Chile peppers are valued worldwide for their distinct capsaicinoid compounds that have been used traditionally in medicine and culinary practices. With 32 known species, five of them domesticated, they provide unique chemical profiles, when consumed by humans. Capsaicinoids, the spicy compounds, are alkaloids used to deter herbivory in the wild, offering protection to the chile pepper fruit seeds. Among the 22 known capsaicinoid structures, capsaicin and dihydrocapsaicin are normally the most abundant. In humans, capsaicin binds to nociceptor TRPV1 that generates a heat sensation. Capsaicin also mitigates inflammation responses in the digestive tract and has the potential to aid in nutrient absorption. Distinct heat profiles were recently described for the five domesticated Capsicum species showing a difference in heat sensations specific to species and pod type. Due to the many capsaicinoid structures, we explore the implications and opportunities of having a diverse array of heat profiles in genetically diverse Capsicum species.
- TRPV1 receptors
- heat sensitization
- chile peppers
Chile peppers (
There is extensive diversity in fruit shapes, sizes and color. Among different pod types fruit length can vary from less than 1 cm to 32.5 cm., the Guinness Record for the world’s largest
It is the capsaicinoids, alkaloids, that cause the heat sensation when consumed by mammals, that distinguishes this genus in the Solanaceae family. The primary function of capsaicinoids is to discourage mammalian feeding of the spicy chile pepper fruit, which results in destroying the seeds, while remaining attractive to birds who disperse the seeds . Most Solanaceous plants have sufficiently high levels of alkaloids in their leaves that are known to be toxic to many mammals. Oddly, chile peppers do not contain alkaloids in their leaves. In fact, in the Philippines, chile pepper leaves are eaten as a leafy vegetable. Without these alkaloids, chile peppers evolved another strategy for partial protection by deterring the wrong herbivores and attracting to the desired ones, the capsaicinoids. Capsaicinoids are not toxic per se, but are ferocious enough to discourage mammalian herbivory. Birds, on the other hand, are attracted to the small red fruit on wild plants and have digestive tracts that chemically and physically soften the seed coats without damaging the seeds, thus encouraging germination. In fact, some seeds will suffer retarded germination if they do not pass through a bird’s digestion system. It is suggested that capsaicinoids are the cause of slow germination of
Capsaicinoids are used in food, and are equally important in pharmaceutical applications, as a repellent in self-defense sprays, as a rodent repellent, as an anti-inflammatory agent, as a pain reliever, and as an antimicrobial agent [2, 10, 13, 14, 15, 16, 17, 18, 19, 20, 21].
2. Capsaicinoid biogenesis
2.1. Capsaicinoid chemistry
Capsaicinoids consist of compounds that belong to the vanilloid group and differ in the structure of branched fatty acid (acyl) moieties attached to the benzene ring of vanillylamine . The chemical structures contain three important regions; an aromatic head, an amide linkage, and a hydrophobic tail. Any variation in the chemical structure of the capsaicinoids, mainly the structure of the fatty acid chain, affects the heat profile and their pharmacological activities (Figure 2). Studies indicate that the aromatic head and the amide structures provide the excitation of sensory neurons while the hydrophobic tail is responsible for maximal potency [22, 23]. Currently, a total of 22 distinct capsaicinoids are found occurring naturally, each with a different hydrophobic fatty acid tail. Capsaicin (8-methyl-N-vanillyl-trans-6-nonenamide) and dihydrocapsaicin (
Due to the slight variations in structure, each capsaicinoid creates a different heat sensation effect in the mouth [5, 24]. The variability of amount and type of capsaicinoids within
Normally in food and processing industries, the level of total capsaicinoids is converted to Scoville Heat Units (SHU), a measurement for heat level developed by Wilbur Scoville . Scoville Heat Units are based on a dilution formula with the approximate number of times a standardized chile pepper extract is diluted to be imperceptible to a set of trained tasters. A modern method of calculation is to use analytical instrumentation that produces part per million (ppm) readings, followed by conversion of the ppm amounts to SHU by multiplying the ppm by 16 . The hottest chile pepper cultivar, as determined by the Chile Pepper Institute is the ‘Trinidad Moruga Scorpion’, that has been documented to have fruits surpassing two million SHU (Figure 1) .
2.2. Capsaicinoid location in chile pepper fruits
The level of heat, i.e., capsaicinoid production, is genetic with a high genotype by environment interaction component. The environment can increase or decrease significantly the heat level of a given cultivar [31, 32, 33, 34, 35, 36]. The capsaicinoid content can be affected by weather conditions, growing conditions and fruit age. Plant breeders selectively develop cultivars within certain ranges of heat, e.g., mild, medium, hot, superhot. Because heat level is augmented with increased environmental stress, growers can moderate heat level by the amount of stress to which they subject their plants [31, 32]. A few hot days can increase the capsaicinoid content significantly. Anthropopathically, the plant has sensed the stress, and has increased the capsaicinoid level in its fruit. If the same cultivar is grown in both a hot semi-arid region and a cool coastal region, the fruit harvested from the hot semi-arid region will be higher in capsaicinoid amounts than that the fruits harvested in the cool coastal climate. Capsaicinoids start to accumulate when fruits begin to ripen and reach their highest content when fruits reach their maximum size. Variation in capsaicinoid content has been observed in wild
Though Bennett and Kirby considered capsaicin and dihydrocapsaicin as the major capsaicinoids, this generalization is not true for all chile pepper varieties . Collins et al. reported a capsaicinoid profile in
It has been shown organoleptically that humans not only note the intensity of hotness, but perceive each capsaicinoid differently [5, 24]. The investigations of Krajewska and Powers revealed that nordihydrocapsaicin was the least irritating, and the burning was located in the front of the mouth and palate. It caused a “mellow warming effect” . The heat sensation developed immediately after swallowing and receded rapidly. In comparison, capsaicin and dihydrocapsaicin were more irritating, and were described as having a “typical” heat sensation. Both compounds produced the heat in the mid-mouth and mid-palate as well as the throat and the back of the tongue. In contrast, homodihydrocapsaicin was very irritating, harsh and very shape. The heat did not develop immediately and it affected the throat, back of the tongue, and the palate for a prolonged period. After ingestion, the heat sensation can last up to 12 hours in some individuals. Different combinations of these capsaicinoids produce the chile pepper heat profile . Capsaicinoids are valuable pharmacological compounds that have been studied for pain relief, weight management, cholesterol management, anti-inflammation, anti-cancer, and anti-oxidant activity.
Because of the natural variation of capsaicinoid content occurring in chile peppers, it is necessary to find their bioactivity differences in the digestive tract and afferent sensory neurons.
3. Capsaicinoid pharmacology
3.1. Capsaicinoids role in pain
Due to the prevalence of capsaicin in
In 1968, Jancso was the first to discover that repeated doses of capsaicin induced pain initially followed by analgesia . This was noticed in response to thermal, mechanical, and chemical noxious stimuli. Inhibition of the receptor function is called desensitization. Topical application of 8% capsaicin produces desensitization by decreasing pain for 12 weeks [42, 45]. Pain relieving effects of an 8% capsaicin patch lasting up to 18 months have been shown in post-traumatic patients suffering with neuropathic pain . In addition, oral capsaicin has been used to treat cough because inflammation of the airways can be caused by noxious stimuli on nociceptors .
Even though capsaicinoids have been used for thousands of years as a medicinal compound and scientific work has proven the efficacy as a pain attenuator, the problematic issue is estimating the correct dosage for the desired response. One method to moderate response is to use different known amounts of capsaicin. For example, topical creams, lotions and patches available on the market, some even over the counter, contain different concentrations of predominantly capsaicin (0.025–0.1% wt/wt) . Another method would be to use a mixture of capsaicinoids to induce a desired effect. Structural studies indicate that the aromatic benzene ring hydrogen bonds to the TRPV1 domains while the fatty acid tail uses van der Waals interactions to bind . This parallels the fact that the capsaicinoid aromatic head provides the excitation of sensory neurons while the hydrophobic tail is responsible for maximal potency. Therefore, we can expect to see differences in overall effects from one capsaicinoid to another. Considering that the 22 capsaicinoids have the aromatic benzene ring in common but differ in the fatty acid tails, the possibility of each one exerting a slightly different response from the TRPV1 is possible. As mentioned previously, capsaicinoid profiles are unique in each chile pepper type and species and the unique profiles exert unique heat sensations from short lasting to long lasting . Not only can different concentrations of capsaicin provide desensitization, but the other capsaicinoids could also provide varying levels pain relief.
3.2. Capsaicinoids, inflammation and the digestive tract
There is more than one mode of action for the capsaicin induced anti-inflammation response. One is by binding to TRPV1, and the other is by regulating pro-inflammatory cytokine production pathways in neurons. By targeting capsaicin-triggered TRPV1 receptors, a select group of compounds have been shown to reduce inflammatory pain. These compounds are flavonoids like naringenin, vitexin, hesperidin methyl chalcone [42, 49]. In the stomach, binding of capsaicin to TRPV1 produces increased mucosal blood flow, mucus secretion and bicarbonate secretion [40, 50]. Employing a capsaicin blocker (capsazepine) on TRPV1, evidence confirmed that there was an increase in blood flow, hyperemia, generated by capsaicin binding to TRPV1 [50, 51]. Just like the topical applications of capsaicin, capsaicin desensitization is used with patients suffering from stomach pain associated with gastric acid, irritable bowel syndrome or irritable bladder [40, 52, 53, 54]. However, there could be a different response in the small intestine, pancreas and colon because their environments and digestive roles are different than the stomach’s environment.
In the mouth, salivary gland epithelial cells (SGEC) release cytokines, such as TNFα and IL-6, both of which are associated with inflammation of salivary glands . If the inflammation response is triggered too often by the cytokines, the result could lead to cancer. The same phenomena exist in the gastrointestinal tract. Striking evidence shows that capsaicin’s inflammation inhibitory action in SGEC is through inhibition of the IkB-α/NF-kB signaling pathway and not TRPV1 . The transcription factor NF-kB regulates the expression of cytokines TNFα and IL-6, two pro-inflammatory signals [56, 57]. Therefore, capsaicin inactivates the transcription factor associated with a pro-inflammatory response . Due to the elevated risk of developing cancers from chronic inflammation, the capsaicin NF-kB interaction has been studied to suppress inflammation associated with cholangiocarcinoma, bile duct cancer, making capsaicin a potential anti-tumor compound [58, 59].
Capsaicin is also able to reduce production of inflammatory cytokines produced as a response to bacterial lipopolysaccharide (LPS) infection in human microphages . After bacterial infection, LPS serves as stimuli promoting NF-kB induced pro-inflammatory cytokine production . This effect is interrupted by capsaicin signaling the expressing Liver X Receptor (LXRα) that inhibits NF-kB, therefore inhibiting inflammatory cytokine production. Capsaicin’s anti-inflammatory response in the gastric epithelial cells extends to inhibiting
Not only does chronic digestive tract inflammation increase the risk of cancer, but it is correlated to decreased gut nutrient absorption. A group of chronic diseases are commonly referred to as inflammatory bowel disease (IBD). Causes are sometimes unknown or could be brought on by pathogenic bacteria. All of these diseases however trigger certain factors that give rise to chronic inflammation . Inflammation causes poor absorption of nutrients by altering the structure, physiology, bile amounts and microbiota of the digestive tract . Patients with an IBD are deficient in minerals and vitamins like folic acid, zinc, iron, selenium, and fat-soluble vitamins like beta-carotene (pro-vitamin A) due to malabsorption .
Additionally, studies show that capsaicin alters the structure of the intestines promoting absorption. Small intestine segments isolated from rats who were fed with capsaicin for 8 weeks were able to absorb higher amounts of iron, zinc and calcium . Veda and Srinivasan also reported an
3.3. Capsaicinoids and absorption of chile pepper carotenoids
Due to the impact capsaicinoids, particularly capsaicin, have on nutrient absorption in the gut, other chile pepper compounds ingested simultaneously are more bioaccessible for absorption. As mentioned, beta-carotene consumed with capsaicin increased the beta-carotene amounts in rats . Besides capsaicinoids,
Currently, there is no recommended daily allowance (RDA) for lutein, however 6–10 mg/day have been reported to decrease macular degeneration risks . Normally, a typical diet will include about 1–3 mg/day of lutein. As a result of capsaicinoids’ anti-inflammation properties, beta-carotene absorption has already been shown to increase when eaten with capsaicin . If a typical diet includes
When reviewing capsaicinoid nutritional and medicinal properties, it is clear why over so many years, people have been saving chile pepper seeds and using them in traditional medicines and culinary practices. As we have shown, their properties go beyond adding heat and flavor to a culinary dish. Capsaicinoids have pharmacological activities that help the human body reduce pain. It also serves as an anti-inflammatory agent which not only aids in pain reduction, but also has the potential to be used to promote absorption of other essential nutrients like beta-carotene, lutein and zeaxanthin. The diversity of
These approaches to reducing pain and inflammation using capsaicin and knowing that there are 21 other capsaicinoids that have yet to be characterized pharmacologically, offers new opportunities to explore