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PubMed1986

Aerobic and anaerobic reduction of nitrated pyrenes in vitro.

Nitrated pyrenes are mutagenic and tumorigenic environmental pollutants that are activated to DNA-binding derivatives via nitroreduction. We have investigated the enzymatic nitroreduction of 1-nitropyrene, 1,3-, 1,6- and 1,8-dinitropyrene to determine if differences in the extent of nitroreduction may help explain differences in their biological potencies. Each nitrated pyrene was incubated aerobically and anaerobically with 105,000 X g supernatant (S105) from Salmonella typhimurium TA98 and the nitroreductase-deficient strain, TA98NR, and with cytosol and microsomes from rat and human liver. Under anaerobic conditions, 1-nitropyrene and 1,3-dinitropyrene were reduced by TA98 S105 to a lesser extent than 1,6- and 1,8-dinitropyrene. The extent of 1,6- and 1,8-dinitropyrene metabolism was not altered relative to TA98 when using TA98NR S105, but the nitroreduction of 1-nitropyrene and 1,3-dinitropyrene was decreased. Both rat and human liver cytosol and microsomes reduced 1,6- and 1,8-dinitropyrene to greater extents than 1-nitropyrene and 1,3-dinitropyrene. Under aerobic conditions rat and human liver cytosols were similar to TA98 S105 in that aminopyrene decreased while nitrosopyrene formation increased. By comparison, oxygen decreased the microsomal formation of both nitrosopyrenes and aminopyrenes. The reduction of succinoylated cytochrome c was measured during the hepatic metabolism of nitro- and nitrosopyrenes under aerobic conditions. The data indicated that reduced nitro- and nitrosopyrene intermediates were directly reducing succinoylated cytochrome c and that the assay could be used as a measure of aerobic nitroreduction. These studies demonstrate that 1,6- and 1,8-dinitropyrene are reduced to a greater extent than 1-nitropyrene and 1,3-dinitropyrene, which corresponds to their relative biological potencies as mutagens and carcinogens. Furthermore, although more extensive nitroreduction is detected under anaerobic conditions, the nitroreduction that occurs aerobically may be important for the mutagenic and tumorigenic properties of these compounds.

Animals↗
PubMed1986

Coinhibition of viral interferon induction by benzo[a]pyrene and chrysotile asbestos.

Benzo[a]pyrene (B[a]P) and its noncarcinogenic analog, benzo[e]pyrene (B[e]P), each in combination with chrysotile, were studied for their inhibitory effects on interferon (IFN) induction by influenza virus in rhesus monkey kidney (LLC-MK2) cell monolayers. B[a]P alone had no adverse effect on IFN induction; however, from 60 to 70% inhibition of IFN production occurred when B[a]P was enzymatically activated by rat liver S9. Chrysotile's inhibitory effect on the IFN process was similar in magnitude to that of activated B[a]P. The combination of activated B[a]P with chrysotile resulted in coinhibition of IFN induction which significantly exceeded (P less than 0.05) the inhibitory activity of the reagents tested alone or in other combinations. B[e]P alone or with S9 neither affected IFN induction nor was it capable of further enhancing chrysotile's inhibition of IFN synthesis. These findings provide further evidence of enhanced deleterious action by the combination of asbestos and activated B[a]P on a biological defense mechanism and further support the discriminatory power and credibility of the inhibition IFN induction assay for evaluating potential carcinogens.

Animals↗
PubMed1998

The oxidation of naphthalene and pyrene by cytochrome P450cam.

Mutants of the heme monooxygenase cytochrome P450cam in which Y96 had been replaced with hydrophobic residues, have been shown to oxidise naphthalene and pyrene with rates one to two orders of magnitude faster than the wild-type. Naphthalene was oxidised to 1- and 2-naphthol, probably via the 1,2-oxide intermediate. In the case of the Y96F mutant, naphthalene was oxidised at a rate comparable to camphor. Pyrene oxidation gave 1,6- and 1,8-pyrenequinone with no evidence for attack at the K-region, in contrast to mammalian enzymes. The results show that the Y96 residue plays a key role in controlling the substrate range of P450cam.

Camphor 5-Monooxygenase↗
PubMed1987

Reversed-phase high-performance liquid chromatographic separation of phenolic derivatives of benzo[a]pyrene, benz[a]anthracene, and chrysene with monomeric and polymeric C18 columns.

The separation of monohydroxylated derivatives (phenols) of benzo[a]pyrene, benz[a]anthracene, and chrysene was studied by reversed-phase high-performance liquid chromatography using a monomeric Zorbax ODS column and a polymeric Vydac C18 column. The Vydac C18 column resolved the phenols of each hydrocarbon with a wide range of retention times than the Zorbax ODS column. Four K-region phenols of benzo[a]pyrene are either not separated or marginally separated on both monomeric and polymeric columns. Other K-region and non-K-region phenols of all three hydrocarbons can be separated by using the monomeric and polymeric columns in combination.

Animals↗
PubMed2002

DNA adducts from a tumorigenic metabolite of benzo[a]pyrene block human RNA polymerase II elongation in a sequence- and stereochemistry-dependent manner.

Many carcinogens exert their cancer-causing effects by reacting with DNA either directly or following metabolic activation, resulting in covalently linked combination molecules known as carcinogen-DNA adducts. The presence of such lesions in the genome increases the error frequency of the replication machinery, causing mutations that contribute to the initiation and progression of cancer. Cellular DNA repair pathways remove carcinogen adducts from DNA, thus averting the mutagenic potential of many DNA lesions by reducing their presence in the genome. Bulky DNA adducts, like those derived from a number of activated environmental carcinogens such as polycyclic aromatic hydrocarbons (PAHs), are primarily repaired by the nucleotide excision repair (NER) pathway. Transcription-coupled NER (TC-NER) preferentially removes lesions from the transcribed strand of actively expressed genes, and RNA polymerase II stalled at the lesion quite possibly initiates the pathway. Among the bulky DNA adducts that are subject to TC-NER are those resulting from the reaction of the metabolically activated PAH benzo[a]pyrene (BP) with DNA. The P450 mixed-function oxygenases convert BP into a number of reactive intermediates, including tumorigenic (+)- and non-tumorigenic (-)-anti-benzo[a]pyrene diol epoxide (BPDE) that react with DNA via trans epoxide opening to form (+)-trans-anti-[BP]-N(2)-dG ((+)-ta[BP]G) and (-)-trans-anti-[BP]-N(2)-dG ((-)-ta[BP]G), respectively. To test the effect of these lesions on RNA synthesis, in vitro transcription assays using human nuclear extracts were performed with DNA templates containing an RNAPII promoter and a stereochemically pure (+)- or (-)-ta[BP]G adduct on the transcribed or non-transcribed strand. Transcription past (+)- or (-)-ta[BP]G adducts was investigated in the same sequence context to examine stereochemical effects. The (+)-ta[BP]G adduct was investigated in two different local sequence contexts to determine if the surrounding bases influence the adduct's ability to block transcription. These experiments revealed that (+)- and (-)-ta[BP]G adducts on the transcribed strand of the DNA template block RNAPII in a sequence and stereochemistry-dependent manner; however, adducts on the non-transcribed strand do not block elongation significantly but may increase pausing at innate pause sites. In order to elucidate biologically influential differences between the (+)- and (-)-ta[BP]G structures, the DUPLEX program was used to carry out potential energy minimization searches at model transcription junctions. The lowest-energy minimum for the (+)-ta[BP]G adduct gives a structure in which the benzo[a]pyrenyl ring system resides in the minor groove of the heteroduplex region. In contrast, the lowest-energy minimum for a (-)-ta[BP]G adduct shows an orientation in which the benzo[a]pyrenyl group adopts a carcinogen/base-stacked conformation. These conformational preferences may contribute to the differential treatment of (+)- and (-)-ta[BP]G adducts by human RNAPII. In addition, while previous experiments showed that BPDE adducts cause T7RNAP to produce a ladder of truncated transcripts, RNAPII is blocked entirely at only one or two positions by the (+)- and (-)-ta[BP]G adducts, depending on sequence context. It is likely that these differences between the behaviors of T7RNAP and human RNAPII are a result of the structural characteristics of the enzymes' active sites, a hypothesis that is explored in light of their known crystal structures.

Autoradiography↗
PubMed2003

Extending the understanding of mutagenicity: structural insights into primer-extension past a benzo[a]pyrene diol epoxide-DNA adduct.

DNA polymerase enzymes employ a number of innate fidelity mechanisms to ensure the faithful replication of the genome. However, when confronted with DNA damage, their fidelity mechanisms can be evaded, resulting in a mutation that may contribute to the carcinogenic process. The environmental carcinogen benzo[a]pyrene is metabolically activated to reactive intermediates, including the tumorigenic (+)-anti-benzo[a]pyrene diol epoxide, which can attack DNA at the exocyclic amino group of guanine to form the major (+)-trans-anti-[BP]-N(2)-dG adduct. Bulky adducts such as (+)-trans-anti-[BP]-N(2)-dG primarily block DNA replication, but are occasionally bypassed and cause mutations if paired with an incorrect base. In vitro standing-start primer-extension assays show that the preferential insertion of A opposite (+)-trans-anti-[BP]-N(2)-dG is independent of the sequence context, but the primer is extended preferentially when dT is positioned opposite the damaged base in a 5'-CG*T-3' sequence context. Regardless of the base positioned opposite (+)-trans-anti-[BP]-N(2)-dG, extension of the primer past the lesion site poses the greatest block to polymerase progression. In order to gain insight into primer-extension of each base opposite (+)-trans-anti-[BP]-N(2)-dG, we carried out molecular modeling and 1.25 ns unrestrained molecular dynamics simulations of the adduct in the +1 position of the template within the replicative pol I family T7 DNA polymerase. Each of the four bases was modeled at the 3' terminus of the primer, incorporated opposite the adduct, and the next-to-be replicated base was in the active site with its Watson-Crick partner as the incoming nucleotide. As in our studies of nucleotide incorporation, (+)-trans-anti-[BP]-N(2)-dG was modeled in the syn conformation in the +1 position, with the BP moiety on the open major groove side of the primer-template duplex region, leaving critical protein-DNA interactions intact. The present work revealed that the efficiency of primer-extension past this bulky adduct opposite each of the four bases in the 5'-CG*T-3' sequence can be rationalized by the stability of interactions between the polymerase protein, primer-template DNA and incoming nucleotide. However, the relative stabilization of each nucleotide opposite (+)-trans-anti-[BP]-N(2)-dG in the +1 position (T > G > A > or = C) differed from that when the adduct and partner were the nascent base-pair (A > T > or = G > C). In addition, extension past (+)-trans-anti-[BP]-N(2)-dG may pose a greater block to a high fidelity DNA polymerase than does nucleotide incorporation opposite the adduct because the presence of the modified base-pair in the +1 position is more disruptive to the polymerase-DNA interactions than it is within the active site itself. The dN:(+)-trans-anti-[BP]-N(2)-dG base-pair is strained to shield the bulky aromatic BP moiety from contact with the solvent in the +1 position, causing disruption of protein-DNA interactions that would likely result in decreased extension of the base-pair. These studies reveal in molecular detail the kinds of specific structural interactions that determine the function of a processive DNA polymerase when challenged by a bulky DNA adduct.

Bacteriophage T7↗
PubMed1988

Molecular orbital study on the metabolic pathway through the diol epoxide form of carcinogenic benzene in comparison with benzo[a]pyrene.

The stabilization energy for the hydronium-ion-catalyzed hydrolysis of benzene diol epoxide (BDE) in the configuration of anti- or syn-form has been estimated by using the semi-empirical molecular orbital calculations with the CNDO/2 method. The values for the formation of carbonium ion from BDE are compared with those from benzo[a]pyrene, and it is suggested that the anti-form BDE belongs to a relatively strong reactive group with benzo[a]pyrene and benz[a]anthracene. The reactivity of BDE to the cation is completely different from that of polycyclic aromatic hydrocarbon diol epoxides (PAHDEs) from the viewpoint of the electronic structure; the cation from the anti-form BDE has a three center-four electron bond, whereas cations from PAHDEs do not have such a bond and the aromaticity still remains.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed2001

Genetic alteration of chromosome 8 is a common feature of human mammary epithelial cell lines transformed in vitro with benzo[a]pyrene.

While some epidemiological risk factors for breast cancer have been identified, the environmental factors responsible for transformation of mammary epithelial cells are not clear. We have exposed the spontaneously immortalized human mammary epithelial cell line MCF-10A to benzo[a]pyrene and selected transformed clones based on a loss of contact inhibition and anchorage-dependent growth. Cytogenetic studies showed that each of the transformed sublines possess an isochromosome 8q aberration. The c-Myc proto-oncogene, which is positioned at 8q24, was analyzed for changes in expression. Both c-Myc mRNA and protein levels were increased in the transformed clones relative to the parental cells. The transformed clones were not able to grow as tumors in vivo when injected into nude or SCID mice. To determine whether the involvement of chromosome 8 in BP-induced mutagenesis was a reproducible event, transformed clones were selected from three additional independently treated sets of BP-exposed MCF-10A cultures and analyzed by spectral karyotyping (SKY). These transformed sublines also harbored the isochromosome 8q abnormality. Data from this model show that benzo[a]pyrene, a ubiquitous procarcinogen, can induce selectable morphologic changes in a human mammary epithelial cell line, and that these transformed cells possess chromosomal aberrations frequently found in human breast tumors.

Animals↗
PubMed2003

Photocatalytic reactions of pyrene at TiO2/water interfaces.

The photocatalytic oxidation of pyrene preadsorbed on TiO2 is examined in aqueous suspension under UV irradiation. Chemical oxygen demand measurements, UV-VIS spectrophotometer, infrared spectrometer and GC-MS analytical techniques were used to monitor the formed intermediates. During the oxidation processes, the ring-open reaction, hydroxylation and ketolysis occurred to produce some intermediate products (4-oxapyrene-5-one, 1,6- or 1,8-pyrenediones, 4,5-phenanthrenedialdehyde, cyclopenta[def]phenanthrene). Some factors affecting the photodegradation rate were also studied. The results were different from other studies: The pH of the dispersion, ratio of Py/TiO2:water had little effect on the photooxidation rate of pyrene catalyzed by TiO2, while the surface coverage, addition of Fe3+ affected it greatly.

Adsorption↗
PubMed1999

An experimental design to probe the interactions of dissolved organic matter and xenobiotics: bioavailability of pyrene and 2,2',5,5'-tetrachlorobiphenyl to Daphnia magna.

Experiments were conducted to probe the interactions between natural dissolved organic matter (DOM) and two xenobiotics, and to determine how DOM influences their bioavailability. The experimental set-up, using dialysis bags, was designed to expose test organisms to the same constant concentration of free dissolved chemical, while increasing the concentration of the bound-to-DOM fraction. Daphnia magna S. were exposed to pyrene or 2,2',5,5'-tetrachlorobiphenyl in the presence of 0, 1, 2, 5, 10 or 20 mg L(-1) of a reference riverine humic acid (Suwannee River Humic Acid). The physico-chemical parameters were well constrained in the microcosm, demonstrating its potential usefulness. However bioaccumulation by D. magna showed important variability between replicate treatments, sufficient to mask any trends as a function of DOM concentration. The organic-carbon-normalised partition coefficients (K(OC)) ranged from 52000 to 92000 L kg(-1) for pyrene and from 8200 to 89000 L kg(-1) for 2,2',5,5'-tetrachlorobiphenyl, with a marked "concentration effect" for the latter compound.

Animals↗
PubMed2000

The nitration of pyrene adsorbed on silica particles by nitrogen dioxide.

Conversion of NO2, HNO2 gas, their mixture and a mixed gas of HNO2 and HNO3 on silica particles was investigated under simulated atmospheric conditions. Both HNO2 and HNO3 were detected as the products from conversion of NO2 on silica particles. However, unlike HNO3, which increased with conversion time, HNO2 underwent an increase-decrease time course due to the increased HNO3 further transformed HNO2 into NO+ on silica particles. Considering the catalytic effect of HNO3 and HNO2 on the nitration of pyrene adsorbed on silica particles by NO2, another electrophilic nitration path, analogous to the one that we previously reported, with NONO2+ and NON2O4+ as electrophiles was suggested. The two paths together gave an appropriate explanation for the catalytic effect of HNO2, HNO3 and their mixed gas on the nitration of the adsorbed pyrene by NO2.

Adsorption↗
PubMedDate not supplied

Total oxyradical scavenging capacity and cell membrane stability of haemocytes of the Arctic scallop, Chlamys islandicus, following benzo(a)pyrene exposure.

Industrial activities, notably oil and gas industries, are expanding in the Arctic. Most of the biomarkers were developed using temperate organisms living at temperatures above 10 degrees C. Little is known about the biomarker responses of organisms living between -1.88 and 5 degrees C. Therefore, assessment of the toxicity of chemicals to cold-water adapted species is required. In this study, the Arctic scallop, Chlamys islandicus, was selected as a key species for bio-monitoring because of wide distribution in Arctic waters and its commercial value. Test animals, stored in seawater at 2 degrees C, were injected with benzo(a)pyrene (diluted in cod liver oil 5 mg ml(-1)) in the adductor muscle every 24 h for four days giving a final dose of 0, 74 and 90.6 mg kg(-1) wet weight for control, low and high dose, respectively. The biomarkers used were total oxyradical scavenging capacity (TOSC) in the digestive gland and cell membrane stability of haemocytes. TOSC values were significantly reduced (ca. 30%) in exposed groups (P < 0.05), indicating a depletion in oxyradical molecular scavengers. The antioxidant defences appeared to be overwhelmed by the reactive oxygen species as the plasma membranes of haemocytes were destabilised (P < 0.05) probably due to lipid peroxidation. These data indicate that reactive oxygen species (ROS) were produced by Arctic scallops via the metabolisation of benzo(a)pyrene at 2 degrees C.

Adaptation, Physiological↗
PubMedDate not supplied

The Japanese medaka (Oryzias latipes) model: applicability for investigating the immunosuppressive effects of the aquatic pollutant benzo[a]pyrene (BaP).

Despite the fact that BaP is a carcinogen, mammalian immunosuppressant, and ubiquitous aquatic pollutant, knowledge regarding the effects of BaP on the immune system of fish is still lacking. To begin to fill this gap, studies were conducted in medaka to examine the effects and mechanisms by which BaP exposure might alter host immunocompetence. Fish, exposed by IP injection of BaP (2-600 microg/g BW), were examined after 48 h for effects upon immune function and CYP1A expression/activity. Benzo[a]pyrene, at a concentration below that which increased levels of CYPIA expression/activity (2 microg BaP/g BW) suppressed lymphocyte proliferation. Concentrations of BaP at 20 and 200 microg/g BW. suppressed antibody-forming cell (AFC) numbers, superoxide production, and host resistance against bacteria. In contrast, exposure to the low affinity aryl hydrocarbon receptor (AhR) agonist, benzo[e]pyrene (BeP), neither induced CYP1A expression nor altered immune function. Given the lack of immunosuppressive effects produced by BeP, and the fact that exposure to the AhR antagonist (and CYP1A inhibitor) alpha-naphthoflavone (ANF) ameliorated the suppressive effects of BaP upon AFC numbers, the AhR pathway (including CYP1A-mediated production of reactive BaP metabolites) appears important in mediating BaP-induced immunotoxicity in fish, as in mammals. In the past, the medaka has proven a successful model for assessing carcinogenic agents. These studies have demonstrated its utility for also determining the immunosuppressive effects of an important aquatic contaminant.

Animals↗
PubMed1996

Stability of benzo[a]pyrene DNA adducts in rat tissues during their long-term storage at -20 degrees C or -80 degrees C.

The aim of this study was to examine whether the storage of tissues at -80 degrees C or -20 degrees C affects the benzo[a]pyrene (B[a]P)-derived DNA adduct pattern and levels in rat tissues. Three rats were treated orally with a single dose of 100 mg B[a]P/kg b.w. and killed 24 h later. White blood cells (WBC) were isolated from the fresh blood. Livers, lungs and hearts were immediately removed, dissected into small fragments and were pooled for each organ. Pooled samples were proportionally divided into 7 aliquots. DNA from the first aliquot was immediately isolated (time 0). The other aliquots were frozen and stored at -20 degrees C or at -80 degrees C. DNA was isolated from the frozen samples at 1, 5 and 10 months later. 32P-postlabeling analysis was performed at the beginning and at the end of study with the whole set of samples. Two B[a]P-derived adducts were detected in all tissues but with different intensities for different tissue types. One of the adducts was found predominantly in WBC (approximately 85%) and liver (approximately 68%), while heart and lung accounted only for approximately 43% and approximately 39%, respectively. This adduct was tentatively identified as benzo[a]pyrene diol-epoxide-N2 adduct (BPDE-N2-dG) based on TLC and HPLC analyses of 32P-postlabeled adducts. The highest total DNA adduct level (sum of 2 spots) was found in lung (4.90 adducts/10(8) nucleotides) compared with heart, liver and WBC (3.55, 2.37 and 2.32 adducts/10(8) nucleotides, respectively). The analysis of variance provided evidence that storage of tissues at -20 degrees C or at -80 degrees C up to 10 months did not significantly affect B[a]P DNA adduct levels and patterns in the rat lung, heart and liver. Our study indicates that properly stored tissues can be used for DNA adduct analysis with confidence.

Animals↗
PubMed2001

Persistence of benzo[a]pyrene--DNA adducts in hematopoietic tissues and blood of the mummichog, Fundulus heteroclitus.

The formation and persistence of benzo[a]pyrene (B[a]P)-DNA adducts were investigated in blood, liver and two hematopoietic tissues (anterior kidney and spleen) of the mummichog (Fundulus heteroclitus). Fish were injected with a single, sublethal dose of B[a]P (12 mg/kg body weight) and sampled from 8 to 96 days post-injection. 32P-Postlabeling analysis and storage phosphor imaging were used to resolve and quantify hydrophobic DNA adducts. One major DNA adduct was present in each of the examined tissues at all sampling times. This adduct had similar chromatographic characteristics to those of the adduct standard, 7R,8S,9S-trihydroxy-10S-(N(2)-deoxyguanosyl-3'-phosphate)-7,8,9,10-tetrahydro-benzo[a]pyrene (B[a]PDE-dG). Minor DNA adduct spots, representing less than 2% of the total DNA adducts, were observed in some liver, anterior kidney and spleen samples for up to 32 days post-injection. The B[a]P-DNA adducts reached maximal levels at 32 days post-injection and persisted for at least 96 days in all examined tissues. B[a]P-DNA adduct levels were significantly higher in the liver and anterior kidney than in the spleen from 16 to 96 days (P<0.001), although liver and anterior kidney DNA adduct levels were not significantly different at any time. This is the first controlled study to demonstrate the formation and persistence of B[a]P-DNA adducts in hematopoietic tissues and blood of fishes exposed to the prototypical polycyclic aromatic hydrocarbon, B[a]P. Although persistent DNA adducts are generally recognized as potential initiators of carcinogenic processes, adducts in these vital tissues may also lead to disruption of physiological functions such defense mechanisms and hematopoiesis.

Animals↗
PubMed1997

Inhibition of benzo[a]pyrene-induced mouse forestomach neoplasia and reduction of H2O2 concentration in human polymorphonuclear leucocytes by flavour components of Japanese-style fermented soy sauce.

Previously it was reported that 4-hydroxy-2 (or 5)-ethyl-5 (or 2)-methyl-3(2H)-furanone (HEMF), a characteristic flavour component of Japanese-style fermented soy sauce that exhibits antioxidant activity, inhibits benzo[a]pyrene-induced forestomach neoplasia in mice. The antioxidant and anticarcinogenic activities of other structurally similar soy sauce flavour components are now reported. 4-Hydroxy-5-methyl-3(2H)-furanone (HMF) and 4-hydroxy-2,5-dimethyl-3(2H)-furanone (HDMF) were found to be antioxidants. In particular, HMF and HDMF (as well as HEMF) reduced hydrogen peroxide concentration in human polymorphonuclear leucocytes stimulated by arachidonic acid or 12-O-tetradecanoylphorbol-13-acetate. HMF and HDMF were administered individually in semipurified diet to female ICR mice previously treated with benzo[a]pyrene (1.5 mg/wk, orally for 4 wk) to initiate forestomach neoplasia. The mice were killed at 30 wk of age. Both furanones reduced forestomach neoplasms, with HDMF exhibiting more potency. The data indicate that HDMF and HMF, like HEMF, inhibit carcinogenesis in this system by acting at the post-initiation stage.

Animals↗
PubMed2000

Potentiation of benzo[a]pyrene-induced pulmonary and forestomach tumorigenesis in mice by D,L-buthionine-S,R-sulfoximine-mediated tissue glutathione depletion.

In vitro studies have suggested that the glutathione (GSH) S-transferase (GST)-catalyzed GSH conjugation is an important mechanism for the detoxification of (+)-anti-7,8-dihydroxy-9, 10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene [(+)-anti-BPDE], which is the activated form of the widespread environmental pollutant benzo[a]pyrene (BP). However, in vivo experimental evidence for the importance of GSH/GST system in defense against carcinogenic effects of BP is lacking. We hypothesized that if GSH/GST were to play an important role in the detoxification of (+)-anti-BPDE, the tumorigenic activity of BP would be increased by depleting the levels of GSH, which is the required nucleophilic substrate for GST-catalyzed conjugation reactions. In the present study, we have tested the above hypothesis by determining the effect of D, L-buthionine-S,R-sulfoximine (BSO)-mediated tissue GSH depletion on BP-induced tumorigenesis of the lung and forestomach in female A/J mice. Treatment of mice with three i.p. injections of 2.5 mmol BSO/kg (12 h apart) plus 20 mM BSO in drinking water, resulted in a statistically significant reduction in hepatic, pulmonary and forestomach GSH levels. At the same time, BSO-administration caused a statistically significant increase in BP-induced pulmonary and forestomach tumor multiplicity. To the best of our knowledge, the present study is the first report that provides in vivo experimental evidence for the importance of GSH/GST system in cellular protection against carcinogenic effects of BP.

Animals↗
PubMed2000

High mobility group 1 and 2 proteins bind preferentially to DNA that contains bulky adducts induced by benzo[a]pyrene diol epoxide and N-acetoxy-acetylaminofluorene.

High mobility group (HMG) proteins 1 and 2 are abundant non-histone chromosomal proteins that bind preferentially DNA that is bent or underwound. Previous studies have shown that these proteins preferentially bind to DNA damaged by the crosslinking agents cis-diammine-dichloro-platinum(II), chromium(III) and UV-C radiation. Here we have studied the binding of HMG-1/2 proteins to a duplex oligonucleotide damaged by benzo(a)pyrene diol epoxide or N-acetoxy-acetylaminofluorene using an electrophoretic mobility shift assay. Both chemicals induce monoadducts that are known to distort DNA structure. The affinities of HMG-1/2 for DNA damaged by benzo[a]pyrene diol epoxide or N-acetoxy-acetylaminofluorene were similar to that for UV-irradiated DNA, which were an order of magnitude higher than for undamaged DNA. In contrast, DNA modified by dimethyl sulfate was not preferentially recognised by HMG-1/2.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗