SEARCH · PubMed Health

Results for “Pyrenes”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 163 records · Page 9Linked to original sources

PubMedDate not supplied

32P-postlabeling analysis of the DNA adducts of 6-fluorobenzo[a]pyrene and 6-methylbenzo[a]pyrene formed in vitro.

Studies of benzo[a]pyrene (BP) and selected derivatives are part of the strategy to elucidate mechanisms of tumor initiation by polycyclic aromatic hydrocarbons. Substitution of BP at C-6 with fluorine to form 6-fluorobenzo[a]pyrene (6-FBP) or a methyl group to form 6-methylbenzo[a]pyrene (6-CH3BP) decreases tumorigenicity compared to BP. BP, 6-FBP, and 6-CH3BP formed adducts with DNA when (1) they were activated by 3-methylcholanthrene-induced rat liver microsomes, (2) they were activated by horseradish peroxidase (HRP), (3) their 7,8-dihydrodiols were activated by microsomes, or (4) the radical cation of BP, 6-FBP, or 6-CH3-BP was directly reacted with DNA. With microsomes, 6.5 mumol of [3H]6-FBP/mol of DNA-P and 10 mumol of [14C]6-CH3BP/mol of DNA-P were bound vs 15 mumol of [3H]BP. With microsomes, two major 6-FBP adducts and some minor adducts were obtained. One major adduct coincided with that from 6-FBP-7,8-dihydrodiol. With microsomes, the minor 6-FBP adducts coincided with the adducts obtained from 6-FBP radical cation plus DNA and the major adduct of HRP-activated 6-FBP. With microsomes, 6-CH3BP showed adducts similar to some formed with HRP and one from 6-CH3BP radical cation. 6-CH3BP-7,8-dihydrodiol produced a small amount of one adduct that did not coincide with any from 6-CH3BP. The adducts of 6-FBP appear to be formed mostly through the diolepoxide pathway, whereas those of 6-CH3BP appear to arise mostly via one-electron oxidation.

Animals↗

PubMedDate not supplied

Adducts of 6-methylbenzo[a]pyrene and 6-fluorobenzo[a]pyrene formed by electrochemical oxidation in the presence of deoxyribonucleosides.

Studies of the DNA adducts of benzo[a]pyrene and selected derivatives are part of the strategy to elucidate mechanisms of tumor initiation by aromatic hydrocarbons. Reference adducts formed by reaction of deoxyribonucleosides with electrophilic intermediates of 6-fluorobenzo[a]pyrene (6-FBP) and 6-methylbenzo[a]pyrene (6-CH3BP) are investigated here because they are essential for identifying the structures of adducts formed in biological systems. Electrochemical oxidation of 6-FBP in the presence of deoxyribonucleosides led to adducts from the 6-FBP radical cation. With dG, a mixture of 6-FBP bound at C-1 or C-3 to the N-7 of Gua was formed in 10% yield, whereas 6-FBP plus dC gave a mixture of 3-(6-FBP-1-yl)Cyt and 3-(6-FBP-3-yl)Cyt (15%). No adducts of 6-FBP were formed with dA or dT. Electrochemical oxidation of 6-CH3BP in the presence of dG produced 8-(BP-6-CH2-yl)dG (5%) and a mixture of 7-(6-CH3BP-1-yl)Gua and 7-(6-CH3BP-3-yl)Gua (23%). The only adduct formed with dA was 3-(BP-6-CH2-yl)Ade (9%). 6-CH3BP did not afford any adducts with dC or dT. The noncarcinogenic 6-ClBP and 6-BrBP did not produce adducts with dG, dA, dC, or dT. These results are consistent with the chemical properties of the 6-FBP and 6-CH3BP radical cations: that is, 6-FBP reacts at C-1 and C-3, whereas 6-CH3BP reacts competitively at C-1 and C-3, as well as at the 6-CH3 position.

Benzopyrenes↗

PubMed1978

Effects of administration to mice of butylated hydroxyanisole by oral intubation on benzo[a]pyrene-induced pulmonary adenoma formation and metabolism of benzo[a]pyrene.

Administration of butylated hydroxyanisole (BHA) by oral intubation 4 hours before challenge with benzo[a]pyrene (BP) inhibited the formation of pulmonary adenomas in A/HeJ mice. Incubation of BP with liver microsomes from mice that received BHA 2,4, or 8 hours before being killed resulted in less binding of BP metabolites to added DNA than occurred with control microsomes. High-pressure liquid chromatography studies of the BP metabolite pattern produced by the incubation of BP with liver microsomes from mice given BHA by oral intubation showed a decrease in formation of BP-4,5-oxide and 9-hydroxybenzo[a]pyrene. In contrast, the formation of 3-hydroxybenzo[a]-pyrene was increased. The was increased. The short interval between the administration of BHA by oral intubation and the observed biochemical changes indicated that BHA could exert a direct effect on the microsomal metabolism of BP. These changes in metabolism of BP occurred under conditions of BHA administration that produced a decreased neoplastic response to this carcinogen.

Adenoma↗

PubMed1975

Comparison of the cellular DNA-bound products of benzo(alpha)pyrene with the products formed by the reaction of benzo(alpha)pyrene-4,5-oxide with DNA.

DNA isolated from mouse embryo cell cultures that had been treated with [3H]benzo(alpha)pyrene was degraded with enzymes to deoxyribonucleosides, and the hydrocarbon-deoxyribonucleoside products were isolated by chromatography on a Sephadex LH20 column eluted with a water: methanol gradient. The hydrocarbon-deoxyribonucleoside products were not identical to those found in similar chromatograms of enzyme digests of DNA that had been reacted with benzo(alpha)pyrene-4,5-oxide in aqueous ethanol solution. This finding suggests that the metabolic activation of benzo(alpha)pyrene that results in this hydrocarbon becoming covalently bound to DNA in mouse embryo cells in culture may be more complex than simply formation of a K-region epoxide and reaction of that compound with the cellular DNA.

Animals↗

PubMed1979

Carcinogenicity of 2-hydroxybenzo(a)pyrene and 6-hydroxybenzo(a)pyrene in newborn mice.

Benzo(a)pyrene (BP), 2-hydroxybenzo(a)pyrene (2-HOBP), and 6-hydroxybenzo(a)pyrene (6-HOBP) were tested for tumorigenicity by i.p. injection into newborn mice. The mice were treated sequentially with 200, 400, and 800 nmol of compound on the first, eighth and fifteenth day of life, and the animals were killed at 24 weeks of age. Treatment with 2-HOBP caused about 4-fold more pulmonary tumors than BP, while 6-HOBP had little or no tumorigenic activity. Newborn mice treated with 2-HOBP, BP, and 6-HOBP had a 98, 81, and 11% incidence of pulmonary adenomas with an average of 24, 6.4, and 0.11 adenomas per mouse, respectively. In the control group, 7.5% of the animals had pulmonary adenomas with an average of 0.08 adenoma per mouse. When 25, 50, or 100 nmol of BP or 2-HOBP was applied to mouse skin once every 2 weeks for 60 weeks, both compounds had about the same carcinogenic activity. These results demonstrate the importance of evaluating the carcinogenic potential of chemicals in more than one tumor system. BP and 2-HOBP were tested for mutagenicity towards two strains of Salmonella typhimurium and towards Chinese hamster V79 cells in the presence of hepatic microsomes from rats pretreated with Aroclor 1254. The products formed during the metabolism of 2-HOBP or BP by liver microsomes had significant mutagenic activity.

Adenoma↗

PubMed2004

Role of cell signalling involved in induction of apoptosis by benzo[a]pyrene and cyclopenta[c,d]pyrene in Hepa1c1c7 cells.

The reactive metabolites of benzo[a]pyrene (B[a]P) and cyclopenta[c,d]pyrene (CPP) induced an accumulation/phosphorylation of p53 in Hepa1c1c7 cells, whereas inhibition of p53 reduced the apoptosis. Judged by the inhibiting effect of wortmannin, phosphatidyl-inositol-3 (PI-3) kinases such as DNA-dependent protein kinase (DNA-PK), ATM (ataxia-telangiectasia mutated), and/or ATR (ATM related kinase), appeared to be involved in the DNA damage recognition and the B[a]P-/CPP-induced accumulation of p53. B[a]P and CPP also induced phosphorylation of jun-N-terminal kinase (JNK) and p38 mitogen activated protein kinase (MAPK). While inhibition of JNK had no effects on the B[a]P-/CPP-induced apoptosis, inhibition of p38 MAPK activity reduced this effect. Interestingly, survival signals such as phosphorylation of Akt and Bad seemed to be induced by the B[a]P-/CPP-compounds. Furthermore, also extracellular signal-regulated kinase (ERK)1/2 was activated and seemed to function as a survival signal in B[a]P-/CPP-induced apoptosis.

Animals↗

PubMed1995

Benzo(a)pyrenediolepoxide-hemoglobin adducts and 3-hydroxy-benzo(a)pyrene urinary excretion profiles in rats subchronically exposed to benzo(a)pyrene.

The time profiles of benzo(a)pyrenediolepoxide (BaPDE)-hemoglobin (Hb) adduct formation and 3-hydroxybenzo(a)pyrene (3-OHBaP) urinary excretion were studied in male Sprague-Dawley rats exposed to daily benzo(a)pyrene (BaP) intraperitoneal doses of 1.25, 6.25, and 31.25 mumol/kg administered Tuesday to Friday for 4 consecutive weeks. Blood was withdrawn weekly, on Tuesdays, prior to dosing. Twenty-four-hour urine samples were collected on Mondays (following 72 h without treatment) and Thursdays. Analytes were quantified by high performance liquid chromatography (HPLC)/fluorescence. Exposure to BaP resulted in the accumulation of BaPDE-Hb adducts, reaching an average of 1.2 +/- 0.3, 8.3 +/- 1.9, and 38.2 +/- 6.1 pmol/g Hb for the 1.25, 6.25, and 31.25 mumol/kg per day doses after 4 weeks of treatment. The expected saw tooth excretion profile of 3-OHBaP was observed, with peaks on Thursdays and troughs on Mondays, and showed a progressive rise on both Mondays and Thursdays. Increase in Monday values with time suggested a possible increase in BaP body burden during exposure. To verify this aspect further, the urinary excretion kinetic of 3-OHBaP following acute intraperitoneal dosing (31.25 mumol/kg) was determined. Urine samples were collected at frequent timed intervals for up to 164 h post-dosing. Two-step elimination was observed, the second step having a half-life of 25 h, presumably linked to the slow release of BaP accumulated in fatty tissues upon repeated treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

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

PubMed1989

Metabolism of benzo[a]pyrene and 7 beta,8 alpha-dihydroxy-9 alpha, 10 alpha-epoxy-7,8,9,10-tetrahydrobenzo[a pyrene in lung and liver of newborn mice.

Although the newborn mouse has been extensively used to test the tumorigenic activities of polynuclear aromatic hydrocarbons and their diol epoxide metabolites, no information is available on their metabolism in the newborn mouse in vivo. Therefore, we have investigated the metabolism and distribution of [3H]benzo[a]pyrene ([3H]BaP) and (+/-)-7 beta,8 alpha-[3H]dihydroxy-9 alpha, 10 alpha-epoxy-7,8,9, 10-tetrahydrobenzo[a]pyrene ([3H]BPDE) in liver and lung of mice given i.p. injections of these compounds on their 1st, 8th and 15th days of life. In lung, identified metabolites of [3H]BaP included diols, quinones, and phenols. Their levels were higher on the 1st day compared to the 8th and 15th days of life. The pattern of organic extractable metabolites detected in mouse liver was different from that in lung, being dominated by unidentified polar metabolites, the levels of which increased with age. Levels of [3H]BPDE in liver and lung were measured by trapping with 2-mercaptoethanol. It was demonstrated that [3H]BPDE rapidly reaches the lung after i.p. injections. The half-lives of [3H]BPDE in lung and liver were similar to those observed in vitro. The results are discussed with respect to the known tumorigenic activities of BaP and BPDE in newborn mice and in mouse skin.

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

PubMed1996

Chemopreventive activity of chlorophyllin against mouse skin carcinogenesis by benzo[a]pyrene and benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide.

Chlorophyllin (CHL), the sodium and copper salt of chlorophyll, was tested for its chemopreventive activity against tumorigenesis induced by benzo[a]pyrene (B[a]P) and its ultimate electrophilic and carcinogenic metabolite, benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide(BPDE). Administration of CHL (15 mg/kg body wt) by gavage to female ICR mice 30 min prior to a topical application of B[a]P or BPDE resulted in significant reduction in both incidence and multiplicity of skin tumors initiated by these carcinogens. CHL was rapidly distributed in the skin and other tissues of mice after oral administration. Taken together, these results suggest that CHL is a potential chemopreventive agent.

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

PubMed2004

Reduction of androgen receptor expression by benzo[alpha]pyrene and 7,8-dihydro-9,10-epoxy-7,8,9,10-tetrahydrobenzo[alpha]pyrene in human lung cells.

5Alpha-dihydrotestosterone significantly increased cell growth of lung adenocarcinoma cell line H1355. Benzo[alpha]pyrene (BaP) was a pulmonary carcinogen found in cigarette smoke. Treatment with 1microM BaP tremendously reduced constitutive androgen receptor (AR) expression, as determined with Western immunoblotting and the real-time RT-PCR assay, as well as testosterone-induced AR protein levels in H1355 cells. Similarly, 1microM BaP significantly reduced AR mRNA levels in human bronchial epithelial cells BEAS-2B. Although BaP, 2,3,7,8-tetrachlorodibenzo-p-dixin and polychlorinated biphenyl 126 activated aryl hydrocarbon receptor (AhR), which subsequently induced cytochrome P4501A1 (CYP1A1) and P4501B1 (CYP1B1) expression in H1355 cells, unexpectedly, neither TCDD nor PCB126 reduced AR expression. Antagonizing AhR activation and cytochrome P4501 activity with alpha-naphthoflavone, or inhibiting CYP1B1 activity with 2,4,3',5'-tetramethoxystilbene, however, prevented BaP-induced AR reduction. Furthermore, 7,8-dihydro-9,10-epoxy-7,8,9,10-tetrahydrobenzo[alpha]pyrene, a BaP carcinogenic metabolite catalyzed by CYP1A1 and CYP1B1, significantly reduced AR expression in H1355 cells and human lung fibroblasts WI-38. This was the first study that reports that BaP and BPDE reduced endogenous AR expression. These data suggest that metabolically activated BaP may disrupt androgen function by reducing AR levels in androgen-responsive organs.

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

PubMed2006

Effects of anthracene, pyrene and benzo[a]pyrene spiking and sewage sludge compost amendment on soil ecotoxicity during a bioremediation process.

The fate of spiked anthracene, pyrene and benzo[a]pyrene in soil with or without sewage sludge compost was assessed during a 6-month bioremediation process simulating landfarming. Bioassays and physico-chemical analyses were employed to monitor toxicity change in soil samples and elutriates through ten sampling campaigns. Pearson product-moment correlation coefficient was determined to measure the strength of relationship between bioassays and physico-chemical analyses. The PAH dissipation in soil was enhanced after the first water addition, and the remaining amounts at the end of the experiment were positively correlated to the number of benzene rings and the presence of sewage sludge compost. Toxicity of soil elutriates to Daphnia magna was evident at early stages, originating exclusively from sewage sludge compost amendment. The lettuce root elongation was continuously inhibited by elutriates for all the treatments including control soil, probably due to high salinity or to unaddressed leachable phytotoxic compounds that were present in the experimental soil. The newly developed direct solid-phase chronic toxicity test using ostracod (Heterocypris incongruens) succeeded in evaluating the soil-bound PAH toxicity, as PAHs could not be detected in elutriates.

Animals↗

PubMed1997

A comparative investigation of DNA adducts, DNA strand breaks and gene mutations induced by benzo[a]pyrene and (+/-)-anti-benzo[a]pyrene-7,8-diol 9,10-oxide in cultured human cells.

Genotoxic effects of benzo[a]pyrene (BP) and its reactive metabolites (+/-)-anti-benzo[a]pyrene-7,8-diol 9,10-oxide ((+/-)-anti-BPDE) were comparatively investigated in vitro with the permanent human fibroblast cell line MRC5CV1. Induced DNA adducts were measured by 32P-postlabeling, DNA strand breakage was determined by the comet assay and the HPRT gene mutation test was used to detect cytotoxicity and mutagenicity. Treatment of MRC5CV1 cells with S9 mix-activated BP or with (+/-)-anti-BPDE resulted in a concentration-dependent increase in DNA adducts and strand breaks. Genotoxic effects of BP and (+/-)-anti-BPDE were detected by 32P-postlabeling and the comet assay with similar sensitivity. However, under the same experimental conditions, a clear induction of gene mutations was only found after (+/-)-anti-BPDE treatment. The relationship between the induction of primary DNA alterations like DNA strand breaks and DNA adducts and the induction of gene mutations is discussed.

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

PubMed2000

Biomonitoring of environmental polycyclic aromatic hydrocarbon exposure by simultaneous measurement of urinary phenanthrene, pyrene and benzo[a]pyrene hydroxides.

A high-performance liquid chromatographic method with fluorescence detection was developed which enables the simultaneous determination of the urinary polycyclic aromatic hydrocarbon metabolites 3-hydroxyphenanthrene, 1-hydroxypyrene and 3-hydroxybenzo[a]pyrene. The method has small solvent consumption because of the use of a microbore RP C18 column and a relatively short run time. Low detection limits of 0.02 nmol/l for 3-hydroxypyrene to 0.19 nmol/l for 3-hydroxybenzo[a]pyrene were attained. In contrast, the detection limits of alpha-naphthol and 9,10-dihydroxy-9,10-dihydrophenanthrene were not adequate for the determination of environmental exposure. The developed method was successfully used for the analysis of urine samples from children.

Air Pollutants↗

PubMed2001

UV-detection capillary electrophoresis for benzo[a]pyrene and pyrene following a two-step concentration system using homogeneous liquid-liquid extraction and a sweeping method.

10(-9) mol l-1 levels of polycyclic aromatic hydrocarbons (PAHs) suspected for certain noxious materials can be determined and separated by UV-detection capillary electrophoresis following a two-step concentration system. When the conditions of the homogeneous liquid-liquid extraction were [THF]T = 5 vol%, [HCl]T = 0.66 mol l-1, and [PFOA]T = 2 x 10(-3) mol l-1 (i.e., the volume of sample solution; 50 ml-->sedimented phase; 30 microliters), the extraction percentages of benzo[a]pyrene (Bap) and pyrene (Py) at 10(-6) mol l-1 were 102 and 97.5%, respectively. Also, when the total concentration factor(volume ratio), which includes that of the sweeping method, was 8335-fold, the determination range of Bap was 6.4 x 10(-9)-8.0 x 10(-7) mol l-1 and for Py, 8.0 x 10(-9)-7.0 x 10(-7) mol l-1. The detection limits (3 sigma) of Bap and Py were 1.6 x 10(-9) and 4.8 x 10(-9) mol l-1, respectively.

Air Pollutants↗

PubMed2004

Studies in the biodegradation of 5 PAHs (phenanthrene, pyrene, fluoranthene, chrysene und benzo(a)pyrene) in the presence of rooted poplar cuttings.

Cuttings of Populus nigra L. cv. Loenen were cultivated in sand treated with one of the following PAHs: phenanthrene (Phen), fluoranthene (Flt), pyrene (Pyr), chrysene (Chr) and benzo[a]pyrene (BaP). The PAHs were applied at varying levels of concentration to each test series. After 6 weeks the concentration and the distribution of the PAHs in the substrate of the various sets of tests were compared with the concentration in the substrate of the control. Additionally the substrate and the plant roots were tested for evidence of degradation products of PAHs. The results revealed that the levels of concentration of Phen and Pyr detected in the substrate surrounding the roots was in some cases significantly lower than in the corresponding section of substrate in the unplanted set (= control). This phenomenon did not occur for Flt and BaP and in the case of Chr only in those substrates, which had been treated with the highest levels of concentration. As the presence of lesser amounts of Phen and Pyr in the plant pots cannot only be attributed to their accumulation and metabolism in the roots, it is fair to assume that the chemical transformation of these three PAHs took place outside the roots. The set of tests treated with Phen revealed the presence of 2- or 3-hydroxy-Phen (main components), a hydroxy-methoxy-Phen, 9,10-Phenanthrenequinone and one unidentified compound in metabolite form. Altogether eleven metabolites of Pyr were identified in the root extracts, which can be divided into three groups: 1-Hydroxy-Pyr and derivatives, dihydroxy-Pyr and derivatives and ring fission products (4-Hydroxy-Pyr and a derivative of the 4-Phen-carbonic acid). However, the metabolite mass detected for Phen and Pyr represents only an insignificant percentage in comparison with the lesser amounts of PAHs observed in the planted set of tests. This indicates that the three PAHs were reduced to lower molecular compounds, which are methodically impossible to record, and subsequently translocated to other parts of the plant and integrated into the biomass. Although no lesser amount for Flt and BaP was found in the plant pots, 1-Hydroxy-Flt, an unidentified compound of Flt and 1-Methoxy-BaP were detected. These are presumably end products which were enhanced in the roots. It was not possible to identify any transformation products of Chr. It can be assumed that the majority of metabolites were not synthesised in the roots but are a result of microbial degradation in the rhizosphere. The test plants improved the conditions for the biotransformation of Phen and Pyr significantly and accumulated Flt, Pyr, Chr and BaP in their roots. It can therefore be concluded that the use of plants in the bioremediation of contaminated soils is a promising option.

Benzo(a)pyrene↗

PubMed1983

Syncarcinogenic effect of the environmental pollutants cyclopenteno[cd]pyrene and benzo[a]pyrene in mouse skin.

Benzo[a]pyrene (BP) and cyclopenteno[cd]pyrene (CPEP) are widespread environmental pollutants. CPEP is a relatively potent carcinogen in mouse skin with an activity second only to BP among environmental aromatic hydrocarbons. We have studied the combined application of BP and CPEP on mouse skin to determine their possible synergistic carcinogenic effect. Nine-week-old female Swiss mice in groups of 30 were treated on the back with high (H), medium (M) and low (L) doses, respectively, of 20 (H), 6.6 (M) or 2.2 (L) nmol BP or 200 (H), 66.6 (M) or 22.2 (L) nmol CPEP in 50 microliters acetone twice weekly for 48 weeks. Other groups received BP-H + CPEP-H, BP-M + CPEP-M, BP-L + CPEP-L, BP-H + CPEP-L, BP-M + CPEP-L, BP-L + CPEP-H, or BP-L + CPEP-M. A significant, 3- to 7-fold syncarcinogenic effect occurred when BP-M + CPEP-M were administered together. A smaller, but significant, synergistic effect (1.2- to 3.8-fold) was also observed when BP-M + CPEP-L or BP-L + CPEP-M was applied. Because of the syncarcinogenic effect of BP and CPEP, their abundance in engine emissions and ambient air samples may present a major source of carcinogenic risk.

Animals↗

PubMed1988

Dose-response relationships of the tumorigenicity of cyclopenta[cd]pyrene, benzo[a]pyrene and 6-nitrochrysene in a newborn mouse lung adenoma bioassay.

Cyclopenta[cd]pyrene (CPP) was a potent tumorigen when tested over a 5-fold dose range in the newborn mouse assay. A 20-fold increase in lung tumor multiplicity and a nearly 8-fold increase in tumor incidence was observed at the lowest total dose tested (1.55 mumol) with the dose-response relationship indicating a saturation of tumor multiplicity at approximately 7 tumors/animal. No liver nodules or lymphatic system tumors were noted. Analysis of dose-response data for benzo[a]-pyrene (BaP) and 6-nitrochrysene (6-NC) showed that tumor multiplicity for BaP also saturated at approximately 7 tumors/animal, whereas no similar saturation was found for 6-NC at up to 40 tumors/animal. Progression of lung adenomas to adenocarcinomas, as measured by the incidence of mice bearing malignant tumors, was essentially a linear function of dose. To facilitate comparison and maximize quantitative data obtainable from the newborn mouse assay-parameters were defined for tumor incidence (ED50), tumor multiplicity (TM1.0) and tumor malignancy (malignancy index). Values for the ED50 and TM1.0 were similar for the same compound and a tumorigenic potency series of 6-NC greater than BaP greater than CPP was obtained corresponding to a ratio of approximately 1:10-25:76.5-135, respectively. The malignancy index, however, indicated increased adenocarcinoma induction in the order CPP greater than 6-NC greater than BaP as expressed by the ratio 1:1.4:8.3, respectively.

Adenoma↗

PubMed2002

Activation of the aromatic hydrocarbon receptor pathway is not sufficient for transcriptional repression of BRCA-1: requirements for metabolism of benzo[a]pyrene to 7r,8t-dihydroxy-9t,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene.

Reduction of BRCA-1 expression through nonmutational events may be a predisposing event in the onset of sporadic breast cancer. In this study, we investigated the mechanisms through which the environmental carcinogen benzo[a]pyrene (B[a]P) lowered BRCA-1 mRNA levels in breast cancer MCF-7 cells. We report that B[a]P does not compromise the stability of BRCA-1 mRNA, but represses transcriptional activity of a 1.69-kb BRCA-1 (pGL3-BRCA-1) promoter fragment that contains both exon-1A and exon-1B transcription start sites. The loss of BRCA-1 promoter activity was accompanied by accumulation of CYP1A1 and BAX-alpha mRNA and p53 and p21 protein, whereas levels of Bcl-2 mRNA were reduced. The aromatic hydrocarbon receptor ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which is not metabolized, did not affect BRCA-1 promoter activity or the cellular levels of BRCA-1 and p53 protein, but it did induce a CYP1A1-like promoter. Conversely, treatment with the B[a]P metabolite 7r,8t-dihydroxy-9t,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE) repressed BRCA-1 promoter activity and protein, while increasing p53 and p21 protein levels. Transient expression of dominant-negative p53 ((175)Arg-->His) counteracted the detrimental effects of BPDE on BRCA-1 promoter activity and protein levels. Similarly, treatment with B[a]P, TCDD, or BPDE failed to repress transcription from the pGL3-BRCA-1 construct transfected into ZR75.1 breast cancer cells containing mutated p53 ((152)Pro-->Leu). We conclude that activation of the aromatic hydrocarbon receptor is not sufficient for down-regulation of BRCA-1 transcription, which is, however, inhibited by the B[a]P metabolite BPDE through a p53-dependent pathway.

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