Novel oxidative pathway of para-substituted phenols in cytochrome P450 chemical model: Substituent elimination accompanying ipso-substitution by the oxygen atom of the active species1

Ohe, Tomoyuki; Mashino, Tadahiko; Hirobe, Masaaki

doi:10.1016/0040-4039(95)01611-k

Cited by 34 publications

(36 citation statements)

References 12 publications

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“…Any working hypothesis suggested for this alkoxylating dehalogenation mediated by MP8 should explain (i) the involvement of high-valent iron-oxo intermediates formed from MP8 and H 2 O 2 ; (ii) elimination of the halogen as an anion, the regioselectivity as well as the rates of substitution that follow the order F Ͼ Cl Ͼ Br; (iii) formation of formaldehyde from the MP8-dependent dehalogenation; and (iv) formation of the alkoxyphenol and not of the benzoquinone normally formed in an oxidative dehalogenation by a high-valent iron-oxo species (11,12,19). The two reaction mechanisms presented in Fig.…”

Section: Discussionmentioning

confidence: 99%

Microperoxidase/H ₂ O ₂ -mediated alkoxylating dehalogenation of halophenol derivatives in alcoholic media

Osman

Boeren

Boersma

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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The results of this study report the H 2 O 2 -driven microperoxidase-8 (MP8)-catalyzed dehalogenation of halophenols such as 4-f luorophenol, 4-chlorophenol, 4-bromophenol, and 2-f luorophenol in alcoholic solvents. In methanol, the conversion of the para-halophenols and 2-f luorophenol to, respectively, 4-methoxyphenol and 2-methoxyphenol, as the major dehalogenated products is observed. In ethanol, 4-ethoxyphenol is the principal dehalogenated product formed from 4-f luorophenol. Two mechanisms are suggested for this MP8-dependent alkoxylating dehalogenation reaction. In one of these mechanisms the oxene resonant form of compound I of MP8 is suggested to react with methanol forming a cofactor-peroxide-alkyl intermediate. This intermediate reacts with the reactive -electrons of the substrate, leading to the formation of the alkoxyphenols and the release of the f luorine substituent as f luoride anion.

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Section: Discussionmentioning

confidence: 99%

Microperoxidase/H ₂ O ₂ -mediated alkoxylating dehalogenation of halophenol derivatives in alcoholic media

Osman

Boeren

Boersma

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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“…The excitation wavelength was 488 nm, and the emission was filtered using a 505-550 nm barrier filter. (27,28). In addition, our recent investigation of the absorption and fluorescence properties of fluorescein derivatives showed that the fluorescence of fluorescein could be quenched by protection of the phenolic hydroxy group at the 6Ј-position of fluorescein with an electron-rich aromatic ring.…”

Section: Methodsmentioning

confidence: 99%

Development of Novel Fluorescence Probes That Can Reliably Detect Reactive Oxygen Species and Distinguish Specific Species

Setsukinai

Urano

Kakinuma

et al. 2003

Journal of Biological Chemistry

1,156

915

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We designed and synthesized 2-[6-(4-hydroxy)phenoxy-3H-xanthen-3-on-9-yl]benzoic acid (HPF) and 2-[6-(4-amino)phenoxy-3H-xanthen-3-on-9-yl]benzoic acid (APF) as novel fluorescence probes to detect selectively highly reactive oxygen species (hROS) such as hydroxyl radical ( ⅐ OH) and reactive intermediates of peroxidase. Although HPF and APF themselves scarcely fluoresced, APF selectively and dose-dependently afforded a strongly fluorescent compound, fluorescein, upon reaction with hROS and hypochlorite ( ؊ OCl), but not other reactive oxygen species (ROS). HPF similarly afforded fluorescein upon reaction with hROS only. Therefore, not only can hROS be differentiated from hydrogen peroxide (H 2 O 2 ), nitric oxide (NO), and superoxide (O 2 . ) by using HPF or APF alone, but ؊ OCl can also be specifically detected by using HPF and APF together. Furthermore, we applied HPF and APF to living cells and found that HPF and APF were resistant to light-induced autoxidation, unlike 2,7-dichlorodihydrofluorescein, and for the first time we could visualize ؊ OCl generated in stimulated neutrophils. HPF and APF should be useful as tools to study the roles of hROS and ؊ OCl in many biological and chemical applications.

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“…Then water (4 ml) was added to the reaction mixture, and extraction was done with diethyl ether (4 × 5 ml). The organic phase was washed with saturated aqueous sodium chloride (2 × 5 ml) and dried over anhydrous MgSO 4 Preparation of Rat Liver Microsomes --Wistar/ST rats (6 weeks old, 200-220 g each) were intraperitoneally injected with phenobarbital (60 mg/ kg in saline) for 3 days and sacrificed 24 hr after the last injection. The liver microsomes were prepared in accordance with previously described procedures.…”

Section: Methodsmentioning

confidence: 99%

“…On the other hand, when a substituent is a halogen or a member of the hydroxymethyl, acetyl, nitro, cyano, carboxyl, or benzoyl group, a hydroquinone or benzoquinone is formed by an ipsosubstitution reaction. [3][4][5] Further, we have demonstrated that estrogen as estrone and 17β-estradiol, each of which contains a para-alkylphenol moiety, is also metabolized through ipso-addition to the corresponding quinols by P450. 6) Estrogens which undergo ipso-addition lose their estrogen receptor (ER)-binding activity.…”

Section: Introductionmentioning

confidence: 99%

Novel Metabolic Pathways of p-n-Nonylphenol Catalyzed by Cytochrome P450 and Estrogen Receptor Binding Activity of New Metabolites

Tezuka

Takahashi

Suzuki

et al. 2007

JOURNAL OF HEALTH SCIENCE

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Nonylphenol, which is used industrially as a surfactant, is an endocrine-disrupting chemical (EDC) which has estrogenic activity. The novel biotransformation of nonylphenol was investigated, based on our previously reported ipso-metabolism of para-substituted phenols by cytochrome P450 (P450). Three novel metabolites of nonylphenol, i.e., nonylquinol, 4 -hydroxynonanophenone (CO-NP) as benzyl-oxidized nonylphenol, and hydroquinone, were detected in a rat liver microsome reaction mixture. On the other hand, production of 1-(4 -hydroxyphenyl)nonan-1-ol (OH-NP), namely benzyl-hydroxylated nonylphenol, was detected in a human liver microsome reaction mixture. The formation of all these metabolites was suppressed by the addition of P450 inhibitor. This showed that all nonylphenol metabolism was catalyzed by P450. To identify which P450 isoenzyme is involved in each reaction, fourteen human P450 (CYP) isozymes, CYP1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4, 3A5, 3A7, and CYP4A11, were examined. CYP1A1, 1A2, and CYP2B6 effectively catalyzed the production of nonylquinol. CYP2B6 also catalyzed the benzyl-hydroxylation to give OH-NP. Hydroquinone was formed mainly from OH-NP, not via CO-NP. We examined the estrogenic activity of these new metabolites by estrogen receptor (ER)-binding reporter gene assay. Nonylquinol, OH-NP and hydroquinone have no ER-binding activity. However, CO-NP showed the same level of estrogen receptor binding activity as nonylphenol. Moreover, the amount of CO-NP formed was small. Therefore, the novel metabolic pathways led overall to metabolic inactivation, as concerns the estrogenic activity of nonylphenol through the ER.

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Novel oxidative pathway of para-substituted phenols in cytochrome P450 chemical model: Substituent elimination accompanying ipso-substitution by the oxygen atom of the active species1

Cited by 34 publications

References 12 publications

Microperoxidase/H ₂ O ₂ -mediated alkoxylating dehalogenation of halophenol derivatives in alcoholic media

Microperoxidase/H ₂ O ₂ -mediated alkoxylating dehalogenation of halophenol derivatives in alcoholic media

Development of Novel Fluorescence Probes That Can Reliably Detect Reactive Oxygen Species and Distinguish Specific Species

Novel Metabolic Pathways of p-n-Nonylphenol Catalyzed by Cytochrome P450 and Estrogen Receptor Binding Activity of New Metabolites

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Novel oxidative pathway of para-substituted phenols in cytochrome P450 chemical model: Substituent elimination accompanying ipso-substitution by the oxygen atom of the active species1

Cited by 34 publications

References 12 publications

Microperoxidase/H 2 O 2 -mediated alkoxylating dehalogenation of halophenol derivatives in alcoholic media

Microperoxidase/H 2 O 2 -mediated alkoxylating dehalogenation of halophenol derivatives in alcoholic media

Development of Novel Fluorescence Probes That Can Reliably Detect Reactive Oxygen Species and Distinguish Specific Species

Novel Metabolic Pathways of p-n-Nonylphenol Catalyzed by Cytochrome P450 and Estrogen Receptor Binding Activity of New Metabolites

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Microperoxidase/H ₂ O ₂ -mediated alkoxylating dehalogenation of halophenol derivatives in alcoholic media

Microperoxidase/H ₂ O ₂ -mediated alkoxylating dehalogenation of halophenol derivatives in alcoholic media