In Vitro Hepatic and Skin Metabolism of Capsaicin

Abstract

ABSTRACT:On the basis of the ability of capsaicin to activate the transient receptor potential vanilloid 1 receptor (TRPV1) expressed in nociceptive sensory neurons, topical and injectable high-concentration formulations are being developed as potential treatments for various pain syndromes. As much of the published literature on capsaicin is based on pepper extracts, which are typically a mixture of capsaicin and other capsaicinoids (including norhydrocapsaicin, dihydrocapsaicin, homocapsaicin and homodihydrocapsaicin), the purpose of this investigation was to study the in vitro metabolism of pure capsaicin. The metabolism of capsaicin was similar in human, rat, and dog microsomes and S9 fractions.In these assays, three major metabolites were detected and identified as 16-hydroxycapsaicin, 17-hydroxycapsaicin, and 16,17-dehydrocapsaicin. In addition to these three metabolites, rat microsomes and S9 fractions also produced vanillylamine and vanillin. Biotransformation of capsaicin was slow in human skin in vitro, with the majority of the applied capsaicin remaining unchanged and a small fraction being metabolized to vanillylamine and vanillic acid. These data suggest that the metabolism of capsaicin by cytochrome P450 enzymes in skin is minimal, relative to hepatic metabolism.Capsaicin is the most abundant pungent molecule produced by pepper plants and thereby represents an important ingredient in spicy foods consumed throughout the world. The capsaicin content of peppers ranges from 0.1 to 2.5 mg/g (Parrish, 1996), and the resulting average human capsaicin consumption is on the order of 0.5 to 4 mg/kg/day (EC Scientific Committee on Food, 2002, http://ec.europa.eu/food/fs/sc/scf/out120_en.pdf). In addition to its extensive role as a food additive, there is also substantial human exposure to capsaicin in the form of nonprescription (in the United States) or prescription (in the European Union) topical analgesics, self-defense products (e.g., pepper spray), and oral herbal supplements.Capsaicin is a highly selective agonist for the TRPV1 [formerly known as the vanilloid receptor 1 (VR1)]. TRPV1 is a ligand-gated, nonselective cation channel preferentially expressed on small-diameter sensory neurons, especially those nociceptors that specialize in the detection of painful or noxious sensations (C-fibers and to a lesser extent A␦-fibers) (Caterina et al., 1997;Szallasi and Blumberg, 1999). The initial effect of capsaicin is the activation of TRPV1-expressing nociceptors, resulting in a burning sensation, hyperalgesia, allodynia, and erythema (Szallasi and Blumberg, 1999); these events are followed by a reversible defunctionalization of nociceptive sensory axons (Bley, 2004). Defunctionalization of hyperactive nociceptors is thought to underlie the pain relief that follows topical application or intra-articular injections of capsaicin (Bley, 2004).Much of the published literature on capsaicin relates to extracts of capsaicin derived from peppers; these extracts are typically a mixture of capsaicin, norhydrocapsaicin...

A Comprehensive Review of the Carcinogenic and Anticarcinogenic Potential of Capsaicin

“…A compilation of potential capsaicin metabolites are shown in Figure 1, based on figures which appeared in , Reilly and Yost (2006), and Chanda et al (2008). It is important to note that while the metabolites depicted in Figure 1 have been reported under in vitro or ex vivo conditions, the in vivo metabolism of capsaicin in humans or animals following experimental, dietary, environmental or medical exposure has not been thoroughly investigated.…”

“…In addition to low maximal levels, the plasma half life of capsaicin was quite short: about 25 min following oral administration (Chaiyasit et al 2009) and about 98 min when delivered through the skin (Babbar et al 2009). The rapid clearance of capsaicin is likely related to significant first-pass hepatic metabolism (Donnerer et al 1990;Chanda et al 2008). Adding to the expectation of very modest systemic exposure, the water solubility of capsaicin is very low, in the range of *60 ng/mL under saturated conditions (Turgut et al 2004).…”

Topical Delivery System for Phytochemicals: Capsaicin and Capsicum Tincture

“…The Capsicum fruits were identified by comparing authentic sample and preserved in the Museum of Natural Medicine, The School of Pharmaceutical and Biomedical Sciences, Pokhara University, Pokhara, Nepal (Voucher Number 316). metabolism in the skin indicates that there is a lack of potential for formation of the covalently bound toxic metabolites [9].…”

Micro-sample analysis of capsaicin by liquid chromatography-tandem mass spectrometry assay and application to oral absorption study

“…These methods provide improved assay sensitivity (LLOQ 0.5-1 ng mL -1 ) and have been applied to in vivo studies where capsaicin was administered by inhalation [13], topical administration [14] and subcutaneous injection [15]. These administration routes bypass the hepatic first-pass metabolism of xenobiotics, especially high extraction ratio chemicals including capsaicin [16]. As a consequence, a significantly larger fraction of administered dose reaches the systemic circulation.…”