Gastrointestinal absorption and metabolism of capsaicin and dihydrocapsaicin in rats

doi:10.1016/0041-008X(84)90121-2

Toxicology and Applied Pharmacology

Volume 72, Issue 3, 15 March 1984, Pages 449-456

https://doi.org/10.1016/0041-008X(84)90121-2 Get rights and content

Abstract

Gastrointestinal absorption of capsaicin and dihydrocapsaicin was studied in rats in vivo and in situ. Rapid absorption of capsaicin or dihydrocapsaicin from stomach and small intestine occurred in vivo. About 85% of the dose was absorbed in the gastrointestinal tract within 3 hr. In situ, within 60 min after the administration of capsaicin and dihydrocapsaicin into stomach, jejunum, and ileum, about 50, 80, and 70% of the respective dose had disappeared from the lumen. When 2,4-dinitrophenol or NaCN was added, no significant reduction in uptake of [³H]dihydrocapsaicin was observed in the jejunum. These results suggested that capsaicin and its analogs were absorbed by a nonactive process in jejunum. [³H]Dihydrocapsaicin was mainly absorbed via the portal system but not a mesenteric lymphangial one. The radioactivity in the portal blood was composed of 85% of [³H]dihydrocapsaicin and 15% of its metabolite (8-methyl nonanoic acid) bound to the albumin fraction. Dihydrocapsaicin-hydrolyzing enzyme activity was found in jejunal tissue. These results suggest that capsaicin and its analogs partly received a first-pass effect, i.e., metabolism of a compound following first absorption in the gastrointestinal tract. It is concluded that capsaicin and its analogs are readily transported to the portal vein through the gastrointestinal tract by a nonactive process and partly metabolized during absorption.

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Citation Excerpt :
Furthermore, the amount of capsaicin in the blood decreased rapidly within 40 min after injection. The half-life of capsaicin was found to be approximately 12 min in the blood (Teruo Kawada & Iwai, 1985; T. Kawada, Suzuki, Takahashi, & Iwai, 1984). The third disadvantage with capsaicin is that it causes skin redness, hyperalgesia, nausea, intense tearing in the eyes, conjunctivitis, blepharospasm (sustained, forced, involuntary closing of the eyelids), vomiting, abdominal pain, stomach cramps, bronchospasm, and burning diarrhea in patients (Drewes et al., 2003; Evangelista, 2015; Hammer, 2006).
Capsaicin (trans-8-methyl-N-vanillyl-6-noneamide) is a hydrophobic, lipophilic vanilloid phytochemical abundantly found in chili peppers and pepper extracts. Several convergent studies show that capsaicin displays robust cancer activity, suppressing the growth, angiogenesis and metastasis of several human cancers. Despite its potent cancer-suppressing activity, the clinical applications of capsaicin as a viable anti-cancer drug have remained problematic due to its poor bioavailability and aqueous solubility properties. In addition, the administration of capsaicin is associated with adverse side effects like gastrointestinal cramps, stomach pain, nausea and diarrhea and vomiting. All these hurdles may be circumvented by encapsulation of capsaicin in sustained release drug delivery systems. Most of the capsaicin-based the sustained release drugs have been tested for their pain-relieving activity. Only a few of these formulations have been investigated as anti-cancer agents. The present review describes the physicochemical properties, bioavailability, and anti-cancer activity of capsaicin-sustained release agents. The asset of such continuous release capsaicin formulations is that they display better solubility, stability, bioavailability, and growth-suppressive activity than the free drug. The encapsulation of capsaicin in sustained release carriers minimizes the adverse side effects of capsaicin. In summary, these capsaicin-based sustained release drug delivery systems have the potential to function as novel chemotherapies, unique diagnostic imaging probes and innovative chemosensitization agents in human cancers.
Capsaicin, its clinical significance in patients with painful diabetic neuropathy
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Diabetic neuropathy is a risk factor for developing complications such as autonomic cardiovascular disease, osteoarthropathy, foot ulcers, and infections, which may be the direct cause of death. Even worse, patients plagued by this condition display painful neuropathic symptoms that are usually severe and frequently lead to depression, anxiety, and sleep disarrays, eventually leading to a poor quality of life. There is a general interest in evaluating the therapeutic properties of topical capsaicin cream as an effective agent for pain relief in these patients. As such, the current review makes use of major search engines like PubMed and Google Scholar, to bring an updated analysis of clinical studies reporting on the therapeutic effects of capsaicin in patients with painful diabetic neuropathy. In fact, most of the summarized literature indicates that topical capsaicin (0.075 %) cream, when applied to the painful areas for approximately 8 weeks, can reduce pain, which may lead to clinical improvements in walking, working, and sleeping in patients with painful diabetic neuropathy. The current review also discusses essential information on capsaicin, including its source, bioavailability profile, as well as treatment doses and duration, to highlight its therapeutic potential.
Beneficial effects of dietary capsaicin in gastrointestinal health and disease
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Chili pepper and its major active compound capsaicin have long been used not only a daily food additive but also medication worldwide. Like in other human organs and systems, capsaicin has multiple actions in gastrointestinal (GI) physiology and pathology. Numerous studies have revealed that capsaicin acts on GI tract in TRPV1-dependent and –independent manners, mostly depending on its consumption concentrations. In this review, we will focus on the beneficial role of capsaicin in GI tract, a less highlighted aspect, in particular how dietary capsaicin affects GI health, the mechanisms of actions and its preventive/therapeutic potentials to several GI diseases. Dietary capsaicin affects GI tract not only via TRPV1-derpendent and independent manners, but also via acute and chronic effects. Although high dose intake of dietary capsaicin is harmful to human health sometimes, current literatures suggest that appropriate dose intake is likely beneficial to GI health and is preventive/therapeutic to GI disease in most cases as well. With extensive and intensive studies on its GI actions, capsaicin, as a daily consumed food additive, has potential to become a safe drug for the treatment of several GI diseases.
Beneficial effect of capsaicin via TRPV4/EDH signals on mesenteric arterioles of normal and colitis mice
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Although capsaicin has long been used as food additive and medication worldwide, its actions on gastrointestinal tract as its most delivery pathway have not been well addressed.
In the present study, we aimed to study GI actions of capsaicin on mesenteric arterioles in normal and colitis mice and to elucidate the underlying mechanisms.
Vasorelaxation of human submucosal arterioles and the mesenteric arterioles from wide-type (WT) mice, TRPV1^−/− and TRPV4^−/− (KO) mice were measured. The expression and function of TRPV channels in endothelial cells were examined by q-PCR, immunostaining, Ca²⁺ imaging and membrane potential measurements.
Capsaicin dose-dependently induced vasorelaxation of human submucosal arterioles and mouse mesenteric arterioles in vitro and in vivo through endothelium-dependent hyperpolarization (EDH), nitric oxide (NO), and prostacyclin (PGI₂). Using TRPV1 and TRPV4 KO mice, we found that capsaicin-induced vasorelaxation was predominately through TRPV4/EDH, but marginally through TRPV1/NO/PGI₂. Capsaicin induced hyperpolarization through activation of endothelial TRPV4 channels and intermediate-conductance of Ca²⁺-activated K⁺ channels to finally stimulate vasorelaxation. Importantly, capsaicin exerted anti-colitis action by rescuing the impaired ACh-induced vasorelaxation in WT colitis mice but not in TRPV4 KO colitis mice.
Capsaicin increases intestinal mucosal blood perfusion to potentially prevent/treat colitis through a novel TRPV4/EDH-dependent vasorelaxation of submucosal arterioles in health and colitis. This study further supports our previous notion that TRPV4/EDH in mesenteric circulation plays a critical role in the pathogenesis of colitis.
Capsaicin inhibits intestinal Cl<sup>-</sup> secretion and promotes Na<sup>+</sup> absorption by blocking TRPV4 channels in healthy and colitic mice
2022, Journal of Biological Chemistry
Although capsaicin has been studied extensively as an activator of the transient receptor potential vanilloid cation channel subtype 1 (TRPV1) channels in sensory neurons, little is known about its TRPV1-independent actions in gastrointestinal health and disease. Here, we aimed to investigate the pharmacological actions of capsaicin as a food additive and medication on intestinal ion transporters in mouse models of ulcerative colitis (UC). The short-circuit current (I_sc) of the intestine from WT, TRPV1-, and TRPV4-KO mice were measured in Ussing chambers, and Ca²⁺ imaging was performed on small intestinal epithelial cells. We also performed Western blots, immunohistochemistry, and immunofluorescence on intestinal epithelial cells and on intestinal tissues following UC induction with dextran sodium sulfate. We found that capsaicin did not affect basal intestinal I_sc but significantly inhibited carbachol- and caffeine-induced intestinal I_sc in WT mice. Capsaicin similarly inhibited the intestinal I_sc in TRPV1 KO mice, but this inhibition was absent in TRPV4 KO mice. We also determined that Ca²⁺ influx via TRPV4 was required for cholinergic signaling–mediated intestinal anion secretion, which was inhibited by capsaicin. Moreover, the glucose-induced jejunal I_sc via Na⁺/glucose cotransporter was suppressed by TRPV4 activation, which could be relieved by capsaicin. Capsaicin also stimulated ouabain- and amiloride-sensitive colonic I_sc. Finally, we found that dietary capsaicin ameliorated the UC phenotype, suppressed hyperaction of TRPV4 channels, and rescued the reduced ouabain- and amiloride-sensitive I_sc. We therefore conclude that capsaicin inhibits intestinal Cl^- secretion and promotes Na⁺ absorption predominantly by blocking TRPV4 channels to exert its beneficial anti-colitic action.
Hot red pepper powder as a safe alternative to antibiotics in organic poultry feed: an updated review
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Globally, several studies have investigated the utilization and efficacy of promising medicinal herbal plants to enhance livestock and poultry production. The most commonly investigated phytobiotics in broiler ration were oregano, garlic, thyme, rosemary, black pepper, hot red pepper (HRP), and sage. Phytobiotics are classified on the basis of the medicinal properties of plants, their essential oil extracts, and their bioactive compounds. The majority of bioactive compounds in plants are secondary metabolites, such as terpenoids, phenolic, glycosides, and alkaloids. The composition and concentrations of these bioactive constitutes vary according to their biological factors and manufacturing and storage conditions. Furthermore, HRP is one of the most important and widely used spices in the human diet. Capsicum annum, that is, HRP, is a species of the plant genus Capsicum (pepper), which is a species native to southern North America and northern South America and is widely grown and utilized for its fresh or cooked fruits. Moreover, these fruits may be used as dried powders or processed forms of oleoresins. Researches have proven that C. annuum is the only plant that produces the alkaloid capsaicinoids. Approximately 48% of its active substances are capsaicin (8-methyl-N-vanillyl-6-nonemide), the main active compound responsible for the intense effects of HRP varieties and the main component inducing the hot flavor. This review aimed to highlight the effects of HRP as a phytobiotic in broiler nutrition and its mode of action as a possible alternative to antibiotics and clarify its impact on broiler and layer productivity.

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^☆: Supported by a grant-in-aid (to K.I.) for Scientific Research from the Ministry of Education, Science, and Culture in Japan. Presented at the Third Southeast Asian and Western Pacific Regional Meeting of Pharmacologists, May 25–28, 1982, Bangkok, Thailand. This article is in the series “Formation and Metabolism of Pungent Principle of Capsicum Fruits”.

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Toxicology and Applied Pharmacology

Abstract

References (20)

Acute toxicity of capsaicin in several animal species

Toxicon

Capsaicin-induced depletion of substance P from primary sensory neurones

Brain Res.

Histological reevaluation of everted gut technique for studying intestinal absorption

Eur. J. Pharmacol.

In vitro intestinal absorption of capsaicin

Toxicol. Appl. Pharmacol.

Disc electrophoresis of rat plasma lipoproteins

J. Lipid Res.

Duodenal mucosal response to the pungent principle of hot pepper (capsaicin) in the rat: Light and electron microscopic study

Toxicol. Appl. Pharmacol.

Effective separation of capsaicin and its analogues by reversed-phase high-performance thin-layer chromatography

J. Chromatogr.

Liquid scintillation counting of tritium in water with Triton emulsion systems

Int. J. Appl. Radiat. Isot.

Mechanism and extent of distribution of inulin and sucrose in chloride space tissues

Amer. J. Physiol.

Cited by (126)

Anti-cancer activity of sustained release capsaicin formulations

Capsaicin, its clinical significance in patients with painful diabetic neuropathy

Beneficial effects of dietary capsaicin in gastrointestinal health and disease

Beneficial effect of capsaicin via TRPV4/EDH signals on mesenteric arterioles of normal and colitis mice

Capsaicin inhibits intestinal Cl<sup>-</sup> secretion and promotes Na<sup>+</sup> absorption by blocking TRPV4 channels in healthy and colitic mice

Hot red pepper powder as a safe alternative to antibiotics in organic poultry feed: an updated review

Gastrointestinal absorption and metabolism of capsaicin and dihydrocapsaicin in rats☆

Abstract

Toxicon

Brain Res.

Eur. J. Pharmacol.

Toxicol. Appl. Pharmacol.

J. Lipid Res.

Toxicol. Appl. Pharmacol.

J. Chromatogr.

Int. J. Appl. Radiat. Isot.

Mechanism and extent of distribution of inulin and sucrose in chloride space tissues

Amer. J. Physiol.