Covalent Bonding of Bay-Region Diol Epoxides to Nucleic Acids

Jerina, Donald M.; Chadha, Anju; Cheh, Albert M.; Schurdak, Mark E.; Wood, Alexander W.; Sayer, Jane M.

doi:10.1007/978-1-4684-5877-0_70

Cited by 109 publications

(103 citation statements)

References 60 publications

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“…As previously mentioned, fjordregion compounds are more active as mutagens and carcinogens (Harvey 1991;Jerina et al 1991). Figure 7 shows examples of PAHs that were either noncarcinogenic or carcinogenic in experimental animals.…”

Section: Mechanisms Of Action Of Pahsmentioning

confidence: 88%

“…It could be noted that halogen-substituted polycyclic compounds such as dioxins and dioxinlike compounds exert biological activity through nongenotoxic mechanisms, whereas the carcinogenic potency of PAHs seems to rely more on genotoxic mechanisms (Harvey 1991;Jerina et al 1991;Sims and Grover 1974;Thakker et al 1985).…”

Section: Mechanisms Of Action Of Pahsmentioning

confidence: 99%

“…It should be emphasized that this conclusion is restricted to the planar bay-region PAHs and may not reflect the very high mutagenic/carcinogenic potency of the fjord-region PAHs. Available information indicates that the latter are strong mutagens and carcinogens (Harvey et al 1991;Jerina et al 1991), despite their lower affinity to bind to the Ah receptor (Ionanides andParke 1990, 1993), and induce their own metabolism to yield DEs through a non-Ah receptor-mediated mechanism (see below). In addition to promoting the carcinogenic process by interacting with the Ah receptor, PAHs may amplify the tumor promotion process via alternative mechanisms such as induction of inflammatory processes and stimulated oxidative stress (Casale et al 1998).…”

Section: Mechanisms Of Action Of Pahsmentioning

confidence: 99%

“…Extensive studies of mutagenic and carcinogenic PAHs and their metabolites have identified so-called bay-and fjord-region DEs as ultimate reactive species (Harvey 1991;Jerina et al 1991). The formation of DEs is a three-step process and it will be described for B[a]P. It should be emphasized that what is described for B[a]P regarding metabolic transformation can be applied to many alternant PAHs.…”

Section: Mechanisms Of Action Of Pahsmentioning

confidence: 99%

See 3 more Smart Citations

Cancer Risk Assessment, Indicators, and Guidelines for Polycyclic Aromatic Hydrocarbons in the Ambient Air

Boström¹,

Gerde²,

Hanberg³

et al. 2002

Environ Health Perspect

873

459

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Section: Mechanisms Of Action Of Pahsmentioning

confidence: 88%

Section: Mechanisms Of Action Of Pahsmentioning

confidence: 99%

Section: Mechanisms Of Action Of Pahsmentioning

confidence: 99%

Section: Mechanisms Of Action Of Pahsmentioning

confidence: 99%

See 2 more Smart Citations

Cancer Risk Assessment, Indicators, and Guidelines for Polycyclic Aromatic Hydrocarbons in the Ambient Air

Boström¹,

Gerde²,

Hanberg³

et al. 2002

Environ Health Perspect

873

459

View full text Add to dashboard Cite

“…Other planar PAH diol-epoxides that contain a bay or fjord region, such as benz [a]anthracene and chrysene, bind covalently and almost exclusively with guanine bases in DNA. By contrast, the fjord region diol-epoxides of benzo[c]phenanthrene, with a distortion from the planarity of the parent molecule, react with adenine and guanine bases in DNA (Dipple et al, 1987;Jerina et al, 1991). The poorly repaired DNA adducts can persist until replication and cause mutations (Smith et al, 2000;Feng et al, 2002;Rodríguez et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the noncovalent binding interactions between polycyclic aromatic hydrocarbon metabolites and human p53 cDNA

Wei¹,

Lin²,

Zhang³

et al. 2010

Science of The Total Environment

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The binding of reactive polycyclic aromatic hydrocarbon (PAH) metabolites, formed enzymatically, to DNA is a crucial step in PAH carcinogenesis in vivo. We investigated the noncovalent binding interactions between 11 PAH metabolites and human p53 complementary DNA (p53 cDNA) using the fluorescence displacement method and molecular docking analysis. All of the examined metabolites predominantly interacted with p53 cDNA by intercalation instead of groove binding. The dissociation constants ranged from 0.02 to 12.34 μM. Of the metabolites tested, 1-hydroxypyrene and 3-hydroxybenzo[a]pyrene showed the strongest binding affinities to DNA, while 2-naphthol was the weakest DNA intercalator. The intercalation of the metabolites was stabilized by stacking the PAH phenyl rings with the DNA base pairs and the formation of hydrogen bonds between the oxide or hydroxyl groups on the metabolites, and DNA bases or backbones. The binding of the metabolites to DNA showed some sequence selectivity. The binding affinities and hydrogen bonds for 3-hydroxybenzo[a]pyrene, benzo[a]pyrene-4,5-dihydroepoxide (BPE) and benzo[a]pyrene-r-7,t-8-dihydrodiol-t-9,10-epoxide (BPDE) differed. It seems that the functional groups on the periphery of the PAH aromatic ring play crucial roles in regulating its binding affinity with DNA. Although it was difficult to determine the correlation between DNA noncovalent binding affinity and carcinogenicity for some of the PAH metabolites, the present study improved our understanding of the formation of PAH metabolite-DNA adducts.

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Polycyclic aromatic hydrocarbons (PAH) [MAK Value Documentation, 2012]

2013

The MAK‐Collection for Occupational Health and Safety

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Published in the series MAK Value Documentations , Vol. 27 (2012) The article contains sections titled: Toxic Effects and Mode of Action Mechanism of Action Toxicokinetics and Metabolism Absorption, distribution and elimination Metabolism Effects in Humans Single exposures Repeated exposures Local effects on skin and mucous membranes Allergenic effect Reproductive and developmental toxicity Genotoxicity Carcinogenicity Animal Experiments and in vitro Studies Acute toxicity Subacute, subchronic and chronic toxicity Local effects on skin and mucous membranes Allergenic effect Reproductive and developmental toxicity Genotoxicity Carcinogenicity Other effects Methylpyrene as representative of alkylated PAH General information Occurrence of alkylated PAH Metabolism Genotoxicity Carcinogenicity Assessment of carcinogenicity Potency balances for PAH Potency equivalents of PAH Equivalency factors of PAH Manifesto (MAK value/classification)

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Covalent Bonding of Bay-Region Diol Epoxides to Nucleic Acids

Cited by 109 publications

References 60 publications

Cancer Risk Assessment, Indicators, and Guidelines for Polycyclic Aromatic Hydrocarbons in the Ambient Air

Cancer Risk Assessment, Indicators, and Guidelines for Polycyclic Aromatic Hydrocarbons in the Ambient Air

Evaluation of the noncovalent binding interactions between polycyclic aromatic hydrocarbon metabolites and human p53 cDNA

Polycyclic aromatic hydrocarbons (PAH) [MAK Value Documentation, 2012]

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