Chlorophyll catalyse the photo-transformation of carcinogenic benzo[a]pyrene in water.
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ABSTRACT:
SUBMITTER: Luo L
PROVIDER: S-EPMC4523946 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Polycyclic aromatic hydrocarbons (PAHs), such as benzo[a]pyrene (BaP), are ubiquitous environmental contaminants that are implicated in causing lung cancer. BaP is a component of tobacco smoke that is transformed enzymatically to active forms that interact with DNA. We reported previously development of a sensitive stable isotope dilution LC/MS method for analysis of BaP metabolites. We now report efficient syntheses of 13C4-BaP and the complete set of its 13C4-labelled oxidized metabolites needed as internal standards They include the metabolites not involved in carcinogenesis (Group A) and the metabolites implicated in initiation of cancer (Group B). The synthetic approach is novel, entailing use of Pd-catalyzed Suzuki, Sonogashira, and Hartwig cross-coupling reactions combined with PtCl2-catalyzed cyclization of acetylenic compounds. This synthetic method requires fewer steps, employs milder conditions, and product isolation is simpler than conventional methods of PAH synthesis. The syntheses of 13C4-BaP and 13C4-BaP-8-ol each require only four steps, and the 13C-atoms are all introduced in a single step. 13C4-BaP-8-ol serves as the synthetic precursor of all the oxidized metabolites of 13C-BaP implicated in initiation of cancer. The isotopic purities of the synthetic 13C4-BaP metabolites were estimated to be ?99.9%.
| S-EPMC3826453 | biostudies-literature
Project description:The formation of polycyclic aromatic hydrocarbons (PAHs) is a strong global concern due to their harmful effects. To help the reduction of their emissions, a crucial understanding of their formation and a deep exploration of their growth mechanism is required. In the present work, the formation of benzo(a)pyrene was investigated computationally employing chrysene and benz(a)anthracene as starting materials. It was assumed a type of methyl addition/cyclization (MAC) was the valid growth mechanism in this case. Consequently, the reactions implied addition reactions, ring closures, hydrogen abstractions and intramolecular hydrogen shifts. These steps of the mechanism were computed to explore benzo(a)pyene formation. The corresponding energies of the chemical species were determined via hybrid density funcional theory (DFT), B3LYP/6-31+G(d,p) and M06-2X/6-311++G(d,p). Results showed that the two reaction routes had very similar trends energetically, the difference between the energy levels of the corresponding molecules was just 6.13 kJ/mol on average. The most stable structure was obtained in the benzo(a)anthracene pathway.
| S-EPMC6470522 | biostudies-literature
Project description:Twenty-eight days after the initial seeding, the terminally differentiated HepaRG cells were treated with 2 µM benzo[a]pyrene (B[a]P) and benzo[e]pyrene (B[e]P) for 72 hours. Following the treatment, the cells were harvested by mild trypsinization, washed in phosphate-buffered saline, and immediately frozen at −80°C for subsequent analyses. Gene expression profiles in the HepaRG cells treated with B[a]P and B[e]P were investigated using Agilent whole genome 8x60K human microarrays according to the manufacturer’s instructions.
2018-07-24 | GSE117476 | GEO
Project description:Benzo(a)pyrene (BaP) is a ubiquitously distributed environmental pollutant and known carcinogen, which can induce malignant transformation in rodent and human cells. Poly(ADP-ribose) glycohydrolase (PARG), the primary enzyme that catalyzes the degradation of poly(ADP-ribose) (PAR), has been known to play an important role in regulating DNA damage repair and maintaining genomic stability. Although PARG has been shown to be a downstream effector of BaP, the role of PARG in BaP induced carcinogenesis remains unclear. In this study, we used the PARG-deficient human bronchial epithelial cell line (shPARG) as a model to examine how PARG contributed to the carcinogenesis induced by chronic BaP exposure under various concentrations (0, 10, 20 and 40 ?M). Our results showed that PARG silencing dramatically reduced DNA damages, chromosome abnormalities, and micronuclei formations in the PARG-deficient human bronchial epithelial cells compared to the control cells (16HBE cells). Meanwhile, the wound healing assay showed that PARG silencing significantly inhibited BaP-induced cell migration. Furthermore, silencing of PARG significantly reduced the volume and weight of tumors in Balb/c nude mice injected with BaP induced transformed human bronchial epithelial cells. This was the first study that reported evidences to support an oncogenic role of PARG in BaP induced carcinogenesis, which provided a new perspective for our understanding in BaP exposure induced cancer.
| S-EPMC4803271 | biostudies-literature
Project description:A diastereoselective synthesis of the nucleoside adducts corresponding to a cis ring-opening of the carcinogen (+/-)-7 beta, 8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BaP DE-2) by 2'-deoxyadenosine and 2'-deoxyguanosine is described. The key intermediate (+/-)-10alpha-amino-7beta,8alpha,9alpha-trihydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene was synthesized by a highly diastereoselective dihydroxylation wherein phenylboronic acid was a water surrogate. The resulting boronate ester was converted to a tetraol derivative in which two of the four hydroxyl groups (trans 7, 8) were protected as benzoate esters while the remaining two (cis 9, 10) were free. The cis glycol entity was then subjected to a reaction with 1-chlorocarbonyl-1-methylethylacetate to yield an intermediate chloro monoacetoxy dibenzoate. Displacement of the halide with azide, complete cleavage of the esters, and catalytic reduction of the azide yielded the requisite amino triol. Fluoride displacement from appropriately protected nucleoside derivatives, 6-fluoropurine 2'-deoxyribonucleoside and 2-fluoro-2'-deoxyinosine, by the amino triol then yielded diastereomeric pairs of diol epoxide-adducted 2'-deoxyadenosine (dA) and 2'-deoxyguanosine (dG) nucleosides. Small aliquots of these adducts were separated for characterization purposes. The present approach provides the first diastereoselective synthesis of the cis adducts of BaP DE-2 with 2'-deoxyguanosine as well as the first synthesis of both dA and dG adducts from a common intermediate. An informative analysis of the 1H NMR spectra of the cis adducts synthesized and comparisons to the trans adducts are reported. To gain insight into the diastereoselectivity in the key dihydroxylation step, a computational analysis, including molecular mechanics (MMFF94) and semiempirical AM1 geometry optimizations, yielded results that are in fairly good agreement with the experimental observations.
| S-EPMC2659345 | biostudies-literature
Project description:Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental pollutants produced in the combustion of organic matter. PAHs are present in automobile exhaust and tobacco smoke, and they have recently been designated as human carcinogens. Current evidence indicates that PAHs are activated enzymatically to mutagenic metabolites that interact with DNA. There is evidence for three pathways of activation: the diol epoxide path, the radical-cation path, and the quinone path. The relative importance of these paths for human lung cancer has not been established. We now report syntheses of the principal phenol and quinone isomers of the prototype PAH carcinogen benzo[a]pyrene (BP) that are known or are suspected to be formed as metabolites of BP in human bronchoalveolar cells. The methods of synthesis were designed to be adaptable to the preparation of the (13)C-labeled analogues of the BP metabolites. These compounds are needed as standards for sensitive LC-MS/MS methods for analysis of BP metabolites formed in lung cells. Efficient novel syntheses of the 1-, 3-, 6-, 9-, and 12-BP phenols and the BP 1,6-, 3,6-, 6,12-, and 9,10-quinones are now reported. The syntheses of the BP phenols (except 6-HO-BP) involve the key steps of Pd-catalyzed Suzuki-Miyaura cross-coupling of a naphthalene boronate ester with a substituted aryl bromide or triflate ester. The BP quinones were synthesized from the corresponding BP phenols by direct oxidation with the hypervalent iodine reagents IBX or TBI. These reagents exhibited different regiospecificities. IBX oxidation of the 7- and 9-BP phenols provided the ortho-quinone isomers (BP 7,8- and 9,10-diones, respectively), whereas TBI oxidation of the 1-, 3-, and 12-BP phenols furnished BP quinone isomers with carbonyl functions in separate rings (BP 1,6-, 3,6-, and 6,12-diones, respectively).
| S-EPMC3418794 | biostudies-literature
Project description:Persistent and ubiquitous organic pollutants, such as the polycyclic aromatic hydrocarbon benzo[⍺]pyrene (BaP), represent a major threat to aquatic organisms and human health. Beside some well-documented adverse effects on the development and reproduction of aquatic organisms, BaP was recently shown to affect fish bone formation and skeletal development through mechanisms that remain poorly understood. In this work, several bone-related in vivo assays were used in zebrafish to evaluate the osteotoxic effects of BaP during bone development and regeneration. Exposure to BaP for 3 days induced a dose-dependent reduction of the size of the opercular bone in 6 days post-fertilization (dpf) larvae, and affected osteoblast maturation as observed by the expression of the mature marker, osteocalcin. Exposure to BaP for 27 days affected the development of the axial skeleton and increased the incidence and severity of skeletal deformities. During bone regeneration, BaP affected the mineralization of newly formed fin rays and scales, while it impaired fin ray patterning and scale shape, through mechanisms that may involve an imbalance of bone remodeling. Transcriptomic and gene expression analyses indicate that BaP induced the activation of xenobiotic and metabolic pathways, while negatively impacting extracellular matrix formation and organization. Interestingly, BaP exposure positively regulated inflammation markers in 6 dpf larvae and increased neutrophil recruitment. A direct interaction between neutrophils and bone extracellular matrix or bone forming cells was observed in vivo, suggesting a role for neutrophils in the mechanisms underlying BaP osteotoxicity. Our work provides novel data on the cellular and molecular players involved in BaP osteotoxicity and brings new insights into a possible role for neutrophils in inflammatory bone reduction.
2024-04-29 | GSE174529 | GEO
Project description:Benzo[a]pyrene (B[a]P), a major human carcinogen in combustion products such as cigarette smoke and diesel exhaust, is metabolically activated into DNA-reactive metabolites via three different enzymatic pathways. The pathways are the anti-(+)-benzo[a]pyrene 7,8-diol 9,10-epoxide pathway (P450/epoxide hydrolase catalyzed) (B[a]PDE), the benzo[a]pyrene o-quinone pathway (aldo ketose reductase (AKR) catalyzed) and the B[a]P radical cation pathway (P450 peroxidase catalyzed). We used a yeast p53 mutagenesis system to assess mutagenesis by B[a]P radical cations. Because radical cations are short-lived, they were generated in situ by reacting B[a]P with cumene hydroperoxide (CuOOH) and horse radish peroxidase (HRP) and then monitoring the generation of the more stable downstream products, B[a]P-1,6-dione and B[a]P-3,6-dione. On the basis of B[a]P-1,6 and 3,6-dione formation, approximately 4 ?M of radical cation was generated. In the mutagenesis assays, the radical cations produced in situ showed a dose-dependent increase in mutagenicity from 0.25 ?M to 10 ?M B[a]P with no significant increase seen with further escalation to 50 ?M B[a]P. However, mutagenesis was 200-fold less than with the AKR pathway derived B[a]P, 7-8-dione. Mutant p53 plasmids, which yield red colonies, were recovered from the yeast to study the pattern and spectrum of mutations. The mutation pattern observed was G to T (31%) > G to C (29%) > G to A (14%). The frequency of codons mutated by the B[a]P radical cations was essentially random and not enriched at known cancer hotspots. The quinone products of radical cations, B[a]P-1,6-dione and B[a]P-3,6-dione were more mutagenic than the radical cation reactions, but still less mutagenic than AKR derived B[a]P-7,8-dione. We conclude that B[a]P radical cations and their quinone products are weakly mutagenic in this yeast-based system compared to redox cycling PAH o-quinones.
| S-EPMC3650728 | biostudies-literature
Project description:Exposure to environmental polycyclic aromatic hydrocarbons (PAHs), such as benzo(a)pyrene (B(a)P), has been linked to several health-threatening risks. PAHs were also shown to hinder adrenergic receptor (ADR) responses. As we previously demonstrated that B(a)P can directly interact with the ?2ADR, we investigated here whether B(a)P could decrease ?2ADR responsiveness by triggering receptor desensitization phenomena. We firstly showed that exposure to B(a)P reduced ?2ADR-mediated epinephrine-induced induction of NR4A gene mRNAs and of intracellular cAMP. Analysis of ?2ADR protein expression demonstrated that B(a)P rapidly decreased membrane expression of ?2ADR with a subsequent degradation of receptor protein. B(a)P exposure concomitantly rapidly increased the ?2ADR mRNA levels. The use of the ?-blockers, propranolol and ICI 118.551, demonstrated the involvement of ?2ADR itself in this increase. However, sustained exposure to B(a)P induced a diminution of ?2ADR mRNA steady-state as a result of the acceleration of its degradation. Together, these results show that, beside the well-known activation of the aryl hydrocarbon receptor, PAH deleterious effects may involve the dysfunction of adrenergic responses through, in part, the desensitization of ?2ADR. This may be taken in consideration when ?2-agonists/antagonists are administered in patients exposed to important concentrations of PAHs, e.g. in cigarette smokers.
| S-EPMC5468268 | biostudies-literature
Project description:The Water-Soluble Chlorophyll Protein (WSCP) of Brassicaceae is a remarkably stable tetrapyrrole-binding protein that, by virtue of its simple design, is an exceptional model to investigate the interactions taking place between pigments and their protein scaffold and how they affect the photophysical properties and the functionality of the complexes. We investigated variants of WSCP from Lepidium virginicum (Lv) and Brassica oleracea (Bo), reconstituted with Chlorophyll (Chl) b, to determine the mechanisms by which the different Chl binding sites control their Chl a/b specificities. A combined Raman and crystallographic investigation has been employed, aimed to characterize in detail the hydrogen-bond network involving the formyl group of Chl b. The study revealed a variable degree of conformational freedom of the hydrogen bond networks among the WSCP variants, and an unexpected mixed presence of hydrogen-bonded and not hydrogen-bonded Chls b in the case of the L91P mutant of Lv WSCP. These findings helped to refine the description of the mechanisms underlying the different Chl a/b specificities of WSCP versions, highlighting the importance of the structural rigidity of the Chl binding site in the vicinity of the Chl b formyl group in granting a strong selectivity to binding sites.
| S-EPMC6890793 | biostudies-literature