Metabolism of Capsaicinoids by P450 Enzymes: A Review of Recent Findings on Reaction Mechanisms, Bio-Activation, and Detoxification Processes

Abstract

Capsaicinoids are botanical irritants present in chili peppers. Chili pepper extracts and capsaicinoids are common dietary constituents and important pharmaceutical agents. Use of these substances in modern consumer products and medicinal preparations occurs worldwide. Capsaicinoids are the principals of pepper spray self-defense weapons and several over-the-counter pain treatments as well as the active component of many dietary supplements. Capsaicinoids interact with the capsaicin receptor (a.k.a., VR1 or TRPV1) to produce acute pain and cough as well as long-term analgesia. Capsaicinoids are also toxic to many cells via TRPV1-dependent and independent mechanisms. Chemical modifications to capsaicinoids by P450 enzymes decreases their potency at TRPV1 and reduces the pharmacological and toxicological phenomena associated with TRPV1 stimulation. Metabolism of capsaicinoids by P450 enzymes also produces reactive electrophiles capable of modifying biological macromolecules. This review highlights data describing specific mechanisms by which P450 enzymes convert the capsaicinoids to novel products and explores the relationship between capsaicinoid metabolism and its effects on capsaicinoid pharmacology and toxicology. CAPSAICINOID PHARMACOLOGY, TOXICOLOGY, AND HUMAN EXPOSURE SOURCESThe capsaicinoids are a family of natural products isolated from the fruits of "hot" peppers (Govindarajan, 1985;Govindarajan and Sathyanarayana, 1991). These substances produce the characteristic sensations associated with the ingestion of spicy food. Capsaicinoids elicit multiple characteristic pharmacological responses that include severe irritation, inflammation, erythema, and transient hyper-and hypoalgesia at exposed sites; capsaicinoids are particularly irritating to the eyes, skin, nose, tongue, and respiratory tract, where large numbers of sensory nerve fibers (C-and Aδ-) terminate that express high quantities of the capsaicin receptor (i.e., VR1 or TRPV1). TRPV1 has been cloned and its pharmacological properties and physiological roles characterized (Caterina et al., 1997). TRPV1 is a calcium channel that, when activated by capsaicinoids, produces the characteristic sensations previously described and causes toxicity in many mammalian cell types (Lee et al., 2000;Maccarrone et al., 2000;Macho et al., 2000;Surh, 2002;Reilly et al., 2003b;Agopyan et al., 2004;Johansen et al., 2006). Several excellent and comprehensive reviews dedicated to TRPV1 have been published (Szallasi and Blumberg, 1999;Caterina and Julius, 2001).There are numerous naturally occurring capsaicinoid analogs (Kozukue et al., 2005;Thompson et al., 2005a;Thompson et al., 2005b) dihydrocapsaicin, nordihydrocapsaicin, nonivamide, homocapsaicin, and homodihydrocapsaicin (Reilly et al., 2001a;Reilly et al., 2001b). The chemical structures of the major capsaicinoid analogs are depicted in Fig. 1. All analogs have the capacity to bind to and activate TRPV1, albeit with different potencies depending primarily upon the alkyl chain structure (Pyman, 1925;Hayes...

A Comprehensive Review of the Carcinogenic and Anticarcinogenic Potential of Capsaicin

“…It has been further suggested that capsaicin is bioactivated through the formation of several electrophilic metabolites that have the potential to lead to hepatotoxic and/or mutagenic responses Reilly et al 2003;Reilly and Yost 2006). However, the formation of reactive metabolites as identified through in vitro experiments such as glutathione trapping and covalent binding has not been directly linked to adverse drug reactions in the clinic .…”

“…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.…”

“…For instance, one recent review states that, ''Capsaicin has been documented to modulate microsomal cytochrome P450-dependent monooxygenase activities with resultant alteration of metabolism of carcinogens and other xenobiotics, to [the] ultimate carcinogen'' (Oyagbemi et al 2010). The general acceptance of the hypothesis, which focuses on the inhibition of CYP2E1 by capsaicin, appears to be due to the influence of reviews by and Reilly and Yost (2006).…”

“…Recent data suggest that concentrations of capsaicin outside of those readily generated in human tissues may be required to produce either substantial inhibition of CYP2E1 or inhibit metabolic activation of carcinogens such as NNK. In the study on capsaicin-mediated CYP inhibition by Reilly and Yost (2006), the lowest capsaicin concentration tested was 10 mM, which is already about 10,000-fold higher than required to activate TRPV1 (Alawi and Keeble 2010). We question the physiological relevance of millimolar capsaicin concentrations.…”

“…Capsaicin is metabolized by a number of cytochrome (CYP) P450 enzymes leading to aromatic and alkyl hydroxylation, O-demethylation and alkyl dehydrogenation (Surh, Ahn, et al 1995;Reilly et al 2003;Reilly and Yost 2006). It has been further suggested that capsaicin is bioactivated through the formation of several electrophilic metabolites that have the potential to lead to hepatotoxic and/or mutagenic responses Reilly et al 2003;Reilly and Yost 2006).…”