Metabolic activation of eugenol by myeloperoxidase in polymorphonuclear leukocytes

Thompson, David C.; Constantin-Teodosiu, D; Norbeck, Kajsa; Svensson, Björn E.; Moldéus, Peter

doi:10.1021/tx00009a011

Cited by 43 publications

(29 citation statements)

References 30 publications

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“…For example, Thompson et al suggested that oxidation of p-eugenol by horseradish peroxidase occurs via a one-electron pathway yielding a phenoxyl radical. 14) Similar observations were made for other phenolic compounds, such as phenol, 5) BHA, 15) acetaminophen, 16) quercetin 17) and 17b -estradiol. 6) Next, we investigated how phenolic compounds affect Eq.…”

Section: Resultssupporting

confidence: 64%

Relationship between Effects of Phenolic Compounds on the Generation of Free Radicals from Lactoperoxidase-Catalyzed Oxidation of NAD(P)H or GSH and their DPPH Scavenging Ability.

Ueda¹,

Tsuchiya²,

Ozawa³

2001

CHEMICAL & PHARMACEUTICAL BULLETIN

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Reactive oxygen species such as superoxide radicals (O 2 · Ϫ ), hydroxyl radicals, and singlet oxygen have been implicated both in the aging process and in degenerative disease. [1][2][3][4] Phenolic compounds are known to act as poisons under certain conditions. The mechanism of toxicity of phenolic compounds such as phenol 5) and 17b -estradiol 6) is suggested to be the generation of O 2 · Ϫ during the reaction of the compounds with oxidative enzymes (peroxidases, tyrosinase, prostaglandin synthase, etc.) in the presence of biological reductants such as reduced b -nicotinamide adenine dinucleotide (NADH), reduced b -nicotinamide adenine dinucleotide phosphate (NADPH) or glutathione (GSH). On the other hand, phenolic compounds that scavenge O 2 · Ϫ may be of potential therapeutic use as antioxidants. 7,8) In consideration of these points, we are interested in elucidating how phenolic compounds can enhance the generation of O 2 · Ϫ from the reaction of lactoperoxidase (LPO) with NAD(P)H and GSH, and whether there is a relationship between the enhancing activity of the phenolic compounds and their electrochemical properties. LPO is a mammalian hemoprotein found in saliva, tears, and milk, and forms part of the antimicrobial defense system. As the electrochemical data for phenolic compounds have been obtained under a wide range of experimental conditions, however, it is difficult to make direct comparisons. Thus, the ability of a phenolic compound to scavenge a stable radical, 1,1-diphenyl-2-picrylhydrazyl (DPPH), was used in this study to assess the electrochemical properties of the compounds. 1,1-Diphenyl-2-picrylhydrazyl is a radical widely used for the rough estimation of the antioxidant activity of phenolic compounds. The ability of a phenolic compound to scavenge DPPH is recently suggested to be related to the redox potential.9) The chemical structure of the nineteen phenolic compounds used in this study are depicted in Fig. 1. The compounds are 17b -estradiol, phenol, p-chlorophenol, p-eugenol, isoeugenol, 3,4-dimethylphenol, quercetin, Trolox C, diethylstilbestrol, bisphenol A, 4-hydroxyphenylacetic acid, 4-hydroxybenzoic acid, acetaminophen, guaiacol, p-methoxyphenol, curcumin, 2-hydroxyestradiol, gallic acid, and 3(2)-tert-butyl-4-hydroxyanisole. Phenolic dental medicaments including phenol, pchlorophenol, p-eugenol, isoeugenol, and guaiacol have been used for disinfection and sedative treatment for pulpitis in dental practice.10) We report here that the ability of phenolic compounds to enhance the LPO/H 2 O 2 -catalyzed oxidation of NAD(P)H or GSH is in inverse proportion to their quenching activity against the DPPH. Materials and MethodsMaterials 17b -Estradiol was purchased from Steraloids Inc. (U.S.A.). p-Chlorophenol, diethylstilbestrol (DES), reduced b -nicotinamide adenine dinucleotide (NADH), lactoperoxidase (LPO), catalase, superoxide dismutase (SOD), and reduced glutathione (GSH) were purchased from Sigma Chemical Co. (U.S.A.). Trolox ® (abbreviated as Trolox C hereinafter) was obtained fro...

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Section: Resultssupporting

confidence: 64%

Relationship between Effects of Phenolic Compounds on the Generation of Free Radicals from Lactoperoxidase-Catalyzed Oxidation of NAD(P)H or GSH and their DPPH Scavenging Ability.

Ueda¹,

Tsuchiya²,

Ozawa³

2001

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…The insertion of oxygen, however, is non-enzymatic and dependent on the particular structure of curcumin that enables a radical intermediate to undergo reaction with molecular oxygen and to further rearrange the peroxide into a stable product. Other natural phenolic compounds that react at the peroxidase site of the COX enzymes, for example eugenol and resveratrol, undergo a similar initial hydrogen abstraction to yield a phenoxyl radical but fail to incorporate molecular oxygen as part of the transformation since phenoxyl radicals are unreactive to O 2 (39,40). By donating a hydrogen, many flavonoids and other plant phenolic compounds have been shown to inhibit the activity of various LOX enzymes (41).…”

Section: Discussionmentioning

confidence: 99%

Autoxidative and Cyclooxygenase-2 Catalyzed Transformation of the Dietary Chemopreventive Agent Curcumin

Grießer

Pistis

Suzuki

et al. 2011

Journal of Biological Chemistry

133

196

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The efficacy of the diphenol curcumin as a cancer chemopreventive agent is limited by its chemical and metabolic instability. Non-enzymatic degradation has been described to yield vanillin, ferulic acid, and feruloylmethane through cleavage of the heptadienone chain connecting the phenolic rings. Here we provide evidence for an alternative mechanism, resulting in autoxidative cyclization of the heptadienone moiety as a major pathway of degradation. Autoxidative transformation of curcumin was pH-dependent with the highest rate at pH 8 (2.2 M/min) and associated with stoichiometric uptake of O 2 . Oxidation was also catalyzed by recombinant cyclooxygenase-2 (COX-2) (50 nM; 7.5 M/min), and the rate was increased ≈10-fold by the addition of 300 M H 2 O 2 . The COX-2 catalyzed transformation was inhibited by acetaminophen but not indomethacin, suggesting catalysis occurred by the peroxidase activity. We propose a mechanism of enzymatic or autoxidative hydrogen abstraction from a phenolic hydroxyl to give a quinone methide and a delocalized radical in the heptadienone chain that undergoes 5-exo cyclization and oxygenation. Hydration of the quinone methide (measured by the incorporation of O-18 from H 2 18 O) and rearrangement under loss of water gives the final dioxygenated bicyclopentadione product. When curcumin was added to RAW264.7 cells, the bicyclopentadione was increased 1.8-fold in cells activated by LPS; vanillin and other putative cleavage products were negligible. Oxidation to a reactive quinone methide is the mechanistic basis of many phenolic anti-cancer drugs. It is possible, therefore, that oxidative transformation of curcumin, a prominent but previously unrecognized reaction, contributes to its cancer chemopreventive activity.The yellow plant phenolic pigment curcumin shows a remarkable ability to affect a wide variety of signaling pathways that are dysregulated during tumorigenesis, including proliferation, invasion, apoptosis, and cell cycle checkpoints (1).Altogether more than one hundred molecular targets of curcumin have been identified using in vitro cell culture-based assays (2). The diversity of biological effects of curcumin has been attributed to its ability to act as an antioxidant, anti-inflammatory, and anti-viral agent (3). As a consequence of promising in vitro results, several clinical trials have been initiated to investigate the effect of dietary curcumin in the prevention of inflammatory bowel disease, colon, and pancreatic cancer, and Alzheimer Disease, among others (3).Prior to the more recent interest in its chemopreventive properties, curcumin was being considered as a food coloring agent but its chemical and photochemical instability prevented widespread application. Light-induced degradation of curcumin in organic solvents results in cleavage of the heptadienone chain, and the most abundant products have been identified as vanillin, ferulic aldehyde, ferulic acid, and feruloylmethane (4, 5). The same products have been observed as degradation products of curcumin in aqueous buf...

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“…as obtained by chemical synthesis or flash photolysis of the corresponding phenols (22)(23)(24)(25)(26). However, spectra of the p-quinone methides of vanillyl alcohol and 4-(methoxymethyl)phenol have never been described.…”

Section: Discussionmentioning

confidence: 99%

Catalytic Mechanism of the Oxidative Demethylation of 4-(Methoxymethyl)phenol by Vanillyl-Alcohol Oxidase

Fraaije

Berkel

1997

Journal of Biological Chemistry

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The catalytic mechanism for the oxidative demethylation of 4-(methoxymethyl)phenol by the covalent flavoprotein vanillyl-alcohol oxidase was studied. ). The kinetic data for the oxidative demethylation of 4-(methoxymethyl)phenol are in accordance with a ternary complex mechanism in which the reduction rate is rate-limiting. It is proposed that, upon reduction, a binary complex is produced composed of the p-quinone methide of 4-(methoxymethyl)phenol and reduced enzyme.

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Metabolic activation of eugenol by myeloperoxidase in polymorphonuclear leukocytes

Cited by 43 publications

References 30 publications

Relationship between Effects of Phenolic Compounds on the Generation of Free Radicals from Lactoperoxidase-Catalyzed Oxidation of NAD(P)H or GSH and their DPPH Scavenging Ability.

Relationship between Effects of Phenolic Compounds on the Generation of Free Radicals from Lactoperoxidase-Catalyzed Oxidation of NAD(P)H or GSH and their DPPH Scavenging Ability.

Autoxidative and Cyclooxygenase-2 Catalyzed Transformation of the Dietary Chemopreventive Agent Curcumin

Catalytic Mechanism of the Oxidative Demethylation of 4-(Methoxymethyl)phenol by Vanillyl-Alcohol Oxidase

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