Metabolism of capsaicinoids: Evidence for aliphatic hydroxylation and its pharmacological implications

Surh, Young‐Joon; Ahn, Seung Ho; Kim, Kee-Cheon; Park, Jeong-Bae; Sohn, Yeo Won; Lee, Sang Sup

doi:10.1016/0024-3205(95)00091-7

Cited by 34 publications

(25 citation statements)

References 15 publications

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“…P450-dependent metabolism of capsaicinoids has been shown to mitigate capsaicinoid toxicity in cell culture (Reilly et al, 2003a). Likewise, metabolites of capsaicin did not prolong phenobarbital-induced sleep, as observed for the parent capsaicinoids (Surh et al, 1995). Structure-activity studies with capsaicin, nonivamide, structural variants, and their metabolites, have also demonstrated marked differences in pain-producing potential and hyper-and hypoalgesic properties.…”

Section: Discussionmentioning

confidence: 85%

Structural and Enzymatic Parameters That Determine Alkyl Dehydrogenation/Hydroxylation of Capsaicinoids by Cytochrome P450 Enzymes

Reilly

Yost²

2005

Drug Metab Dispos

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ABSTRACT:Previous studies on the metabolism of capsaicinoids, natural products isolated from chili peppers, demonstrated the production of unique macrocyclic, alkyl dehydrogenated, -, and -1-hydroxylated products. This study investigated the structural and enzymatic parameters that direct selective alkyl dehydrogenation and hydroxylation of capsaicinoids, using a variety of structurally related capsaicinoid analogs and cytochrome P450 (P450) enzymes. CYP2C9 preferentially catalyzed alkyl dehydrogenation, whereas CYP2E1 and 3A4 catalyzed -and -1-hydroxylation, respectively. Analysis of incubations containing various P450s and structural variants of capsaicin by liquid chromatography-tandem mass spectrometry demonstrated similarities in the rate of capsaicinoid metabolism, but marked differences in the metabolite profiles. Production of macrocyclic and -1-hydroxylated metabolites from the various capsaicinoids was dependent on the structure of the alkyl terminus and P450 enzyme. A tertiary carbon at the -1 position, coupled to an adjacent unsaturated bond at the -2,3 position, enhanced the formation of the macrocyclic and dehydrogenated metabolites and were requisite structural features for -1-hydroxylated product formation. Conversely, substrates lacking these structural features were efficiently oxidized to thehydroxylated metabolite. These data were consistent with our hypothesis that metabolism of the alkyl portion of capsaicinoids was governed, in part, by the stability and propensity to form an intermediate radical and a carbocation, and a direct interaction between the alkyl terminus and the heme of many P450 enzymes. These results provided valuable insights into potential mechanisms by which P450s metabolize capsaicinoids and highlight critical chemical features that may also govern the metabolism of structurally related compounds including fatty acids, monoterpenes, and isoprenoids.The capsaicinoids are a family of natural products isolated from the dried fruits of chili peppers (Capsicum annum and Capsicum frutescens) (Govindarajan, 1985;Govindarajan and Sathyanarayana, 1991;Caterina et al., 1997). These substances are the principals that produce the characteristic sensations associated with the ingestion of spicy cuisine as well as the agents responsible for causing severe irritation, inflammation, erythema, and transient hyper-and hypoalgesia at sites exposed to capsaicinoids; capsaicinoids are particularly irritating to the eyes, skin, nose, tongue, and respiratory tract. There are six naturally occurring capsaicinoid analogs: capsaicin, dihydrocapsaicin, nordihydrocapsaicin, nonivamide, homocapsaicin, and homodihydrocapsaicin ( Fig. 1) (Reilly et al., 2001). All capsaicinoid analogs possess a 3-hydroxy-4-methoxy-benzylamide (vanilloid ring) pharmacophore, but differ from capsaicin in their hydrophobic alkyl side chain. Differences in the side chain moiety include saturation of C 15-16 (the -2,3 position), deletion of a methyl group at C 17 (loss of the tertiary carbon), and changes in the length of t...

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Section: Discussionmentioning

confidence: 85%

Structural and Enzymatic Parameters That Determine Alkyl Dehydrogenation/Hydroxylation of Capsaicinoids by Cytochrome P450 Enzymes

Reilly

Yost²

2005

Drug Metab Dispos

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“…It has also been previously demonstrated that concomitant exposure to phenobarbital and capsaicin increased the duration of phenobarbital-induced anesthesia, presumably due to a decreased rate of metabolism of phenobarbital caused by capsaicin (49). Coadministration of either the ring or the alkyl hydroxylated metabolites (presumably mixtures of M2, M5, and M7) of capsaicin, however, had no effect on the duration of anesthesia (49). We have characterized several metabolites of capsaicin that would be predicted by structure-activity relationship studies to ameliorate the pharmacological (TRPV1 binding), and possibly toxicological, properties of capsaicin.…”

Section: Discussionmentioning

confidence: 95%

Metabolism of Capsaicin by Cytochrome P450 Produces Novel Dehydrogenated Metabolites and Decreases Cytotoxicity to Lung and Liver Cells

Reilly

Ehlhardt

Jackson

et al. 2003

Chem. Res. Toxicol.

120

131

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Capsaicin is a common dietary constituent and a popular homeopathic treatment for chronic pain. Exposure to capsaicin has been shown to cause various dose-dependent acute physiological responses including the sensation of burning and pain, respiratory depression, and death. In this study, the P450-dependent metabolism of capsaicin by recombinant P450 enzymes and hepatic and lung microsomes from various species, including humans, was determined. A combination of LC/MS, LC/MS/MS, and LC/NMR was used to identify several metabolites of capsaicin that were generated by aromatic (M5 and M7) and alkyl hydroxylation (M2 and M3), O-demethylation (M6), N- (M9) and alkyl dehydrogenation (M1 and M4), and an additional ring oxygenation of M9 (M8). Dehydrogenation of capsaicin was a novel metabolic pathway and produced unique macrocyclic, diene, and imide metabolites. Metabolism of capsaicin by microsomes was inhibited by the nonselective P450 inhibitor 1-aminobenzotriazole (1-ABT). Metabolism was catalyzed by CYP1A1, 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4. Addition of GSH (2 mM) to microsomal incubations stimulated the metabolism of capsaicin and trapped several reactive electrophilic intermediates as their GSH adducts. These results suggested that reactive intermediates, which inactivated certain P450 enzymes, were produced during catalytic turnover. Comparison of the rate and types of metabolites produced from capsaicin and its analogue, nonivamide, demonstrated similar pathways in the P450-dependent metabolism of these two capsaicinoids. However, production of the dehydrogenated (M4), macrocyclic (M1), and omega-1-hydroxylated (M3) metabolites was not observed for nonivamide. These differences may be reflective of the mechanism of formation of these metabolites of capsaicin. The role of metabolism in the cytotoxicity of capsaicin and nonivamide was also assessed in cultured lung and liver cells. Lung cells were markedly more sensitive to cytotoxicity by capsaicin and nonivamide. Cytotoxicity was enhanced 5 and 40% for both compounds by 1-ABT in BEAS-2B and HepG2, respectively. These data suggested that metabolism of capsaicinoids by P450 in cells represented a detoxification mechanism (in contrast to bioactivation).

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“…Animal studies have shown that capsaicin is eliminated mainly by the kidneys, with a small untransformed proportion excreted in the feces and urine (Leelahuta et al, 1983;Kawada et al, 1984;Surh et al, 1995). It is excreted in both free form and glucuronide form.…”

Section: Capsaicin Eliminationmentioning

confidence: 99%

Unravelling the Mystery of Capsaicin: A Tool to Understand and Treat Pain

O’Neill

Brock²,

Olesen³

et al. 2012

Pharmacol Rev

285

244

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Metabolism of capsaicinoids: Evidence for aliphatic hydroxylation and its pharmacological implications

Cited by 34 publications

References 15 publications

Structural and Enzymatic Parameters That Determine Alkyl Dehydrogenation/Hydroxylation of Capsaicinoids by Cytochrome P450 Enzymes

Structural and Enzymatic Parameters That Determine Alkyl Dehydrogenation/Hydroxylation of Capsaicinoids by Cytochrome P450 Enzymes

Metabolism of Capsaicin by Cytochrome P450 Produces Novel Dehydrogenated Metabolites and Decreases Cytotoxicity to Lung and Liver Cells

Unravelling the Mystery of Capsaicin: A Tool to Understand and Treat Pain

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