, and neurodegenerative conditions. A prominent example of the utility of the NQO1 bioassay is the isolation of the isothiocyanate sulforaphane from broccoli extracts [11] and the subsequent demonstrations of its chemoprotective activities in animals and in humans [12]. In a continuation of our interest in the complete inventory, chemical and biological evaluation of the medicinal plant resources of Saudi Arabia under the auspices of the Medicinal, Aromatic and Poisonous Plant Research Center (MAPPRC) and the Department of Pharmacognosy, both of the College of Pharmacy, King Saud University, Saudi Arabian plants which belong to 18 different families were tested for their ability to induce NQO1. The 8 plants in which we found inducer activity are currently under phytochemical screening, including quantitative analysis using HPLC and HPTLC, in order to isolate and identify the active principals.
Materials and Methods !
Chemicals and reagents All general chemicals and reagents were of analytical grade and were purchased from Sigma-Aldrich. Sulforaphane (99% pure) was from LKT laboratories, Inc. Artemisinin (98 % pure) was obtained from Sigma. Deoxyartemisinin (99% pure) was purchased from Toronto Research Chemicals.
Plant material All plants were collected from the Tanhat protected area except Cleome ambliocarpa and Artemisia monosperma, which were collected from Um-Rugum and Aldahna, respectively, in April 2012. Ononis serrata and Achillea beibersteni were collected from Kaba and Albaha, Saudi Arabia in March 2010. The plants were identified by the plant taxonomist at the Herbarium Unit. The voucher specimens have been deposited at the Herbarium of the Faculty of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
Sample preparation The plants were collected and dried under shade. The dried samples were powdered and used for solvent extraction. For extract preparation, 100 g of dried sample was extracted twice with 300 mL of 80 % methanol. The extracts were filtered through Whatman No. 1 filter paper and concentrated using a rotary evaporator under reduced pressure at 40 °C. The dry extract obtained with each solvent was weighed. The percentage yield was expressed in terms of air dried weight of plant materials.
Shahat AA et al. NAD(P)H : Quinone Oxidoreductase 1 …
NQO1 assay Murine hepatoma (Hepa1c1c7) cells (ATCC) were maintained in α-MEM supplemented with 10% (v/v) fetal bovine serum that had been heat- and charcoal-inactivated, and grown in a humidified atmosphere at 37 °C, 5% CO2. Dried extracts were redissolved in 50 % CH3OH/H2O (v/v) at a final concentration of 100 mg/mL. Hepa1c1c7 cells (104 per well) were grown in 96-well plates for 24 h and then exposed in 8 replicates to 8 different concentrations of extracts ranging from 0.8 to 100 µg/mL for 48 h. The final concentration of CH3OH in the cell culture medium was maintained at 0.05 % (v/v) in all wells. The specific activity of NQO1 was evaluated in cell lysates using menadione as a substrate [9]. The concentration which doubles the specific activity of NQO1 (CD value) was used to quantify inducer potency. The well-established NQO1 inducer sulforaphane was used as a positive control in each assay at a concentration range from 0.04 to 2.5 µM and consistently found to give a CD value of 0.2 µM.
Results and Discussion !
We prepared methanolic (80%, v/v) extracts of 27 medicinal plants which belong to 18 different families: Apiaceae, Apocynaceae, Asteraceae, Boraginaceae, Brassicaceae, Caealpiniaceae, Cleomaceae, Convolvulaceae, Cucurbitaceae, Fabaceae, Lamiaceae, Neuradaceae, Papilionaceae, Polygonaceae, Resedaceae, " Table 1), and Rhamnaceae, Rutaceae, and Scrophulariaceae (l tested their ability to induce NQO1 using the well-established in" Fig. 1 A). In each assay, ducer sulforaphane as a positive control (l sulforaphane consistently had a CD value of 0.2 µM and a maximal magnitude of induction of 4.7-fold at a concentration of 2.5 µM. Eight plant extracts showed substantial dose-dependent " Table 2 and Fig. 1). In agreement with preinducer activity (l vious studies on extracts and pure compounds isolated from plant species that belong to the Brassicaceae family [10, 13, 14], the extract of Zilla spinosa (SY-187) showed inducer activity, with a CD value of 81 µg/mL and no detectable cytotoxicity " Fig. 1 D). The extract of Ducrosia anethifolia (Apiaceae) (SY(l 182) was more potent, with a CD value of 32 µg/mL and a maxi" Fig. 1 C). Extract SYmal magnitude of induction of 2.5-fold (l 195 (from Rhazya stricta, Apocynaceae) was similar in potency (CD = 40 µg/mL) but higher in magnitude of induction: 3.6-fold " Fig. 1 E). Interestingly, 5 of at a concentration of 100 µg/mL (l the total of 8 active extracts were from plants which belong to the Asteraceae family. The most potent among all of the 27 extracts tested in this study was the extract of Pulicaria crispa (As" Fig. 1 B). teraceae) (SY-179), with a CD value of 3.3 µg/mL (l However the protein concentrations in cell lysates that had been exposed to concentrations of SY-179 greater than 25 µg/mL was dose-dependently lower than in control cells, indicative of cytotoxicity. The least potent was the extract from Achillea biebersteinii (Asteraceae) (SY-200) which only reached a CD value at the " Fig. 1 G). The extract highest concentration tested, 100 µg/mL (l from Anthemis deserti (SY-185, also from the Asteraceae family) showed high potency (CD = 16 µg/mL) and magnitude (4.5-fold) of induction, with no detectable cytotoxicity even at 100 µg/mL, " Fig. 1 D). Similar in potency the highest concentration tested (l (CD = 14 µg/mL) and magnitude of induction (5-fold) was the ex" Fig. 1 E). tract of Achillea fragrantissima (Asteraceae) (SY-191) (l Extract SY-198 (Artemisia monosperma) (Asteraceae) had a CD value of 38 µg/mL and a magnitude of induction of 3.5-fold with
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Table 1 Medicinal plants used in the present study. * 80 % methanol extracts prepared from the aerial parts (leaves and stems) of the plants. Family (Plant species) (Voucher specimen)
Traditional use
Sample used*
Index
Apiaceae (Ducrosia anethifolia) (15937) Apocynaceae (Rhazya stricta) (15957) Asteraceae (Achillea biebersteinii) (15960) Asteraceae (Achillea fragrantissima) (15952) Asteraceae (Anthemis deserti) (15940) Asteraceae (Artemisia monosperma) (15960) Asteraceae (Picriscy anocarpa) (15939) Asteraceae (Pulicaria crispa) (15934) Asteraceae (Rhantarium epapposum) (15935) Boraginaceae (Echium arabicum) (15931) Boraginaceae (Heliotropium ramosissimum) (15938) Brassicaceae (Zilla spinosa) (15946) Caealpiniaceae (Senna italic) (15933) Cleomaceae (Cleome ambliocarpa) (15945) Convolvulaceae (Convolvulus prostates) (15953) Cucurbitaceae (Citrullus colocynthis) (15954) Fabaceae (Ononis serrata) (15925) Lamiaceae (Teucrium oliverianum) (15930) Lamiaceae (Teucrium polium) (15961)
Neuradaceae (Neurada procumbens) (15949) Papilionaceae (Trigonella hamosa) (15951) Polygonaceae (Emex spinosa) (15955) Polygonaceae (Rumex vasicanus) (15936) Resedaceae (Caylus eahexagyna) (15959) Rhamnaceae (Ziziphus nummularia) (15947) Rutaceae (Haplophyllum tuberculatum) (15932)
Scrophulariaceae (Scrophularia hypericifolia) (15958)
Analgesic and pain reliever for headache, backache, colic, and colds [20]. Diabetes mellitus, fever, sore throat, inflammatory conditions and helminthiasis [21]. Spasmolyse, cholerese, treatment of wounds and anti-inflammatory activities make it an important medicinal plant [22]. Respiratory diseases and gastrointestinal disturbances [23]. Herbal medicines, insecticides, and dyes, food additives, as well as an important source in aromatic and cosmetic industries [24]. Antispasmodic, anthelmintic, and antihypertensive [25]. Treatment of indigestion, against intestinal nematodes and other parasites [26]. Treatment of inflammation and as an insect repellent and is also used as an herbal tea [27]. Skin infections and gastrointestinal disturbances and as an insecticide [28]. Antiplasmodial and antitrypanosomal activity [29]. Treatment of gout, rheumatism, and as an anti-inflammatory and healing agent [30]. Antioxidant, antifungal, hepatoprotective, and antiviral activities [31]. Diarrhea, stomach ache, female infertility, tuberculosis, asthma [32]. Stomachics, rubefacients, in the treatment of scabies, rheumatic, fever, inflammation, and as a hypoglycemic agent [33]. Brain related disease; improve memory, skin disease [34]. Treatment of constipation, diabetes, edema, fever, jaundice, bacterial infections as well as cancer [35]. Antibiotic, antipyretic, anti-inflammatory, antifungal, and antiseptic activities, treatment of skin and rheumatic diseases as well as gout [36]. Antinociceptive effect, antioxidant and antimicrobial activities [37]. Gastrointestinal disorders, inflammations, diabetes and rheumatism, antibacterial, antiulcer, hypotensive, antispasmodic, anorexic, and antipyretic agent. The plant possesses hypoglycemic and insulinotropic activities, reduces body weight, lowers high blood pressure and has hypolipidemic, antinociceptive, and antioxidant properties [38]. Diarrhea and dysentery; as well, it has been used as a tonic to increase heart and respiration functions [39]. A condiment and seasoning in food preparations and hypoglycemic [40]. Purgative, diuretic, a remedy for stomach disorders, dyspepsia, and colic [41]. Treatment of pain, inflammation, bleeding, tinea, tumor, and constipation cough, headache, and fever [42]. Anticancer (melanoma cell lines) [43]. Antibacterial, analgesic activities and as an anthelmintic [44]. Headaches and arthritis, to remove warts and freckles from the skin and also to treat skin discoloration, infections, and parasitic diseases [45]; it is used to treat malaria, rheumatoid arthritis, and gynecological disorders [46]. Antipyretic, febrifuge, and antibacterial, as a remedy for evening fever, mouth dryness, constipation, prurigo, furunculosis, sore throat, ulcerous stomatitis, tonsillitis, and in the treatment of cancer [47].
no detectable cytotoxicity at any of the concentrations tested " Fig. 1 F). (l Artemisia monosperma is a source of the antimalarial agent arte" Fig. 2 A). The presence of artemisinin has been demisinin (l tected in both Artemisia herba-alba (4.9 % of dry weight) and Artemisia monosperma (3.6 % of dry weight) [15]. Artemisininbased combination therapies are now widely used in malaria treatment worldwide [16]. Artemisinin contains an unusual intramolecular peroxide bond. Peroxides are known inducers of NQO1 [17]. We therefore considered that the inducer activity of " Fig. 1 F) could be, the Artemisia monosperma (SY-198) extract (l at least in part, due to the presence of artemisinin. To examine this possibility, we tested the inducer activity of pure artemisinin
(26%) (22%)
SY-182 SY-195
(10.4 %)
SY-200
(6.2 %) (10.8 %)
SY-191 SY-185
(16.4 %) (19.5 %)
SY-198 SY-184
(6.7 %)
SY-179
(3.1 %) (14.5 %) (2.58 %)
SY-180 SY-176 SY-183
(13.5 %) (14.9 %) (14.9 %)
SY-187 SY-178 SY-186
(15.3 %) (14.2 %)
SY-192 SY-193
(5.5 %)
SY-199
(20%) (11.5 %)
SY-175 SY-201
(8.6 %)
SY-189
(22%) (16.8 %)
SY-190 SY-194
(13%)
SY-181
(13.04 %) (11.6 %) (19.6 %)
SY-197 SY-188 SY-177
(12.12 %)
SY-196
and found a modest dose-dependent increase of the specific activity of NQO1, with a maximal magnitude of induction of 1.5" Fig. 3). To establish the imporfold at a concentration of 25 µM (l tance of the endoperoxide moiety for the inducer activity of artemisinin, we tested the ability of deoxyartemisinin, a metabolite of artemisinin which only differs from the parent compound by the " Fig. 2 B), to induce NQO1 and found lack of the peroxide bond (l " Fig. 3). that it is inactive in this assay (l Notably, deoxyartemisinin is also inactive as an antiparasitic agent, highlighting the endoperoxide-dependent mode of action of artemisinin [18]. As NQO1 is a marker enzyme for a large network of cytoprotective proteins, its induction by artemisinin suggests that, in addition to being toxic to the parasite, artemisinin
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(yield in %)
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Fig. 1 NQO1 inducer activity of sulforaphane (A) and extracts of medicinal plants (B–G) used in this study. Hepa1c1c7 cells (104 per well) were grown in 96-well plates for 24 h. The medium was removed and replaced with fresh medium containing sulforaphane at concentrations ranging from 0.04 to 2.5 µM or extracts at concentrations ranging from 0.8 to100 µg/mL, and the cells were grown for a further 48 h. Cells were then lysed with digitonin, and
Index 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
SY-182 SY-195 SY-200 SY-191 SY-185 SY-198 SY-184 SY-179 SY-180 SY-176 SY-183 SY-187 SY-178 SY-186 SY-192 SY-193 SY-199 SY-175 SY-201 SY-189 SY-190 SY-194 SY-181 SY-197 SY-188 SY-177 SY-196
Plant species Ducrosia anethifolia Rhazya stricta Achillea biebersteinii Achillea fragrantissima Anthemis deserti Artemisia monosperma Picriscy anocarpa Pulicaria crispa Rhantarium epapposum Echium arabicum Heliotropium ramosissimum Zilla spinosa Senna italic Cleome ambliocarpa Convolvulus prostates Citrullus colocynthis Ononis serrata Teucrium oliverianum Teucrium polium Neurada procumbens Trigonella hamosa Emex spinosa Rumex vasicanus Caylus eahexagyna Ziziphus nummularia Haplophyllum tuberculatum Scrophularia hypericifolia Sulforaphane
CD value
Maximal magnitude of
(µg/mL)
induction (fold)
32 40 100 14 16 38
2.5 3.6 2.0 5.1 4.5 3.5 1.6 3.8 1.5 1.2 1.2 2.2 1.4 1.4 1.4 1.7 1.7 1.8 1.6 1.3 1.3 1.3 1.3 1.3 1.4 1.3 1.3 4.7
3.3
81
0.2 µM
may provide a further benefit by increasing the host cytoprotective responses. The importance of this finding is supported by the fact that artemisinin-related compounds have been shown to have anti-inflammatory, growth inhibitory, anti-angiogenic, and
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the specific activity of NQO1 was determined in the lysates using menadione as a substrate. The concentration which doubles the specific activity of NQO1 (CD value) was used to quantify inducer potency. Mean values for 8 replicate wells are shown for each data point. The standard deviation for each data point was < 5% of the value.
Table 2 NQO1 inducer potencies of plant extracts.
anti-metastatic effects, and various analogues of artemisinin are being developed as anticancer agents [19]. Moreover, both the potency and the magnitude of induction of the extract of Artemisia monosperma are greater than that of pure artemisinin. In ad-
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Chemical structures of artemisinin (A) and deoxyartemisinin (B).
dition, the extract did not show any cytotoxicity at any of the concentrations tested, whereas pure artemisinin was toxic at concentrations greater than 25 µM. We therefore conclude that induction of NQO1 by the extract of Artemisia monosperma is only partially due to the presence of artemisinin, and other, perhaps more potent constituents contribute to the overall inducer activity. In summary, 8 out of 27 extracts of selected Saudi Arabian medicinal plants, 5 of which belong to the Asteraceae family, have the ability to induce the cytoprotective marker enzyme NQO1. Although the specific indications for use of these plants in traditional medicine are somewhat different, they all have two common components in the disease pathogenesis: oxidative stress and inflammation. Therefore next, it will be important to identify the active components of these extracts and test their ability to protect against chronic degenerative diseases using models of the most common human chronic diseases such as cardiovascular disease, neurodegenerative conditions, and cancer.
Acknowledgements !
The authors are grateful for the Sponsorship of the Research Centre, College of Pharmacy, the Deanship of the Scientific Research, King Saud University, Riyadh, Saudi Arabia. We also thank Research Councils UK and Cancer Research UK (C20953/A10270) for financial support.
Conflict of Interest !
The authors declare that they have no competing interests.
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Fig. 3 NQO1 inducer activity of artemisinin and deoxyartemisinin. Hepa1c1c7 cells (104 per well) were grown in 96-well plates for 24 h. The medium was then removed and replaced with fresh medium containing serial dilutions of artemisinin or deoxyartemisinin that were prepared from stock solutions in DMSO. The final concentration of DMSO in the cell culture medium was 0.1 % (v/v). Cells were grown in the presence of the compounds for a further 48 h and then lysed with digitonin. The specific activity of NQO1 was determined in the cell lysates using menadione as a substrate. Mean values for 8 replicate wells are shown for each data point. The standard deviation for each data point was < 5% of the value.
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