Peroxidase-catalyzed Oxidation of Eugenol: Formation of a Cytotoxic Metabolite(s)

Thompson, David C.; Norbeck, Kajsa; Olsson, Lars‐Inge; Constantin-Teodosiu, D; Zee, Jolanda Van der; Moldéus, Peter

doi:10.1016/s0021-9258(19)85046-9

Cited by 91 publications

(35 citation statements)

References 34 publications

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“…S3, ESI †). The m/z and fragment signals indicate that compound A is likely to be a ''eugenol quinone methide'' species reported in previous literature, 23,25,38,39 such as HRP and DPPH catalyzed oxidation of EUG. Moreover, theoretical analysis was used to evidence the identification of the eugenol quinone methide observed in this work.…”

Section: Hplc-ms Analysismentioning

confidence: 54%

“…19,20 In vitro experiments have shown that the oxidation of EUG and ISO also leads to lignin-like polymers, implying similar reaction pathways. 21,22 Horseradish peroxidase (HRP) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical catalyzed oxidation of EUG has been demonstrated to form a yellow-colored quinone methide intermediate and a dehydrodieugenol product, [23][24][25] while in the DPPH-catalyzed oxidation of ISO, dehydrodiisoeugenol and its nucleophilic adducts have been identified to be the main products, 23,26 suggesting that EUG and ISO could be used as excellent chemical probes to investigate the active intermediates and secondary reactions occurring in the enzymatic oxidation catalyzed by laccase.…”

Section: Introductionmentioning

confidence: 99%

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Multicomponent kinetic analysis and theoretical studies on the phenolic intermediates in the oxidation of eugenol and isoeugenol catalyzed by laccase

Wang

Shi

et al. 2015

Phys. Chem. Chem. Phys.

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Laccase catalyzes the oxidation of natural phenols and thereby is believed to initialize reactions in lignification and delignification. Numerous phenolic mediators have also been applied in laccase-mediator systems. However, reaction details after the primary O-H rupture of phenols remain obscure. In this work two types of isomeric phenols, EUG (eugenol) and ISO (trans-/cis-isoeugenol), were used as chemical probes to explore the enzymatic reaction pathways, with the combined methods of time-resolved UV-Vis absorption spectra, MCR-ALS, HPLC-MS, and quantum mechanical (QM) calculations. It has been found that the EUG-consuming rate is linear to its concentration, while the ISO not. Besides, an o-methoxy quinone methide intermediate, (E/Z)-4-allylidene-2-methoxycyclohexa-2,5-dienone, was evidenced in the case of EUG with the UV-Vis measurement, mass spectra and TD-DFT calculations; in contrast, an ISO-generating phenoxyl radical, a (E/Z)-2-methoxy-4-(prop-1-en-1-yl) phenoxyl radical, was identified in the case of ISO. Furthermore, QM calculations indicated that the EUG-generating phenoxyl radical (an O-centered radical) can easily transform into an allylic radical (a C-centered radical) by hydrogen atom transfer (HAT) with a calculated activation enthalpy of 5.3 kcal mol(-1) and then be fast oxidized to the observed eugenol quinone methide, rather than an O-radical alkene addition with barriers above 12.8 kcal mol(-1). In contrast, the ISO-generating phenoxyl radical directly undergoes a radical coupling (RC) process, with a barrier of 4.8 kcal mol(-1), while the HAT isomerization between O- and C-centered radicals has a higher reaction barrier of 8.0 kcal mol(-1). The electronic conjugation of the benzyl-type radical and the aromatic allylic radical leads to differentiation of the two pathways. These results imply that competitive reaction pathways exist for the nascent reactive intermediates generated in the laccase-catalyzed oxidation of natural phenols, which is important for understanding the lignin polymerization and may shed some light on the development of efficient laccase-mediator systems.

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Section: Hplc-ms Analysismentioning

confidence: 54%

Section: Introductionmentioning

confidence: 99%

Multicomponent kinetic analysis and theoretical studies on the phenolic intermediates in the oxidation of eugenol and isoeugenol catalyzed by laccase

Wang

Shi

et al. 2015

Phys. Chem. Chem. Phys.

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“… a Coupling constants are in mT (1 mT = 10 gauss). b Numbers in parentheses are numbers of equivalent hydrogen atoms contributing to the stated hyperfine coupling. c Coupling constants assigned arbitrarily and may be interchanged. d Coupling constants were not resolved and are less than the linewidths of EPR lines, ca. < 0.020 mT. e Coupling constants were not observed or not reported. f Coupling constants in square brackets are literature values reported by ref . …”

Section: Resultsmentioning

confidence: 99%

“…Atsumi et al, Okada, et al, Satoh et al, and Fujisawa et al observed phenoxyl radicals of EUG in alkaline solution but do not report any EPR hyperfine analysis. − Nakagawa et al reported resolved and assigned EPR spectra for sesmolyl and related phenoxyl radicals that were generated by continuous UV-irradiation of benzene solutions of the corresponding phenols . Thompson et al oxidized EUG to its phenoxyl radical using HRP in a fast-flow system and report EPR parameters similar to those for related methoxy-substituted phenoxyl radicals …”

Section: Introductionmentioning

confidence: 99%

Free Radical Metabolism of Methyleugenol and Related Compounds

Sipe

Lardinois

Mason

2014

Chem. Res. Toxicol.

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Methyleugenol, the methyl ether of eugenol, both of which are flavorant constituents of spices, has been listed by the National Toxicology Program’s Report on Carcinogens as reasonably anticipated to be a human carcinogen. This finding is based on the observation of increased incidence of malignant tumors at multiple tissue sites in experimental animals of different species. By contrast, eugenol is not listed. In this study, we show that both methyleugenol and eugenol readily undergo peroxidative metabolism in vitro to form free radicals with large hyperfine interactions of the methylene allylic hydrogen atoms. These large hyperfine splittings indicate large electron densities adjacent to those hydrogen atoms. Methyleugenol undergoes autoxidation such that the commercial product contains 10–30 mg/L hydroperoxide and is capable of activating peroxidases without the presence of added hydrogen peroxide. Additionally, the hydroperoxide is not a good substrate for catalase, which demonstrates that these antioxidant defenses will not be effective in protecting against methyleugenol exposure.

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“…Quinone intermediates can also be formed by ketoenol tautomeric distribution of electrons (Smith and Hotchkiss, 2011). Thompson et al (1989) described a peroxidase-mediated radical formation at the aromatic hydroxyl group of isoeugenol; this oxygen radical is highly reactive towards proteins. • p-Phenylendiamine (PPD) is a hair dye ingredient; it is also widely used as an industrial chemical in plastics and azo dye syntheses, and as an intermediate in pesticide production.…”

Section: Activation Of Select Pro-sensitizersmentioning

confidence: 99%

Relevance of xenobiotic enzymes in human skinin vitromodels to activate pro-sensitizers

Jäckh

Fabian

Ravenzwaay

et al. 2012

Journal of Immunotoxicology

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Skin exposure to sensitizing chemicals can induce allergic reactions. Certain chemicals, so called pro-sensitizers, need metabolic activation to become allergenic. Their metabolic activation occurs in skin cells such as keratinocytes or dendritic cells. These cell types are also incorporated into dermal in vitro test systems used to assess the sensitizing potential of chemicals for humans. In vitrosystems range from single cell cultures to organotypic multi-cellular reconstructed skin models. Until now, their metabolic competence to unmask sensitizing potential of pro-sensitizers was rarely investigated. This review aims to summarize current information on available skin in vitro models and the relevance of xenobiotic metabolizing enzymes for the activation of pro-sensitizers such as eugenol, 4-allylanisole, and ethylendiamine. Among others, these chemicals are discussed as performance standards to validate new coming in vitro systems for their potential to identify pro-sensitizers.

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Peroxidase-catalyzed Oxidation of Eugenol: Formation of a Cytotoxic Metabolite(s)

Cited by 91 publications

References 34 publications

Multicomponent kinetic analysis and theoretical studies on the phenolic intermediates in the oxidation of eugenol and isoeugenol catalyzed by laccase

Multicomponent kinetic analysis and theoretical studies on the phenolic intermediates in the oxidation of eugenol and isoeugenol catalyzed by laccase

Free Radical Metabolism of Methyleugenol and Related Compounds

Relevance of xenobiotic enzymes in human skinin vitromodels to activate pro-sensitizers

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