Novel bay-region diol epoxides from benzo[c]phenanthrene

Sayer, Jane M.; Yagi, Haruhiko; Croisy-Delcey, Martine; Jerina, Donald M.

doi:10.1021/ja00406a063

Cited by 73 publications

(70 citation statements)

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“…In the present study, we find that ferulic, caffeic, chlorogenic, and ellagic acids, four naturally occurring plant phenols that share the common structural elements of a meta-or para-hydroxylated benzoic or cinnamic acid ( Fig. 1 (12) were synthesized as previously described, as were B[a]P H4-9, 10-epoxide (18) and B[a]P 4,5-oxide (19). All compounds were free of detectable impurities, and the diol epoxides were free of diastereomeric contamination, as determined by mass spectral and nuclear magnetic resonance analyses.…”

supporting

confidence: 51%

“…Chemical and kinetic studies have demonstrated that bayregion diol epoxides are subject to general acid catalysis to form chemically unreactive and biologically inactive tetraols (7)(8)(9)(10)(11)(12) as well as to form covalent adducts with low molecular weight nucleophiles such as p-nitrothiophenol and 2-mercaptoethanol (7,8,12). Thus a chemical basis exists for a rational approach to the identification of nontoxic compounds that can block the adverse biological effects of the ultimate carcinogens of polycyclic aromatic hydrocarbons.…”

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confidence: 99%

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Inhibition of the mutagenicity of bay-region diol epoxides of polycyclic aromatic hydrocarbons by naturally occurring plant phenols: Exceptional activity of ellagic acid

Wood

Huang

Chang

et al. 1982

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

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Ferulic, caffeic, chlorogenic, and ellagic acids, four naturally occurring plant phenols, inhibit the mutagenicity and cytotoxicity of (+)-7,8,8a-dihydroxy-9a,10a-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (B[a]P 7,8-diol-9,10-epoxide-2), the only known ultimate carcinogenic metabolite of benzo [a]pyrene. The mutagenicity of 0.05 nmol of B[a]P 7,8-diol-9,10-epoxide-2 in strain TA100 of Salmonella typhimurium is inhibited 50% by incubation ofthe bacteria and the diol epoxide with 150 nmol offerulic acid, 75 nmol of caffeic acid, 50 nmol of chlorogenic acid or, most strikingly, 1 nmol of ellagic acid in the 0.5-ml incubation mixture. A 3-nmol dose of ellagic acid inhibits mutation induction by 90%. Ellagic acid is also a potent antagonist of B[a]P 7,8-diol-9,10-epoxide-2 in Chinese hamster V79 cells. Mutations to 8-azaguanine resistance induced by 0.2 ,AM diol epoxide are reduced by 50% when tissue culture media also contains 2 ,uM ellagic acid. Similar to results obtained with the bacteria, ferulic, caffeic, and chlorogenic acids are approximately two orders of magnitude less active than ellagic acid in the mammalian cell assay. The antimutagenic effects of the plant phenols result from their direct interaction with B[a]P 7,8-diol-9,10-epoxide-2, because a concentration-dependent increase in the rate ofdiol epoxide disappearance in cell-free solutions of 1:9 dioxane/water, pH 7.0, is observed with all four phenols. In parallel with the mutagenicity studies, ellagic acid is 80-300 times more effective than the other phenols in accelerating the disappearance of B[a]P 7,8-diol-9,10-epoxide-2. Ellagic acid at 10 ,M increases the disappearance of B[a]P 7,8-diol-9,10-epoxide-2 by approximately 20-fold relative to the spontaneous and hydronium ion-catalyzed hydrolysis of the diol epoxide at pH 7.0. Ellagic acid is a highly potent inhibitor of the mutagenic activity of bay-region diol epoxides of benzo[a]pyrene, dibenzo[a,h]pyrene, and dibenzo[a,ijpyrene, but higher concentrations of ellagic acid are needed to inhibit the mutagenic activity of the chemically less reactive bay-region diol epoxides of benz [a]anthracene, chrysene, and benzo [c]phenanthrene. These studies demonstrate that ellagic acid is a potent antagonist of the adverse biological effects of the ultimate carcinogenic metabolites of several polycyclic aromatic hydrocarbons and suggest that this naturally occurring plant phenol, normally ingested by humans, may inhibit the carcinogenicity ofpolycyclic aromatic hydrocarbons.Polycyclic aromatic hydrocarbons are relatively inert environmental precarcinogens that must be metabolized by mammalian enzymes to their biologically active products (ultimate carcinogens). Mutagenicity, metabolism, DNA-binding, and tumorigenicity studies during the past 8 years have shown that benzoring diol epoxides, in which the epoxide moiety forms part of the bay region (1, 2) of the hydrocarbons, are ultimate carcinogens of polycyclic hydrocarbons (3-6).Chemical and kinetic studies have demonstrated that bayregion diol epoxid...

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supporting

confidence: 51%

mentioning

confidence: 99%

Inhibition of the mutagenicity of bay-region diol epoxides of polycyclic aromatic hydrocarbons by naturally occurring plant phenols: Exceptional activity of ellagic acid

Wood

Huang

Chang

et al. 1982

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

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203

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“…[In the case of benzo[c]-phenanthrene, the racemic diol epoxide-1 diastereomer has skin tumor-initiating activity equal to that of racemic diol epoxide-2 (27). However, because of steric crowding in the bay region of benzo[c]phenanthrene, the hydroxyl groups of both diastereomers prefer the pseduoequatorial conformation (5).] However, interpretation of these results is complicated in that the (R,S,S,R) enantiomer of each diol epoxide-2 diastereomer has high tumorigenic activity (9,(16)(17)(18), despite the fact that the enantiomer with the (S,R,R,S) absolute configuration also has hydroxyl groups that prefer the pseudoequatorial conformation.…”

Section: Discussionmentioning

confidence: 99%

“…In the absence of specific structural features, the hydroxyl groups of benzo-ring dihydrodiols prefer the pseudoequatorial conformation (1). Although this conformational preference is maintained for the diol epoxide-2 diastereomers, the diol epoxide-1 diastereomers have a slight preference for the conformation in which the hydroxyl groups are pseudoaxial (2)(3)(4)(5). Tumor studies with bay-region diol epoxides derived from benzo[a]pyrene (B[a]P) (6, 7), chrysene (8, 9), benz[a]anthracene (10,11), and benz[c]acridine (12,13) have shown that the diol epoxide-2 diastereomers have high tumorigenic activity relative to the diol epoxide-1 diastereomers, which in some cases are inactive.…”

Section: Introductionmentioning

confidence: 99%

Role of diaxial versus diequatorial hydroxyl groups in the tumorigenic activity of a benzo[a]pyrene bay-region diol epoxide.

Chang

Wood

Conney

et al. 1987

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

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Tumorigenic activities of the (7R,8S,9S,10R)-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydro derivatives of benzo [a]pyrene [(+)-B[a]P diol epoxide-21 and 6-fluorobenzo- [a]pyrene (6-FB[a]P diol epoxide-2) were evaluated in newborn CD-1 mice. A total dose of 14 nmol of either diol epoxide was administered to preweanling mice, and tumorigenic activity was determined when the mice were 32 to 36 weeks old. At the termination of the study, 13% of solvent-treated control mice had developed lung tumors with an average of 0.19 tumor per mouse. No other tumors were observed in control animals.(+)-B[a]P diol epoxide-2 induced pulmonary tumors in 60% of the mice with an average of 1.9 tumors per mouse, and 14% of the male mice developed hepatic tumors with an average of0.18 tumor per mouse. In contrast, 6-FB[a]P diol epoxide-2 had no significant tumorigenic activity at the 14-nmol dose. Although both bay-region diol epoxides have the same absolute configuration, (7R,8S,9S,1OR), the hydroxyl groups of (+)-B[a]P diol epoxide-2 prefer the pseudoequatorial conformation whereas the hydroxyl groups of 6-FB[a]P diol epoxide-2 prefer the pseudoaxial conformation. The tumorigenicity results reported here are the first direct demonstration that conformation of the hydroxyl groups in a bay-region diol epoxide, in addition to the documented effect of absolute configuration, is an important determinant in the tumorigenic activity of these ultimate carcinogens.The bay-region diol epoxides derived from trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene exist as a pair of diastereomers in which the 7-hydroxyl group is either cis (diol epoxide-1) or trans (diol epoxide-2) to the 9,10-epoxide oxygen. In the absence of specific structural features, the hydroxyl groups of benzo-ring dihydrodiols prefer the pseudoequatorial conformation (1). Although this conformational preference is maintained for the diol epoxide-2 diastereomers, the diol epoxide-1 diastereomers have a slight preference for the conformation in which the hydroxyl groups are pseudoaxial (2)(3)(4)(5). Tumor studies with bay-region diol epoxides derived from benzo[a]pyrene (B[a]P) (6, 7), chrysene (8, 9), benz[a]anthracene (10,11), and benz[c]acridine (12,13) have shown that the diol epoxide-2 diastereomers have high tumorigenic activity relative to the diol epoxide-1 diastereomers, which in some cases are inactive. Both diastereomers of the benzo[e]pyrene bay-region 9,10-diol-11,12-epoxides, which have their hydroxyl groups essentially locked in the pseudoaxial conformation due to steric crowding in the bay region (14), have little or no tumorigenic activity (15). These observations have implicated the potential importance of conformational factors in the expression of tumorigenic activity of bay-region diol epoxides.

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“…Benzo[a]pyrene was purchased from the Biochemical Institute for Environmental Carcinogens, Grosshansdorf, Germany with a purity of 499% as determined by gas chromatography-mass spectrometry. Synthesis of anti-dihydrodiol epoxides of benzo[a]pyrene 51,52 and benzo[c] phenanthrene 53,54 was performed according to literature methods. CDDP, actinomycin D, anisomycin, wortmannin and doxorubicin were purchased from Sigma (München, Germany); ATM/ATR -(KU55933 and ETP-46464) and DNA-PK II (NU7026) Kinase inhibitors from Merck Millipore (Darmstadt, Germany); PP1 (src-kinase inhibitor) from Biomol (Hamburg, Germany) and SB203580 from Enzo Life Sciences (Loerrach, Germany).…”

Section: Materials and Methods Materialsmentioning

confidence: 99%

The nucleotide excision repair protein XPC is essential for bulky DNA adducts to promote interleukin-6 expression via the activation of p38-SAPK

Schreck¹,

Grico

Hansjosten³

et al. 2015

Oncogene

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Polycyclic aromatic hydrocarbons (PAHs) are environmental pollutants, and many are potent carcinogens. Benzo[a]pyrene (B[a]P), one of the best-studied PAHs, is metabolized ultimately to the genotoxin anti-B[a]P-7,8-dihydrodiol-9,10-epoxide (BPDE). BPDE triggers stress responses linked to gene expression, cell death and survival. So far, the underlying mechanisms that initiate these signal transduction cascades are unknown. Here we show that BPDE-induced DNA damage is recognized by DNA damage sensor proteins to induce activation of the stress-activated protein kinase (SAPK) p38. Surprisingly, the classical DNA damage response, which involves the kinases ATM and ATR, is not involved in p38-SAPK activation by BPDE. Moreover, the induction of p38-SAPK phosphorylation also occurs in the absence of DNA strand breaks. Instead, increased phosphorylation of p38-SAPK requires the nucleotide excision repair (NER) and DNA damage sensor proteins XPC and mHR23B. Interestingly, other genotoxins such as cisplatin (CDDP), hydrogen peroxide and ultraviolet radiation also enhance XPC-dependent p38-SAPK phosphorylation. In contrast, anti-benzo[c]phenanthrene-3,4-dihydrodiol-1,2-epoxide, the DNA adducts of which are not properly recognized by NER, does not trigger p38-SAPK activation. As a downstream consequence, expression and secretion of the pro-inflammatory cytokine interleukin-6 is induced by BPDE and CDDP in vitro and by CDDP in the murine lung, and depends on XPC. In conclusion, we describe a novel pathway in which DNA damage recognition by NER proteins specifically leads to activation of p38-SAPK to promote inflammatory gene expression.

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Novel bay-region diol epoxides from benzo[c]phenanthrene

Cited by 73 publications

References 1 publication

Inhibition of the mutagenicity of bay-region diol epoxides of polycyclic aromatic hydrocarbons by naturally occurring plant phenols: Exceptional activity of ellagic acid

Inhibition of the mutagenicity of bay-region diol epoxides of polycyclic aromatic hydrocarbons by naturally occurring plant phenols: Exceptional activity of ellagic acid

Role of diaxial versus diequatorial hydroxyl groups in the tumorigenic activity of a benzo[a]pyrene bay-region diol epoxide.

The nucleotide excision repair protein XPC is essential for bulky DNA adducts to promote interleukin-6 expression via the activation of p38-SAPK

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