This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.The development of strategies to reduce the risk of cancer by administration of dietary phytochemicals that elevate the activities of Phase 2 detoxication enzymes and the tissue levels of glutathione has been a long-standing goal of this laboratory (1). We have designated this strategy as 'chemoprotection.' A large body of evidence demonstrates that the susceptibility of animals and their cells to the toxic and neoplastic effects of electrophilic carcinogens and reactive oxygen intermediates can be substantially reduced by raising cellular glutathione (GSH) levels and the activities of Phase 2 enzymes (e.g., glutathione transferases, glucuronosyltransferases, and quinone reductase) (2). Our laboratory has shown that a variety of chemical agents induce Phase 2 enzymes and raise GSH levels without significantly influencing the activities of Phase 1 cytochromes P450 (3). A substantial number of these inducers are present in edible plants, especially in cruciferous vegetables (e.g., broccoli, cabbage, Brussels sprouts, kale) and their widely distributed, close botanical relatives (e.g. Moringa sp.) (4-6). There is mounting evidence that the capacity of these phytochemicals to raise Phase 2 enzymes may be in part responsible for the well-recognized protection against cancer afforded by consumption of large quantities of vegetables (7). As described in RPN # 03-05-28-03, broccoli contains an isothiocyanate, known as sulforaphane, which is one of the most potent naturally occurring Phase 2 inducers (8) and it inhibits chemically induced tumor formation in response to several carcinogens (9-12). More recently, we discovered that Moringa sp. contain an isothiocyanate, 4-(rhamnopyranosyloxybenzyl) isothiocyanate [4RBITC], which is at least as potent an inducer of Phase 2 enzymes as sulforaphane in multiple animal cell lines (13). We have developed analytical and preparative methods for producing this isothiocyanate and its cognate glucosinolate (14) and we have shown that it is taken up by cultured animal cells with similar uptake kinetics to those of sulforaphane (J.W. Fahey, unpublished observation). Moreover, and in contrast to broccoli, topical application of Moringa sp. preparations (e.g. root exudates, seed oil, bark, and leaf homogenates and extracts) have been utilized for medicinal purposes for centuries (15-19). We now wish to apply extracts of leaves of the Moringa tree to the skin of normal volunteers to establish whether Phase 2 enzymes are induced and glutathione levels are elevated in biopsies of the skin. Ethnobotany, Pharmacology, and Nutritional Value. The most common species is Moringa oleifera. All parts of the Moringa tree are edible and have long been consumed by humans, this tree has recently been advocated as an outstanding indigenous source of highly digestible protein, Ca, Fe, Vitamin C, and carotenoids in many undernourished 'developing' regions of the world (17). Moringa trees also have a long history of traditional medicinal use in these areas of the tropics (17,18). We propose to develop the chemoprotective potential of [1] and closely related glucosinolates from Moringa species. Since familiarity with Moringa is quite limited among scientists, we summarize the present state of knowledge below.Moringa oleifera, the most widely cultivated species, is a member of a monogeneric family, the Moringaceae, that is native to the sub-Himalayan tracts of India, Pakistan, Bangladesh and Afghanistan. This rapidly-growing tree (also known as the horseradish, drumstick, or Ben oil tree), was cultivated and utilized by the ancient Romans, Greeks and Egyptians; it is now widely cultivated and has become naturalized in many locations in the tropics. It is a perennial softwood tree with timber of low quality, but which for centuries has been advocated for traditional medicinal and industrial uses. It is already an important crop in India, Ethiopia, the Philippines and the Sudan, and is being grown in West, East and South Africa, tropical Asia, Latin America, the Caribbean, Florida and the Pacific islands. Moringa trees have been used to combat malnutrition, especially among infants and nursing mothers. Non-governmental organizations such as Church World Service (CWS) and Educational Concerns for Hunger Organization (ECHO) have advocated Moringa as 'natural nutrition for the tropics.' Leaves can be eaten fresh, cooked, or stored as dried powder for many months without refrigeration, and apparently without loss in nutritional value. Moringa is especially promising as a food source in the tropics because the tree is in full leaf at the end of the dry season when other foods are typically scarce. Moringa seed oil (yield 30-40%, by weight), also known as Ben oil, is a sweet non-sticking, non-drying oil, that resists rancidity, and has been used in salads, for fine machine lubrication, and in the manufacture of perfume and hair care products (20). Powdered seeds are used to flocculate contaminants and purify drinking water (21-23). Seeds are also eaten green, roasted, powdered and steeped for tea or used in curries, and used by Europeans to treat fever (21). Widespread claims for the medicinal effectiveness of various Moringa tree preparations support our desire to concentrate on the potential cancer preventive activity of this family and its glucosinolates. A plethora of traditional medicine references attest to its curative power, and scientific validation of these popular uses is developing to support at least some of the claims. Moringa preparations have been cited in the scientific literature as having antibiotic (24-28), antitrypanosomal (29), hypotensive (30-32), antispasmodic (33), antiulcer (34), anti-inflammatory (33,35), hypocholesterolemic (36), and hypoglycemic (37) activities as well as having considerable efficacy in water purification by flocculation, sedimentation, antibiosis and even reduction of schistosome cercariae titer (21,23,26). Specific components of these Moringa preparations that were active as hypotensives include 4-[(4'-O-acetyl-?-L-rhamnopyranosyloxy)benzyl] isothiocyanate [2] (30). Moringa species have long been recognized by folk medicinepractitioners as a tumor therapeutic (26,35). Recently, 4-(?-L-rhamnopyranosyloxy)-benzyl isothiocyanate, [3] 4-[(4'-O-acetyl-?-L-rhamnopyranosyloxy)benzyl] isothiocyanate and the related 4-(?-L-rhamnopyranosyloxy)benzyl compound, niazimicin, were shown to be potent inhibitors of phorbol ester (TPA)-induced Epstein-Barr virus-early antigen activation in lymphoblastoid (Burkitt's lymphoma) cells (38,39). In one of these studies, niazimicin also inhibited tumor promotion in the mouse two-stage DMBA-TPA model but the cognate isothiocyanate was not tested (38). We have previously conducted a pharmacokinetic study at Johns Hopkins on healthy volunteers to obtain pilot data on the effects of dietary isothiocyanates on Phase 2 enzymes and on indicators of oxidative damage (oxidized DNA bases and Comet assays of DNA) in lymphocytes (RPN 98-12-03-01). We have also obtained data on oral tolerance of repetitive doses of isothiocyanates on healthy human volunteers (40,41). The findings are summarized under 'Risks' and give no cause for concern about tolerance. We have however been concerned that isothiocyanates may not reach the target tissues. These compounds may be metabolized by the gut and liver before they reach the compartments we are sampling (plasma, lymphocytes, urine) (42,43). Thus, plant preparations rich in isothiocyanates (e.g. Moringa leaf or seed extracts) may enhance detoxication capacity in organs of first defense (gut, liver), but their effects may not be apparent in peripheral sites. We have therefore searched for more direct methods for assessing effects on Phase 2 activities. We have shown that primary human skin culture cells (obtained commercially) as well as cultured rodent and human keratinocytes are induced by low levels of an isothiocyanate with respect to quinone reductase activity and glutathione levels (unpublished observations). These are parameters that are easily measurable on a few milligrams of tissue. These findings encourage us to examine the feasibility of measuring these indices of Phase 2 activity as well as enzymes concerned with glutathione metabolism (glutathione reductase and glutathione transferases) in human skin biopsies, following topical application of Moringa leaf or seed extracts containing 4RBITC.
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