Plant Foods Hum Nutr (2007) 62:165–175 DOI 10.1007/s11130-007-0058-4 ORIGINAL PAPER Biological Activities of Extracts from Sumac (Rhus spp.): A Review Sierra Rayne & G. Mazza Published online: 2 October 2007 # Springer Science + Business Media, LLC 2007 Abstract Sumac is the common name for a genus (Rhus) that contains over 250 individual species of flowering plants in the family Anacardiaceae. These plants are found in temperate and tropical regions worldwide, often grow in areas of marginal agricultural capacity, and have a long history of use by indigenous people for medicinal and other uses. The research efforts on sumac extracts to date indicate a promising potential for this plant family to provide renewable bioproducts with the following reported desirable bioactivities: antifibrogenic, antifungal, antiinflammatory, antimalarial, antimicrobial, antimutagenic, antioxidant, antithrombin, antitumorigenic, antiviral, cytotoxic, hypoglycaemic, and leukopenic. As well, the bioactive components can be extracted from the plant material using environmentally benign solvents that allow for both food and industrial end-uses. The favorable worldwide distribution of sumac also suggests that desirable bioproducts may be obtained at the source, with minimal transportation requirements from the source through processing to the end consumer. However, previous work has focussed in just a few members of this large plant family. In addition, not all of the species studied to date have been fully characterized for potential bioactive components and bioactivities. Thus, there remains a significant research gap spanning the range from lead chemical discovery through process development and optimization in order to better understand the full potential of the Rhus genus as part of global green technology based on bioproducts and bioprocesses research programs. S. Rayne : G. Mazza (*) Pacific Agri-Food Research Centre, Agriculture and Agri-Food Canada, 4200 Highway 97, Summerland, British Columbia V0H 1Z0, Canada e-mail: MazzaG@agr.gc.ca Keywords Biological activities . Extracts . Rhus spp. . Sumac . Bioproducts . Antiinflammatory . Antioxidant . Antimicrobial . Nutraceuticals Introduction A central tenet of green chemistry is the ability to obtain a commercially viable product with desirable properties from a widely available renewable feedstock using environmentally benign processes [1–3]. In particular, there is significant interest in obtaining extracts with particular biological activities from plants using green technologies [4–7]. However, there is a tension in the use of agriculturally optimum land worldwide for producing biologically sourced industrial- and health-based chemicals, versus the production of food products for human consumption [8, 9]. Thus, efforts are underway to identify and investigate potential industrially valuable crops rich in bioactive components that can grow in marginal lands with little or no fertilizer or irrigation inputs [9, 10]. Sumac is the common name for a genus (Rhus) that contains over 250 individual species of flowering plants in the family Anacardiaceae [11]. This genus is found in temperate and tropical regions worldwide, with representative members by geographic location given in Table 1. In general, sumac can grow in non-agriculturally viable regions, and various species have been used by indigenous cultures for medicinal and other purposes, suggesting potential for commercializing the bioactivity of these plants without competing for food production land uses [12]. For example, R. glabra (smooth sumac) is traditionally used by native peoples of North America in the treatment of bacterial diseases such as syphilis, gonorrhea, dysentery, and gangrene [13]. R. coriaria (tanner’s sumac), which grows wild in the region from the Canary Islands through the Mediterranean region to Iran and Afghanistan, is commonly used as 166 Plant Foods Hum Nutr (2007) 62:165–175 Table 1 Summary of the geographic distribution of representative members of the sumac genus (Rhus spp.) Location Representative members Asia R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. Australia Mediterranean Mexico and Central America Pacific Ocean Africa chinensis (Chinese Sumac) hypoleuca javanica punjabensis (Punjab Sumac) verniciflua taitensis coriaria (Tanner's Sumac) pentaphylla tripartite muelleri (Müller's Sumac) sandwicensis acocksii albomarginata angustifolia batophylla baurii bolusii burchellii carnosula chirindensis ciliate crenata cuneifolia dentate discolor dissecta divaricata dracomontana dregeana dura engleri erosa fastigiata. gerrardii glauca gracillima grandidens gueinzii harveyi horrida incise kirkii keetii krebsiana laevigata lancea leptodictya longispina lucens lucida macowanii magalismontana maricoana marlothii microcarpa Table 1 (continued) Location North America Representative members R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. R. montana natalensis nebulosa pallens pendulina pentheri pondoensis populifolia problematodes pterota pygmaea pyroides quartiniana refracta rehmanniana rigida rimosa rogersii rosmarinifolia rudatisii scytophylla sekhukhuniensis stenophylla tenuinervis tomentosa transvaalensis tridactyla tumulicola undulate volkii wilmsii zeyheri aromatica (Fragrant Sumac) choriophylla (Mearns Sumac) copallina (Winged Sumac) glabra (Smooth Sumac) integrifolia (Lemonade Sumac) lanceolata (Prairie Sumac) laurina (Laurel Sumac) michauxii (Michaux's Sumac) microphylla (Desert Sumac) ovata (Sugar Sumac) trilobata (Skunkbush Sumac) typhina (Staghorn Sumac) toxicodendron vernix virens (Evergreen Sumac) Adapted from ref. [11] a spice by grinding the dried fruits with salt, and is also widely used as a medicinal herb in the Mediterranean and Middle East, particularly for wound healing [14]. Over the past few decades, a number of publications have reported on the biological activities of extracts from sumac. However, no comprehensive review has been Plant Foods Hum Nutr (2007) 62:165–175 performed to summarize the state-of-the-art, especially in light of the recent focus on the use of bioproducts in a sustainable world economy. Thus, in the current work, we critically review the known biological activity of extracts from sumac species, and suggest future research avenues that warrant exploration. In addition, we found that the research to date has focussed on only a few members of this large plant family. Because of this, the review is timely in helping to suggest increasing our breadth of research and development efforts for obtaining bioactive extracts from sumac using green technologies, by building on the promising findings from the selected members of the Rhus genus investigated to date. If there are generalizable bioactive properties within the genus to be discovered, the favorable worldwide distribution of sumac suggests that desirable bioproducts may be obtained at the source, with minimal transportation requirements from the source through processing to the end consumer. This makes sumac an appealing genus on which to possibly focus substantial green chemistry research efforts, as its ability to grow on marginal land, produce potentially useful bioactive products, be and ubiquitous in nature warrant its consideration as a potential signature species for bioproducts and bioprocesses research programs. Bioactivity of Sumac Extracts Sumac extracts have been shown to exhibit a wide range of biological activities, which are summarized in Table 2 and discussed in more detail below. Antimicrobial, Antifungal, and/or Antiviral Activity Sumac extracts are most notable for their antimicrobial activities, although some limited information is available on their antifungal and antiviral activities. As part of a screening of 100 medicinal plants in British Columbia (Canada), crude methanolic extracts of R. glabra branches exhibited both the widest zones of inhibition in a disc assay, and the broadest spectrum of inhibition (active against all of the following species of bacteria tested: Bacillus subtilis, Enterobacter aerogenes, Escherichia coli DC2, Klebsiella pneumoniae, Mycobacter phlei, Pseudomonas aeruginosa H187, Serratia marcescens, Staphylococcus aureus methS, Staphylococcus aureus methR P00017, and Salmonella typhimurium TA98) [15]. To obtain the crude extracts, the plant material was air dried and ground in a Wiley mill with a 2 mm mesh, followed by extraction with methanol and filtration through cheesecloth, cotton wool, and a paper filter. Similarly, in a follow-up study, the same methanolic extracts from R. glabra branches inhibited the following nine fungal strains tested: Aspergillus flavus, A. fumigatus, 167 Candida albicans, Fusarium tricuictum, Microsporum cookerii, M. gypseum, Saccharomyces cerevisiae, Trichoderma viridae, and Trichophyton mentagrophytes [16]. While the R. glabra extract had the strongest antibiotic activity among the 100 plants surveyed, it was only moderately inhibitory of the fungi although it exhibited a broad spectrum of activity. To better understand the compounds likely responsible for the observed antimicrobial activity of R. glabra, ground dried branches were exhaustively extracted with methanol and fractionated with hexane, chloroform, chloroform/ methanol (3:2 v/v) and water [17]. All fractions were tested against Gram positive and Gram negative bacteria, with the most active fraction being chloroform/methanol (3:2 v/v). Subsequent column chromatography allowed the isolation and purification of the following three compounds, which were found to be the only active constituents against the bacteria: methyl gallate (1; minimum inhibitory concentration (MIC) of 13 μg/ml), 4-methoxy-3,5-dihydroxybenzoic acid (2; MIC of 25 μg/ml), and gallic acid (3; MIC of >1,000 μg/ml) (Fig. 1). The majority of the antimicrobial studies on sumac have focussed on R. coriaria, and specifically, on the fruits because of their widespread use in the Mediterranean and Middle East as a dried spice. All of the studies have used either ethanol or water based extracts. Fruits of R. coriaria extracted with 95% (v/v) ethanol exhibited a broad range of antimicrobial activity by inhibiting the growth of all of the following Gram positive and Gram negative species tested: Bacillus cereus, Escherichia coli strains B, 01111, 2759, and 25922, Klebsiella pneumoniae, Proteus vulgaris, Pseudomonas aeruginosa, Shigella dysentariae, Staphylococcus aureus, S. epidermidis, Streptococcus pyogenes, Enterococcus faecalis, and Yersinia enterocolitica [18]. The observed antimicrobial activity was ascribed to the tannins in the ethanolic extracts, with MICs in the range of 10 to 26 mg/ml depending on the bacterial species. Subsequent work also investigated the inhibitory effect of 97% (v/v) ethanol extracts from ripened and unripened R. coriaria fruits against six Gram positive (Bacillus cereus, B. megaterium, B. subtilus, B. thuringiensis, Listeria monocytogenes, and Staphylococcus aureus) and six Gram negative (Citrobacter freundii, Escherichia coli strains Type I and O157:H7, Hafnia alvei, Proteus vulgaris, and Salmonella enteritidis) bacteria [19]. The extract was found to be effective against all tested bacteria, with the Gram positives more sensitive. Bacillus spp. was the most sensitive, with MICs at about 500 μg/ml, followed by S. aureus (1,000 μg/ml), and L. monocytogenes (1,500 μg/ml). Among the Gram negative bacteria, S. enteritidis and E. coli type I were the most resistant (MICs up to 3,000 μg/ml), followed by E. coli O157:H7 (2,500 μg/ml), H. alvei (2,000 μg/mL), P. vulgaris (1,500 μg/ml), and C. freundii (1,000 μg/ml). Ripened fruits 168 Plant Foods Hum Nutr (2007) 62:165–175 Table 2 Summary of reported biological activities of compounds and fractions extracted from sumac Biological activity Species Plant part Antifibrogenic Antifungal Antiinflammatory Antimalarial R. R. R. R. Bark Branches Roots Leaves Antimicrobial R. retinorrhoea R. glabra verniciflua glabra undulate retinorrhoea R. coriaria Antimutagenic R. verniciflua Antioxidant R. verniciflua R. succedanea R. coriaria Antithrombin Antitumorigenic R. hirta R. verniciflua R. verniciflua Antiviral R. succedanea Cytotoxic R. verniciflua Hypoglycaemic Leukopenic R. coriaria R. vernificera Compound(s) and/or extract type Butein Methanol extract Apigenin dimethyl ether 7-O-methylnaringenin, eriodictyol, 7,3’-O-dimethylquercetin, 7-Omethylapigenin, 7-O-methylluteolin, and (2S,2”S)-7,7”-di-O-methyltetrahydroamentoflavone Leaves 7-O-methylnaringenin Branches (a) Methyl gallate, 4-methoxy-3,5-dihydroxybenzoic acid, and gallic acid (b) Methanol extract Seed Ethanol and methanol extracts Fruits (a) Water extract (b) Ethanol/water (19:1 v/v) (c) Hydrodistillation extract (d) Water-soluble fraction of methanol extract partitioned against chloroform (e) Ethanol/water (4:1 v/v) Heartwood Garbanzol, sulfuretin, fisetin, fustin, and mollisacasidin Branches Protocatechuic acid, fustin, fisetin, sulfuretin, and butein Branches (a) Ethanol extract fractionated on Sephadex G-150 (activity ascribed to laccase, benzenediol/oxygen oxidoreductase) (b) Fustin, quercitin, butein, and sulfuretin (c) Crude Ethanol extract further fractionated using prep-LC with acetonitrile/ water gradient Bark Ethanol/water (3:1 v/v) extract Sap 10’(Z),13’(E),15’(E)-heptadecatrienylhydroquinone, 10’(Z),13’(E)heptadecadienylhydroquinone, and 10’(Z)-heptadecenylhydroquinone Fruits (a) Methanol extract (b) Water extract (c) Water-soluble fraction of methanol extract partitioned against chloroform Leaves Methanol extract Whole Ethyl acetate and methanol fractions after initial defatting (petroleum ether), plant extraction with aqueous/methanol (1:4 v/v), and partitioning (n-hexane/ethyl acetate) Fruits Methanol extract Stems 6-Pentadecylsalicylic acid Branches (a) Ethanol extract fractionated on Sephadex G-150 (activity ascribed to laccase, benzenediol/oxygen oxidoreductase) (b) Protocatechuic acid, fustin, fisetin, sulfuretin, and butein Fruits Robustaflavone, amentoflavone, agathisflavone, volkensiflavone, succedaneaflavone, and rhusflavanone Branches Ethanol extract fractionated on Sephadex G-150 (activity ascribed to laccase, benzenediol/oxygen oxidoreductase) Fruits Methanol extract further fractionated with ethyl acetate and hexane Sap Polysaccharide extracts were also found to have a significant higher antimicrobial activity compared to unripened fruits. Most recently, additional work using dried R. coriaria seed, found an antibacterial effect of a combined ethanol/ methanol extract against Pseudomonas aeruginosa [20]. As well, hydroalcoholic extracts of R. coriaria fruits prepared by a cool percolation method using 80% (v/v) ethanol were tested against representative Gram positive and negative Reference(s) [49] [16] [50] [26] [26] (a) [17] (b) [15] [19] (a) [22, 23] (b) [18, 19] (c) [24] (d) [44] (e) [21] [52] [53] (a) [37] (b) [30] (c) [29] [38] [47] (a) [40] (b) [45] (c) [43] [41] [42] [46] [48] (a) [37] (b) [58] [25] [37] [51] [55, 56] bacteria such as Staphylococcus aureus, Bacillus cereus, Escherichia coli, Salmonella typhi, Proteus vulgaris, and Shigella flexneri [21]. The sumac extract exhibited antibacterial activity against all the species tested, with MICs ranging from 0.05 mg/ml (B. cereus) to 0.20 mg/ml (E. coli and S. flexneri) on a weight/volume percentage. Water extracts of R. coriaria fruits, like the ethanolic extracts, also display antimicrobial activity. Water extracts Plant Foods Hum Nutr (2007) 62:165–175 O O OCH3 HO OH HO OH 169 O OH HO OCH3 OH OH Abbas et al. [22] found that water extracts from R. coriaria fruits had the greatest effectiveness against Gram positive bacteria, with Gram negative strains being more resistant, and a four to five log cycle reduction in Bacillus spp. after 1 h exposure to a 1.0% (w/v) sumac extract. Other microbial species tested had a two to three log cycle reduction after the 1 h exposure period. Similarly, Gulmez et al. [23] reported that a water extract (45 °C for 12 h) from R. coriaria fruits exhibited antimicrobial activity at a concentration of 8% (w/v)—particularly towards coliforms (total and fecal)—on poultry meat during storage. In contrast to the conventional alcoholic and aqueous extracts from sumac, which appear to have substantial antimicrobial activity, a hydrodistillation extract of dried R. coriaria fruits was found to be ineffective as an antimicrobial agent [24]. To the best of our knowledge, only one study has examined the broad spectrum antiviral properties of sumac extracts, and the work focussed on biflavonoids isolated from the seed kernels of R. succedanea [25]. Six biflavonoids [robustaflavone (4), amentoflavone (5), agathisflavone (6), volkensiflavone (7), succedaneaflavanone (8), and rhusflavanone (9)] were isolated from R. succedanea seeds and tested for inhibitory activities against a number of viruses including respiratory viruses (influenza A, influenza B, respiratory syncytial, parainfluenza type 3, adenovirus type 5, and measles) and herpes viruses (HSV-1, HSV-2, HCM, and VZV) (Fig. 2). The results indicated that 4 exhibited strong inhibitory effects against influenza A and OH OH 1 2 3 Fig. 1 Compounds exhibiting antimicrobial activity in sumac extracts (1 h at 25 °C following by 2 min of boiling) of dried R. coriaria fruits at 0.1 to 5% (w/v) exhibited antimicrobial activity against the following bacteria: Bacillus cereus, B. megaterium, B. subtilis, B. thuringiensis, Listeria monocytogenes, S. aureus, C. freundii, E. coli (Type I and O157: H7), H. alvei, P. vulgaris, and S. enteritidis [22]. Both ripened and unripened fruits displayed similar antibacterial effectiveness (in contrast to ethanolic extracts obtained by the same research group, where ripened fruits had a significant higher antimicrobial activity compared to unripened fruits [19]), but differences in antimicrobial activity were found between the various bacteria. The Bacillus group was, in general, found to be more sensitive among Gram positive bacteria with B. subtilis being the most sensitive [MICs from 0.25–0.32% (w/v)]. L. monocytogenes was the most resistant among Gram positive strains with a MIC of 0.67% (w/v). P. vulgaris was the most sensitive Gram negative strain [MIC of 0.63% (w/v)], with S. enteritidis and E. coli having the highest resistance. Overall, Nasar- OH OH OH HO HO O OH O O OH HO O HO O HO O OH OH OH O OH OH 5 OH OH O O OH HO OH O O O O OH H HO 6 OH 4 OH O O O HO OH O HO OH O O O HO 7 OH OH 8 O O OH HO O OH OH OH O 9 Fig. 2 Compounds exhibiting antiviral activity in sumac extracts 170 influenza B viruses with EC50 values of 2.0 and 0.1 μg/ml, respectively. 5 and 6 also demonstrated significant activity against influenza A and B viruses. 4 and 5 showed moderate anti-HSV-1 and anti-HSV-2 activities with EC50 values of 18 μg/ml (HSV-1) and 48 μg/ml (HSV-2), and 8.5 μg/ml (HSV-1) and 8.6 μg/ml (HSV-2), respectively. 9 demonstrated inhibitory activities against influenza B, measles, and HSV-2 viruses, while 8 exhibited inhibitory activities against influenza B virus and VZV. It is also of note that 5 has been reported in R. retinorrhoea leaves [26] and 6 in R. semialata leaves [27], suggesting that other Rhus species may contain antiviral constituents. The literature strongly suggests the potential for useful antimicrobial, antifungal, and antiviral agents to be obtained from sumac extracts, but the work to date has been too focussed on one primary species and plant part (fruits of R. coriaria) given its regional use as a spice. This focus is understandable, but (as with the other bioactive properties discussed below) future efforts should survey the worldwide sumac species to determine if these properties are generalizable across the Rhus genus. In addition, since the bioactivities appear to be ascribed to polar compounds extractable with protic solvents, additional studies are required on whether these properties occur in extracts from other plant parts (e.g., stems/branches, roots, and leaves), and that the optimum extraction and storage conditions are to obtain the highest quality yields of desired functionality. The use of other green solvent systems, particularly suband super-critical fluids (e.g., CO2, water), also warrants investigation. Plant Foods Hum Nutr (2007) 62:165–175 cytes. Results from deoxyribose, DNA nicking, and glucose/glucose oxidase enzyme assays indicated that the extract contained a strong scavenging activity of oxygen free radicals, particularly hydroxyl radicals, but also exhibited cytotoxicity at higher concentrations towards the thymocytes. In further studies on the same extract, the crude ethanol extract was separated using column chromatography into three water-eluted fractions and three organic solvent fractions [30% ethanol in water (v/v), absolute ethanol, and 5% acetic acid in water (v/v)] to better understand the source of the observed bioactivity in the R. verniciflua wood [30]. The water eluted fractions were the most protective against reactive oxygen species generated by iron and enzymes. As well, one of the water eluted fractions [shown to contain the flavonoids fustin (10), quercitin (11), butein (12), and sulfuretin (13)] protected against thymocyte apoptosis mediated by hydroxyl radicals, and these compounds were attributed to the antioxidant activity (Fig. 3). 10 and 13 have also been reported in the wood of R. copallina [31], R. glabra [31–33], and R. typhina [31], suggesting that these species may also yield extracts with antioxidant behaviour. 11 has also been found in the leaves of R. coriaria [34] and R. typhina [35, 36]. Kitts and Lim investigated the antioxidant, cytotoxic, and antitumorigenic activities of a fractionated ethanol extract derived from branches of R. verniciflua, and gel electrophoresis results suggested that the active component of a Sephadex G-150 fractionated extract was a copper containing protein, possibly a plant laccase (benzenediol/ oxygen oxidoreductase EC 1.10.3.2) [37]. Antioxidant Antioxidant Activity Developing new, safe, and naturally derived antioxidants for food and health applications is a major goal in sustainable bioproducts. Synthetic antioxidants such as butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) are widely used in spite of concerns regarding their toxicology and a sustainable supply [28]. Most of the research performed on sumac extracts has examined antioxidant activity, and there appears to be potential for commercial development of the products from a number of species. However, as with other areas of bioactivity, the work to date has been focussed on a limited number of species (R. verniciflua and R. succedanea in Asia, R. coriaria in the Mediterranean/Middle East, and R. hirta in northeastern North America). More breadth in worldwide species is required to better understand the potential of sumac as a commercial source of natural antioxidants. Crude ethanol extracts from R. verniciflua wood have exhibited strong antioxidant activity using cultured neuronal cells [29]. The unfractionated ethanol extract showed both antioxidant and cytotoxic effects on mouse thymo- OH OH OH HO O OH HO O OH O 10 HO OH OH OH OH HO OH O 11 HO OH O O O 12 13 OH R R=10'(Z),13'(E),15'(E)-heptadecatrienyl (14) R=10'(Z),13'(E)-heptadecatrienyl (15) R=10'(Z)-heptadecenyl (16) OH Fig. 3 Compounds exhibiting antioxidant activity in sumac extracts Plant Foods Hum Nutr (2007) 62:165–175 activity of the extract was observed in both aqueous and lipid in vitro oxidation reactions using DPPH, Fenton reaction deoxyribose, and lipid emulsion test systems, and cultured mouse brain neurons were protected against glucose oxidase induced hydroxyl radical in the presence of 4.9 μM (58% protection) and 22.7 μM (95% protection) fractionated R. verniciflua extract. In addition, 2.5 μM fractionated extract led to 70% tumor cell death after 24 h incubation in the HeLa and CT-26 cell lines. In terms of direct practical industrial antioxidative application, the only study using R. verniciflua wood involved a 75% ethanol (v/v) extract obtained at 80 °C for 3 h and evaluated in frying oil of Yukwa base (rice snack) [38]. Additions of 400 and 1,000 mg/l of sumac extract to the frying oil indicated a superior antioxidative action compared to BHA and α-tocopherol. Other work at stabilizing food products with sumac extracts includes the use of a methanol extract from R. coriaria fruits tested in sunflower oil stored at 70 °C by measuring peroxide values after regular intervals [39]. Along with rosemary and Turkish sage, sumac extracts were found to be most effective in stabilizing sunflower oil, followed by wild thyme and black thyme. Antioxidant properties for stabilizing peanut oil were also reported on the methanol extracts of R. coriaria fruits and leaves [40, 41]. Fruit extract addition to peanut oil from 1 to 5% (w/v) generally inhibited the formation of hydroperoxide during the initial 7 days after addition [40], but at 28 days of storage, the sumac extract had substantially lower antioxidant potential compared to BHA controls. Similar results were observed with leaf extracts [41], whereby the addition to peanut oil at 4% (w/v) had a limited effect relative to the BHT controls. Other work has examined the antioxidant and free radical scavenging activities of R. coriaria fruit extracts obtained by extraction with 80% methanol (v/v), and further fractionated using n-hexane, ethyl acetate, and water [42]. The ethyl acetate fraction exhibited greater antioxidant activity than the corresponding BHA and BHT controls as measured using the DPPH assay, but tests using the linoleic acid peroxidation assay indicated lower activity than the synthetic controls. Candan’s group has also examined the antioxidative ability of chloroform partitioned methanol extracts from R. coriaria fruits for lipid peroxidation, free radical scavenging, superoxide radical scavenging, and xanthine oxidase activity [43, 44]. The IC50 value for lipid peroxidation was estimated at 1,200 μg/ml in the Fe2-ascorbate system, while those for superoxide scavenging ability in the xanthine–xanthine oxidase method and hydroxyl radical scavenging activity in the deoxyribose decomposition method with 283 and 3,850 μg/ml, respectively [43]. As well, the fractionated extract was an uncompetitive inhibitor of xanthine oxidase and scavenger of superoxide radical in vitro with IC50 values of 173 and 232 μg/ml, respectively [44]. 171 In the only aqueous extraction study regarding the antioxidative behaviour of R. coriaria fruits, a water extract (25 °C for 24 h) was more effective than BHT in preserving sausage, decreasing formation of putrescine, histamine, tyramine, and thiobarbituric acid reactive substances during storage [45]. Other than R. verniciflua and R. coriaria, only two other sumac species (R. hirta and R. succedanea) have been investigated for their extracts’ antioxidant activities. A methanolic extract from the fruits of R. hirta performed similarly to green teas for scavenging superoxides produced by a NBT/xanthine oxidase (XO) assay, and greater than green tea and ascorbic acid for peroxyl radical scavenging using a DCF/AAPH assay [46]. Of the 35 native plant species from the boreal forest region of northeastern North America that were tested based on their historical use by indigenous peoples for treating diabetes and its complications, R. hirta exhibited the lowest IC50 (3.7 μg/ml) in the DPPH assay, and the highest percent inhibition in the NBT/ XO (44.5%) and DCF/AAPH (31.5%) assays. An antioxidant directed HPLC fractionation of the 80% ethanol (v/v) extract from the sap of R. succedanea was used to isolate three heptadecenyl compounds (14, 15, and 16; see Fig. 3 for structures) with antioxidative and cytotoxic activities against five cancer lines [cervix epitheliod carcinoma (HeLa), hepatoma cell line (Huh7), colorectal cancer cell line (HCT116), colon adenocarcinoma (LoVo), and rat C6 glioma cells] with IC50 concentrations ranging from 0.9 to 6.4 μg/ml [47]. With a number of studies indicating that sumac extracts display considerable antioxidant behaviour, and with a few applied examples, we argue that this genus may offer promise for a natural source of commercial antioxidants. However, more species breadth is required in delineating the possible generality of obtaining viable natural antioxidants from sumac, as well as studies that consider the agronomic growth potential, optimized extraction and processing methods, and corresponding economic aspects at the feasibility level. Anticlotting Activity Limited work has been done on the antithrombin activity of sumac extracts, with only a single report of 6pentadecylsalicylic acid (17) being isolated from air-dried stems of R. semialata after methanol extraction and subsequent column chromatographic purification [48]. The compound showed antithrombin activity at 50 μg/ml using the amidolytic method, and prolonged clotting time in a dose-dependent manner in the clotting assay of thrombin– fibrinogen interaction. As with other areas of potentially bioactive agents from sumac, significantly most breadth in research efforts worldwide is required to determine not only the feasibility of obtaining commercially viable products 172 Plant Foods Hum Nutr (2007) 62:165–175 from the plants, but also in whether all members of the genus display similar bioactive possibilities. O OH HO C15H31 17 Antifibrogenic, Antiinflammatory, Hypoglycemic, and/or Leukopenic Activities Antifibrogenic activity of R. verniciflua was assigned to 12 [49], which was isolated from the bark by drying and pulverizing, extracting with hot methanol for 3 hours, subsequently dissolving the methanol extract in water/ methanol (3:2 v/v), and partitioning with n-hexane followed by dichloromethane. The dichloromethane extract was separated by Sephadex LH-20 column chromatography (dichloromethane:methanol, 20:1 v/v) to yield five fractions, the fourth was further chromatographed to give pure 12 in 0.035 w/w% yield. Testing of the isolated 12 on liver fibrosis in rats indicated that the compound had antifibrotic effects, and dose levels of 10 to 25 mg kg−1 day−1 showed a significant reduction of hydroxyproline and malondialdehyde levels in rats. The expression of α1(I)collagen and tissue inhibitor of metalloproteinase-1 (TIMP-1) mRNAs in liver was reduced in a dose-dependent manner in rats given 12 compared with corresponding carbon tetrachloride controls. Thus, 12 appears to act as an antifibrogenic agent by inhibition of collagen accumulation and lipid peroxidation, and by down regulation of the expression of both α1 (I)collagen and TIMP-1 mRNA. From the roots of R. undulata, apigenin dimethyl ether (18) was isolated and found that, at a dose of 75 mg/kg, this compound exhibited 81% inhibition of the phlogistic response (carrageenan induced edema) in a rat [50]. biological activity in the ethyl acetate extract was attributed to the presence of flavonoids as tentatively identified by thin-layer chromatography, while dominantly terpenoids were found in the n-hexane fraction. The exudate that can be obtained from the stem bark of lac tree (R. vernicifera) has been used mainly as a material for traditional paint and lacquer in East Asian countries [52]. The lacquer polysaccharide is an acidic heteropolysaccharide with a 1,3-β-linked D-galactopyranosidic main chain having complex branches with 4-O-methyl-β-glucoronic acid in the terminal [53, 54]. Studies on isolated Chinese laquer polysaccharide from R. vernicifera have found significant bioactivity against leukopenia [55, 56]. In addition to the material properties of this product, further work is required to better understand its range of potential bioactivities. Antimalarial Activity Work with dried and ground leaves of R. retinorrhoea from Saudi Arabia, which were extracted using dichloromethane, suggests that a modest antimalarial activity can be obtained [26]. Partitioning of the dichloromethane extract between hexane and acetonitrile, followed by silica gel column chromatography (benzene/ethyl acetate) yielded the following five flavonoids, 7-O-methylnaringenin (19), eriodictyol (20), 7,3′-O-dimethylquercetin (21), 7-O-methylapigenin (22), 7-O-methylluteolin (23), and the biflavone (2S,2″S)7,7″-di-O-methyltetrahydroamentoflavone (24) (Fig. 4). OH H3CO OH OH O HO OH O O 19 OCH3 OH O OH 20 H3CO O H3CO OCH3 H3CO O OH O OH O OH OH 21 OH O OH 22 OH O H3CO O 18 Methanol extracts of R. coriaria fruits were recently studied for potential hypoglycemic activity [51]. The crude extracts were further fractionated by ethyl acetate and nhexane, and the ethyl acetate extracts exhibited significant hypoglycemic activity through α-amylase inhibition (87% inhibition at 50 μg/ml), with lower activity from the nhexane fraction (77% inhibition at 250 μg/ml). The higher OH OH OH O O 23 H3CO O O H3CO OH OH OH O 24 Fig. 4 Compounds exhibiting antimalarial activity in sumac extracts Plant Foods Hum Nutr (2007) 62:165–175 173 The biflavone 24 exhibited moderate antimalarial activity with an IC50 of 0.98 μg/ml against Plasmodium falciparum (W2 clone) and weak activity against P. falciparum (D6) with an IC50 of 2.8 μg/ml, but was not cytotoxic. 19 showed weak antimicrobial activity against Candida albicans, C. krusei, Staphylococcus aureus, Mycobacterium smegmatis, M. intracellulare, and M. xenopi. Given the global interest in environmentally and economically sustainable antimalarial treatments, further work is needed on ascertaining whether this desirable bioactivity can be obtained from the numerous sumac species indigenous to malarial regions of sub-Saharan Africa (see Table 1). and apoptosis-inducing effects in mouse tumorigenic hepatic cells. Additional work on a chloroform-methanol fraction from a crude acetone extract of R. verniciflua wood suggested that these flavonoids may also be responsible for inhibiting the growth of human lymphoma cells [58]. O OH OH 27 Antimutagenic, Cytotoxic, and/or Antitumorigenic Activities Park et al. examined the heartwood of R. verniciflua, and following an initial methanol extraction, the following four flavonoids were separated by ethyl acetate fractionation and column chromatography: 10, 13, fisetin (25), and garbanzol (26) [52]. The crude methanolic extract was applied to rats, and prevented the activation of hepatic microsomal cytochrome P450 enzymes and inhibition of hepatic glutathione S-transferase, leading to further isolation efforts to identify the specific compounds responsible for the observed bioactivity. When the individual flavonoids were subjected to the Ames test, it was observed that 13 might effectively prevent the metabolic activation, or scavenge the electrophilic intermediates, capable of causing mutation. In contrast, 10 showed a dose-independent antimutagenic activity with mutagenic and antimutagenic behaviour. However, a 1:1 (w/w) mixture of 10 and 13 exhibited dose-dependent antimutagenicity, indicating that 13 inhibited the mutagenicity of 10. OH OH OH HO HO O O OH OH O O 25 26 OH Compounds 10, 13, and 25 have also been reported in the wood of R. copallina [31], R. glabra [31–33], and R. typhina [31], suggesting that these species may also yield extracts with antitumorigenic behaviour. Similarly, Son et al. prepared a flavonoid containing chloroform-methanol fraction from a crude acetone extract of R. verniciflua wood that contained the following compounds: 10, 12, 13, 25, and protocatechuic acid (27) [57]. The fraction exhibited selective growth inhibition Conclusions The research efforts on sumac extracts indicate a promising potential for the plant family to provide renewable bioproducts with the following desirable bioactivities: antifibrogenic, antifungal, antiinflammatory, antimalarial, antimicrobial, antimutagenic, antioxidant, antithrombin, antitumorigenic, antiviral, cytotoxic, hypoglycaemic, and leukopenic. As well, the bioactive components can be extracted from the plant material using environmentally benign solvents (e.g., ethanol, water) that allow for both food and industrial end-uses. Furthermore, a substantial opportunity exists to investigative the use of other green solvents (e.g., sub- and super-critical liquids, ionic liquids) for obtaining bioactive compounds and other phytochemicals from sumac, and in processing the residue for complete biomass conversion. However, as this overview demonstrates, the previous work has focussed on only a few members (eight) of this large plant family (ca. 250 species). In addition, not all of the species studied to date have been fully characterized for potential bioactivities. Thus, there remains a significant research gap spanning the range from chemical discovery through process development and optimization in order to better understand the full bioactive potential of the Rhus genus as part of global green technology based on bioproduct and bioprocess research programs. Acknowledgements We thank the Natural Sciences and Engineering Research Council (NSERC) of Canada for financial support. References 1. 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