Whole cloves are prepared from the dried, unopened flower buds of the tropical evergreen tree Eugenia caryophyllata L. Merr and Perry (Myrtaceae), also known as Syzygium aromaticum and Eugenia aromatica. Clove trees are indigenous to the Maluku Islands of Indonesia, although now are cultivated in such diverse areas as Madagascar, Tanzania, the West Indies, China, and Malaysia. The name for this hard, brown nail-shaped spice derives from the Latin clavus, meaning “nail.” In traditional Chinese medicine, clove is known as ding xiang or “nail spice” and was used to treat among other things indigestion, nausea, vomiting, and infections.1 Even today clove purportedly can be a remedy for such diverse problems as coughs and colds, diarrhea, digestive disorders, diabetes, toothaches, memory loss, erectile dysfunction, and arthritis.2,3 Culinary uses for clove include as a flavoring addition to meats, especially ham, stewed fruits, pickles, curries, pies, salads, and spiced alcoholic beverages.1 Clove is known to mask spoiled food smells by interfering with odor maps in the olfactory bulb of the forebrain.4 It also finds application in perfumes, oral products, and soaps and detergents. In Indonesia, cloves are added to tobacco in kreteks, aromatic high-tar cigarettes.
Cloves owe their value to the aromatic essential oil, obtained from the steam distillation of powdered clove buds or leaves. A predominant constituent of it is the allyl chain-substituted guaiacol compound eugenol [2-methoxy-4-(2-propenyl)phenol] (Figure). Other active components include β-caryophyllene (Figure), α-humulene, isoeugenol, eugenyl acetate, flavonoids, and cinnamic acids.5–7 The identities of the active compounds in clove have not been fully characterized, but eugenol is believed to be a main contributor to its biological actions. In fact, E caryophyllata is considered the main natural source of eugenol, although this compound has been identified in other spices such as nutmeg, cinnamon, and basil. The bioavailability and tissue distribution of eugenol and other clove components have been studied in animals, humans, and other organisms.6–14 In healthy male and female human volunteers, acute oral administration of eugenol is followed by rapid absorption in the digestive tract, evidence of a first-pass effect, and almost complete excretion in the urine within 24 hours.9,10 Following an acute oral dose of 150 mg eugenol, amounts in the range of 0.02 to 100 µg/mL were detected in serum, urine, and bile. A serum concentration of 7 µg/mL (42.6 nM) was specifically reported.9 Eugenol levels in the blood of rats peak rapidly after repeated oral administration and exhibit a mean half-life in blood of 14.0 hours.6 It should be noted that eugenol and clove oil have been reported to improve the oral and percutaneous absorption and bioavailability of a variety of drugs.15,16
This discussion of the potential health benefits of clove is intended to be a general overview of the scientific literature associated with the biological actions of clove potentially impacting human health. Information is presented to introduce the reader to the variety of topics on clove and health, to highlight some topics where there is a better understanding of clove’s possible benefits, and to assess the relevance of culinary use of this spice to any benefits.
The PubMed literature database was consulted for this overview. Search terms included S aromaticum, flos caryophyllata, E caryophyllata, clove, clove oil, eugenol, and β-caryophyllene. Full reports and English abstracts of foreign-language articles from peer-reviewed journals were primary sources of information. The quality of some studies’ methodologies varied, particularly in regard to adequately describing the composition of test samples. Nonetheless, these were included in this discussion so that the variety of information can be evaluated and important issues for future research can be identified. Commercial and governmental reports also were supplementary sources.
Numerous research studies have attempted to characterize the potential health benefits attributed to clove and its constituents, particularly eugenol. These include antioxidant, anti-inflammatory, antimicrobial, cardiovascular, and neurological benefits. Table 1 provides an overview of select, potential health benefits of clove. Table 2 lists the potential mechanisms of action for those topics presented in Table 1. The author’s points of view for rating of evidence in each category are based on consideration of cell culture and animal studies and on human data published primarily from the peer-reviewed scientific literature. A rating of preliminary indicates that the collective evidence for a specific health benefit is not conclusive in light of the limited and sometimes inconsistent data from animal studies and well-controlled human trials. A rating of emerging indicates that data were suggestive of health benefits based on preclinical investigations and some clinical studies. The strength of a potential relationship between clove and improved health would be improved by additional and consistent reports from larger, well-controlled human studies. A rating of strong is for data that are consistent among preclinical experiments and at least 2 well-conducted human trials. In addition, evidence for a plausible biological mechanism is available.
It should be noted that the referenced studies evaluate effects of diverse clove samples, including its essential oil, as well as water and alcoholic and hexane extracts. Often the composition of the sample is not reported or not quantitatively analyzed. However, general qualitative information can be used to discern major differences in composition among the samples. For example, clove oil is reported to contain 75% to 90% eugenol, followed by β-caryophyllene and lesser amounts of α-humulene and eugenyl acetate.5–7 Ethanolic extracts contain eugenol, β-caryophyllene, and eugenol acetate as major components and possibly some flavonoids, tannins, and alkaloids.17,18 Hexane extracts have been reported to contain eugenol, eugenol acetate, and β-caryophyllene, as well as flavonoids, phenols, saponins, alkaloids, and tannins.19,20 Water extracts can contain eugenol, trans-caryophyllene, anthraquinones, saponins, flavonoids, tannins, and eugenol derivatives.21 Eugenol, β-caryophyllene, and eugenol acetate are likely present in all types of samples, although the relative composition of components within an extract will vary considerably, depending on specific isolation protocols used by each investigator.
There are a variety of purported actions of clove supported mainly by preliminary evidence. For example, there are numerous reports identifying extracts of clove, clove essential oil, and eugenol with antioxidant activity in vitro173–185 using a variety of assays. Considered collectively, these extracts and clove oil were effective in demonstrating antioxidant efficacy against such end points as inhibiting lipid peroxidation and malonaldehyde formation and in scavenging superoxide anions. The method of clove extraction varied considerably and included such diverse procedures as hot water extraction, extraction with 80% ethanol, and steam distillation with dichloromethane extraction. Thus, the chemical composition of extracts likely varied widely in content of flavonoids, phenolics, and hydrolyzable tannins. Often, the composition of the extracts was not well documented.
In vivo support for the antioxidant action of clove and eugenol are limited. For example, in vivo treatment of rats with clove oil (5 mg/kg body weight per day for 30 days) reduced free-radical damage associated with aflatoxin toxicity.186 Oral eugenol dosing (0.2–25 mg/kg body weight) inhibited lipid peroxidation–mediated liver necrosis following CCl4 administration to rats, in part due to its apparent ability to intercept secondary radicals from endoplasmic reticulum–derived lipids.187 In another study, when mice were treated with eugenol (75–300 mg/kg, intragastric) prior to exposure to γ-irradiation, oxidation-induced genetic damage in bone marrow was significantly reduced.188 Oral dosing of rats with eugenol (1000 mg/kg) for 15 and 90 days led to increased intestinal activity of glutathione-S-transferase, an enzyme that plays an important role in controlling oxidative stress in cells.189
Despite these studies, there is limited in vivo evidence that dietary clove can suppress established oxidative stress biomarkers associated with human chronic conditions.
There are several potential mechanisms by which clove might counteract cardiovascular disease processes. For example, clove oil, eugenol, acetyl eugenol, and clove polysaccharides were effective as in vitro inhibitors of platelet aggregation. In 2 of these reports, eugenol exhibited potency similar to aspirin.190–195 The clove constituents eugenol and β-caryophyllene oxide were reported, mostly in in vitro or ex vivo studies, to cause vasodilation of blood vessels and relaxation of vascular smooth muscle cells, an effect that could not be completely explained by calcium-channel blockade activity. Eugenol also showed vasodilator activity by inhibiting [K+]o-induced aorta contractions.195–205 In 1 dog and 1 rodent experiment, intravenous administration of eugenol (1–10 mg/kg) was observed to elicit hypotensive effects in part by causing a transient reduction in blood pressure and myocardial contractile force without changing the heart rate.206,207 Inhibiting the oxidation of low-density lipoproteins (LDLs) also may elicit antiatherosclerotic consequences. Eugenol inhibited oxidation of LDL in plasma samples208–210 and changed the affinity of LDL particles for the LDL receptor in vitro.211 In plasma samples isolated from non–insulin-dependent diabetic patients, eugenol suppressed oxidation of LDL and very-low-density lipoprotein in a manner similar to the synthetic antioxidant butylated hydroxytoluene.212 Eugenol also protected against oxidized LDL-induced dysfunction in endothelial cell cultures,213 and humulene and caryophyllene were able to attenuate endothelial cell damage associated with bacterial infections.214 In the hypercholesterolemic zebrafish model, in vivo administration of an aqueous extract of clove substantially decreased serum cholesterol and triglyceride levels, apparently due to suppression of oxidative stress, prevention of LDL phagocytosis, and inhibition of cholesteryl ester transfer protein function.12 Determination of clove’s in vivo actions toward cardiovascular end points is clearly needed.
Clove and its constituents exhibit multiple actions in modulating inflammation and immune responses in vitro. Clove and eugenol were reported to inhibit cyclooxygenase 2 and nitric oxide synthase in a variety of cell lines, in part by modulating signaling pathways and by inhibiting oxygen radical generation and the production of proinflammatory mediators.215–227 Eugenol and, to a lesser extent, β-caryophyllene and isoeugenol demonstrated anti-inflammatory potency in several animal models of animal inflammation.228–235 Clove oil and eugenol have been shown to produce diverse immunomodulatory activities including anaphylaxis suppression, improved humoral- and cell-mediated immunity, and inhibition of immediate hypersensitivity.236–244 It should be kept in mind, however, that clove oil and its constituents may have complex effects on immune-responsive cells. Depending on the dose, target tissue, and method of administration, clove and its constituents may act as contact sensitizers or have anti-inflammatory actions, as well as elicit apparently opposing effects on intracellular signaling pathways and immune system behavior. It is interesting that eugenol is being developed as part of a prodrug to treat inflammation. When combined with aspirin into an aspirin-eugenol-ester compound, adverse effects of each individual compound were reduced, and agent stabilization and overall therapeutic efficacy were enhanced.245
HUMAN CONSUMPTION OF CLOVE
In 1 report, human consumption of clove in India was estimated to be 0.43 mg/kg per day and that of clove oil to be 0.045 mg/kg per day.112 When used as intended as a food additive, clove is considered GRAS (generally recognized as safe) by the US Food and Drug Administration. The US Food and Drug Administration has approved clove oil for use as an analgesic in dentistry, for use as a flavoring additive in foods, and as a fragrance component in personal care and aromatherapy products. Risk of food allergy from clove oil appears to be small.246 Although clove oil is considered safe for use as a food additive in small quantities (<1500 ppm), when taken acutely at high levels, far greater than amounts occurring in foods, it can cause systemic poisoning and severe complications including respiratory distress, rapid heartbeat, liver failure, and nervous system depression and seizures.247–251
Human per-capita consumption of eugenol is estimated to be 0.6 mg/d.3 The World Health Organization has established an Acceptable Daily Intake level for eugenol of 2.5 mg/kg per day based on a NOAEL (no observed adverse effect level) of 250 mg/kg per day in rats.3,251–254 The European Food Safety Authority has concluded that eugenol is “unlikely to be genotoxic at exposures that do not result in cytotoxicity and saturation of conjugation pathways.” The European Food Safety Authority also concluded that based on available data eugenol is not carcinogenic and did not exhibit teratogenic or neurotoxic effects.255,256 Following short-term (7 days) dietary administration of eugenol (150 mg/d) to humans, no biochemical or cytogenetic evidence of toxicity was observed.257
There are substantial health hazards associated with inhaling clove cigarette smoke, including severe lung injury to individuals with prodromal respiratory infections and aspiration pneumonitis in some individuals with normal respiratory tracts.3,258–260 Clove cigarettes or kreteks are more potent than regular cigarettes in delivering carbon monoxide, tar, and nicotine.
The scientific literature provides some support mostly from preclinical studies that clove or individual constituents can have health benefits toward suppression of microbial growth, improvement of diabetes symptoms, and improvement of neurological problems. Beyond this, there is preliminary evidence that clove and its constituents can contribute to inhibiting oxidative stress, counteracting inflammation, and opposing processes associated with cardiovascular disease. Besides eugenol, other constituents of clove are likely making important contributions to these actions
A number of general research issues need to be addressed in appropriate animal models and eventually in human studies as to whether clove can have any impact on health when used as a spice in food. A considerable limitation of the evidence base is the lack of information on the chemical composition of clove samples used for both in vitro and in vivo investigations. In addition, in vivo benefits of clove, clove oil, extracts of clove, and individual constituents toward established biomarkers of chronic disease need to be conducted using culinary-relevant doses. Estimates of individual human consumption of clove and clove oil are available112 that can be used to design studies with greater nutritional relevance. These studies also can provide useful information about bioavailability of constituents and possible mechanisms of action when this spice is used as a dietary ingredient.
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