Polycyclic Aromatic Hydrocarbons: Metabolism, Activation and Tumour Initiation

Hall, Michael; Grover, Philip L.

doi:10.1007/978-3-642-74775-5_9

Cited by 87 publications

(64 citation statements)

References 167 publications

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“…ras) and tumor-suppressor genes (e.g. p53) (Hall and Grover, 1990). The initial step is thought to be the interaction of electrophilic metabolites with DNA, which may result in a changed nucleotide sequence due to misincorporation of a nucleotide opposite the damaged base.…”

Section: Criteria For Dna Adducts As Biomarkers Of Exposure To Aromatmentioning

confidence: 99%

A Critical Evaluation of DNA Adducts as Biological Markers for Human Exposure to Polycyclic Aromatic Compounds

Godschalk¹,

Schooten²,

Bartsch³

2003

BMB Reports

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The causative role of polycyclic aromatic hydrocarbons (PAH) in human carcinogenesis is undisputed. Measurements of PAH-DNA adduct levels in easily accessible white blood cells therefore represent useful early endpoints in exposure intervention or chemoprevention studies. The successful applicability of DNA adducts as early endpoints depends on several criteria: i. adduct levels in easily accessible surrogate tissues should reflect adduct levels in target-tissues, ii. toxicokinetics and the temporal relevance should be properly defined. iii. sources of interand intra-individual variability must be known and controllable, and finally iv. adduct analyses must have advantages as compared to other markers of PAHexposure. In general, higher DNA adduct levels or a higher proportion of subjects with detectable DNA adduct levels were found in exposed individuals as compared with nonexposed subjects, but saturation may occur at high exposures. Furthermore, DNA adduct levels varied according to changes in exposure, for example smoking cessation resulted in lower DNA adduct levels and adduct levels paralleled seasonal variations of air-pollution. Intraindividual variation during continuous exposure was low over a short period of time (weeks), but varied significantly when longer time periods (months) were investigated. Inter-individual variation is currently only partly explained by genetic polymorphisms in genes involved in PAH-metabolism and deserves further investigation. DNA adduct measurements may have three advantages over traditional exposure assessment: i. they can smooth the extreme variability in exposure which is typical for environmental toxicants and may integrate exposure over a longer period of time. Therefore, DNA adduct assessment may reduce the monitoring effort. ii. biological monitoring of DNA adducts accounts for all exposure routes. iii. DNA adducts may account for inter-individual differences in uptake, elimination, distribution, metabolism and repair amongst exposed individuals. In conclusion, there is now a sufficiently large scientific basis to justify the application of DNA adduct measurements as biomarkers in exposure assessment and intervention studies. Their use in risk-assessment, however, requires further investigation.

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Section: Criteria For Dna Adducts As Biomarkers Of Exposure To Aromatmentioning

confidence: 99%

A Critical Evaluation of DNA Adducts as Biological Markers for Human Exposure to Polycyclic Aromatic Compounds

Godschalk¹,

Schooten²,

Bartsch³

2003

BMB Reports

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“…However, among the PAHs encountered in work environments, 16 have been classified by US Environmental Protection Agency (EPA) and National Institute of Occupational Safety and Health (NIOSH) as priority pollutants, based on their relative abundance and toxicological profiles (USEPA 1979), and two of them-benzo(a)pyrene (BaP) and pyrene (P)-have been most extensively studied. The aetiology of PAH toxicity is complex given the following: (i) PAHs are metabolically activated by phase I enzymes to electrophilic intermediates that bind covalently to DNA, RNA and proteins; (ii) PAHs are biotransformed into water soluble derivatives by both phase I and phase II enzymes; (iii) PAHs induce numerous enzymes of the cytochrome P450 (CYP450) group via the aryl hydrocarbon receptor (AhR) signalling pathway; (iv) PAHs governing CYP450 induction could produce an imbalance between detoxification and activation, leading to activation of carcinogenicity (Hall and Grover 1990;Hankinson 1995;Witlock 1999;Delescluse et al 2000). Consequently, many aspects concerning possible antagonism or synergism between the components of the complex mixtures PAHs are still to be clarified.…”

Section: Introductionmentioning

confidence: 99%

Electrophilic tissue burden in male Sprague-Dawley rats following repeated exposure to binary mixtures of polycyclic aromatic hydrocarbons

Tzekova

Leroux

Viau

2004

Archives of Toxicology

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The aim of this study was to investigate the electrophilic tissue burden (ETB) formation, assessed as covalent binding of the ultimate carcinogen benzo( a)pyrene diolepoxide (BaPDE) with cellular proteins, in liver, lung and heart, as well as with haemoglobin (Hb) following repeated exposure to binary mixtures of benzo( a)pyrene (BaP) and pyrene (P). Male Sprague-Dawley rats were injected intraperitoneally, once daily for 10 consecutive days, with binary mixtures of BaP and P in three different exposure scenarios corresponding to BaP/P ratios of 0.2, 1 and 5 and with three dose levels of BaP (2, 6 and 20 mg/kg) for each scenario. ETB levels were measured as the ultimate analyte benzo( a)pyrene tetrol (BaPTeT) obtained after mild acid hydrolysis of BaPDE-adducts with proteins. A high-performance liquid chromatography fluorescence technique was used to quantify the analyte. Similar ETB levels (within a factor of 4) were observed in all tissues studied at any given binary dose. However, the ETB generally tended to be somewhat higher in metabolically active tissues (i.e. liver and lung) than in metabolically non-active tissues (i.e. heart and Hb). Lack of influence of pyrene on ETB levels in all tissues was confirmed over the binary dose range examined. Linear BaP-dose-dependent ETB formation in all tissues (at P

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“…Many of these adverse effects are thought to be linked to the cytosolic arylhydrocarbon receptor (AhR), a liganddependent basic helix-loop-helix transcription factor to which PAHs bind, thereby triggering translocation of the AhR into the nucleus, association with the AhR nuclear translocator (ARNT), and ultimately interaction with xenobiotic responsive elements found in the 5Ј flanking regions of responsive genes (6). In this way, AhR is notably implicated in up-regulation of drug-metabolizing enzymes such as cytochromes P450 (CYPs), especially CYP1A1 (7), which metabolize PAHs into reactive intermediates that are capable of interacting with DNA and most likely account for mutagenic properties of these environmental contaminants (8).…”

mentioning

confidence: 99%

Polycyclic Aromatic Hydrocarbons Inhibit Differentiation of Human Monocytes into Macrophages

Grevenynghe

Rion

Ferrec

et al. 2003

The Journal of Immunology

143

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Polycyclic aromatic hydrocarbons (PAHs) such as benzo(a)pyrene (BP) are ubiquitous environmental carcinogenic contaminants exerting deleterious effects toward cells acting in the immune defense such as monocytic cells. To investigate the cellular basis involved, we have examined the consequences of PAH exposure on macrophagic differentiation of human blood monocytes. Treatment by BP markedly inhibited the formation of adherent macrophagic cells deriving from monocytes upon the action of either GM-CSF or M-CSF. Moreover, it reduced expression of macrophagic phenotypic markers such as CD71 and CD64 in GM-CSF-treated monocytic cells, without altering cell viability or inducing an apoptotic process. Exposure to BP also strongly altered functional properties characterizing macrophagic cells such as endocytosis, phagocytosis, LPS-triggered production of TNF-α and stimulation of allogeneic lymphocyte proliferation. Moreover, formation of adherent macrophagic cells was decreased in response to PAHs distinct from BP such as dimethylbenz(a)anthracene and 3-methylcholanthrene, which interact, like BP, with the arylhydrocarbon receptor (AhR) known to mediate many PAH effects. In contrast, benzo(e)pyrene, a PAH not activating AhR, had no effect. In addition, AhR was demonstrated to be present and functional in cultured monocytic cells, and the use of its antagonist α-naphtoflavone counteracted inhibitory effects of BP toward macrophagic differentiation. Overall, these data demonstrate that exposure to PAHs inhibits functional in vitro differentiation of blood monocytes into macrophages, likely through an AhR-dependent mechanism. Such an effect may contribute to the immunotoxicity of these environmental carcinogens owing to the crucial role played by macrophages in the immune defense.

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Polycyclic Aromatic Hydrocarbons: Metabolism, Activation and Tumour Initiation

Cited by 87 publications

References 167 publications

A Critical Evaluation of DNA Adducts as Biological Markers for Human Exposure to Polycyclic Aromatic Compounds

A Critical Evaluation of DNA Adducts as Biological Markers for Human Exposure to Polycyclic Aromatic Compounds

Electrophilic tissue burden in male Sprague-Dawley rats following repeated exposure to binary mixtures of polycyclic aromatic hydrocarbons

Polycyclic Aromatic Hydrocarbons Inhibit Differentiation of Human Monocytes into Macrophages

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