Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Pyrenes”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

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

At least 1,693 records · Page 94Linked to original sources
PubMed1997

Inhibition of benzo[a]pyrene-DNA adduct formation by Aloe barbadensis Miller.

The antigenotoxic and chemopreventive effect of Aloe barbadensis Miller (polysaccharide fraction) on benzo[a]pyrene (B[a]P)-DNA adducts was investigated in vitro and in vivo. Aloe showed a time-course and dose-dependent inhibition of [3H]B[a]P-DNA adduct formation in primary rat hepatocytes (1x10(6) cells/ml) treated with [3H]B[a]P (4 nmol/ml). At concentrations of 0.4-250 microg/ml aloe, the binding of [3H]B[a]P metabolites to rat hepatocyte DNA was inhibited by 9.1-47.9%. Also, in rat hepatocytes cultured for 3-48 h with aloe (250 microg/ml) and [3H]B[a]P (4 nmol/ml), [3H]B[a]P-DNA adducts were significantly reduced by 36% compared with [3H]B[a]P alone. Aloe also inhibited cellular uptake of [3H]B[a]P in a dose-dependent manner at a concentration of 0.4-250 microg/ml by 6.3-34.1%. After a single oral administration of B[a]P to male ICR mice (10 mg/mouse), benzo[a]pyrene diol epoxide I (BPDE-I)-DNA adduct formation and persistence for 16 days following daily treatment with aloe (50 mg/mouse) were quantitated by enzyme-linked immunosorbent assay using monoclonal antibody 8E11. In this animal model, BPDE-I-DNA adduct formation was significantly inhibited in various organs (liver, kidney, forestomach and lung) (P < 0.001). When mice were pretreated with aloe for 16 days before B[a]P treatment, inhibition of BPDE-I-DNA adduct formation and persistence was enhanced. Glutathione S-transferase activity was slightly increased in the liver but cytochrome P450 content was not affected by aloe. These results suggest that the inhibitory effect of aloe on BPDE-I-DNA adduct formation might have a chemopreventive effect by inhibition of B[a]P absorption.

Aloe↗
PubMed1998

Mechanism of inhibition of benzo[a]pyrene-induced forestomach cancer in mice by dietary curcumin.

Curcumin (diferuloylmethane), the major yellow pigment in turmeric, has been shown to inhibit benzo[a]pyrene (BaP)-induced forestomach cancer in mice through mechanism(s) not fully understood. It is well known that while cytochrome P4501A1 (CYP1A1) and epoxide hydrolase (EH) are important in the conversion of BaP to its activated form, (+)-anti-7,8-dihydroxy-9,10-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene [(+)-anti-BaPDE], the detoxification of (+)-anti-BaPDE is accomplished by glutathione (GSH) S-transferases (GST). Therefore, it seems reasonable to postulate that curcumin may exert anti-carcinogenic activity either by inhibiting activation of BaP or (and) by enhancing the detoxification of (+)-anti-BaPDE. Administration p.o. of 2% curcumin in the diet to female A/J mice for 14 days, which has been shown to cause a significant inhibition in BaP-induced forestomach tumorigenesis, resulted in a modest but statistically significant reduction in hepatic ethoxyresorufin O-deethylase (EROD) activity, a reaction preferentially catalyzed by CYP1A1. While EROD activity could not be detected in the forestomach of either control or treated mice, curcumin feeding caused a statistically significant increase (approximately 2.3-fold) in hepatic EH and GST activities. Hepatic and forestomach GSH levels, and forestomach EH and GST activities were not affected by curcumin treatment. Even though the levels of various hepatic GST isoenzymes were significantly increased upon curcumin feeding, maximum induction was noticed for the pi class isoenzyme (mGSTP1-1), which among murine hepatic GSTs is highly efficient in the detoxification of (+)-anti-BaPDE. In conclusion, the results of the present study suggest that curcumin may inhibit BaP-induced forestomach cancer in mice by affecting both activation as well as inactivation pathways of BaP metabolism in the liver.

Animals↗
PubMed1981

Metabolism of benzo[a]pyrene and DNA adduct formation in cultured human epidermal keratinocytes.

Cultured human epidermal cells which require no feeder layer were used to study metabolism of benzo[a]pyrene (BP) and DNA adduct formation. The cultures were prepared from a single cell suspension and maintained at a pH of 5.9--6.2. At 2 microM BP some cell toxicity was observed, and substantial cell death occurred at 4 microM BP. The metabolism and DNA binding of BP were followed from 6 to 48 h of incubation. High pressure liquid chromatography (h.p.l.c.) revealed that BP was metabolized into 9,10-diol, 7,8-diol, quinones, phenols and tetraols of BP. The DNA binding levels increased linearly up to 28 h of incubation. At 18 h, the level of DNA binding at 0.4 microM BP was 1.5 x 10(-6) mol BP/mol DNA and increased to 6.0 x 10(-6) mol BP/mol DNA at a dose of 4 microM BP. Analysis of the DNA adducts by h.p.l.c. indicates that the 2'-deoxy-N2-(7,8,9,10-tetrahydro-7 beta-,8 alpha, 9 alpha-trihydroxybenzo[a]pyrene-10-yl) guanosine was the predominant adduct formed in cells exposed to BP. The prevalence of the minor DNA adducts varies as a function of the source of the primary skin cells. These results confirm that human cells with no feeder layer metabolize BP and the resultant DNA damage is similar to that found in other mammalian systems.

Benzo(a)pyrene↗
PubMed1981

Metabolism of benzo[a]pyrene by brain microsomes of fetal and adult rats and mice. Induction by 5,6 benzoflavone, comparison with liver and lung microsomal activities.

Using brain, lung and liver microsomes as the enzyme source in in vitro assays, benzo[a]pyrene (B[a]P) metabolism was studied in fetuses and dams of mice (C57B1/6) and rats (WAG). Separation and quantitation of B[a]P metabolites were performed by h.p.l.c. Microsomal preparations were tested for cytochrome P-450 dependent O-dealkylation of 7-ethoxycoumarin and epoxide hydrolase activities. Another parameter measured included the conjugation of 1-chloro-2,4 dinitrobenzene to glutathione by cytosolic glutathione-S-transferase activity. The induction of B[a]P metabolism was studied after treatment of animals with 5,6-benzoflavone (BF). Mixed function oxygenase, epoxide hydrolase and glutathione-S-transferase activities were transplacentally inducible after dams were treated with BF. Metabolic activation of B[a]P by fetal brain microsomes was lower in both species than that by fetal lung and liver microsomes, but it was higher in fetuses than in adults. All metabolites of B[a]P increased after BF treatment; the production of 7,8-dihydro-7,8-dihydroxybenzo[a]pyrene (7,8-dihydrodiol B[a]P) was higher in brain microsomes from BF-treated rats than that in mice. In stimulated rats, the formation of 7,8-dihydrodiol B[a]P by fetal brain microsomes were higher than that by fetal lung microsomes, whereas in mice, the opposite was observed. These data suggest that initiation could occur in utero, and partially explain the species-specific differences in susceptibility to transplacental tumorigenesis by polycyclic aromatic hydrocarbons by differences in biotransformation in the target organ.

Animals↗
PubMed1999

Effects of anti-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene on human small airway epithelial cells and the protective effects of myo-inositol.

Benzo[a]pyrene (B[a]P), a tobacco-derived carcinogen, induces lung tumors in rodents through its carcinogenic metabolite, anti-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (B[a]PDE). Tumorigenesis is inhibited by dietary myo-inositol in the post-initiation phase. However, little is known about how B[a]PDE and myo-inositol affect normal human lung cells. We addressed this question using untransformed human small airway epithelial (SAE) cells. SAE cell viability decreased <50% in parallel to an increase of apoptotic cells (>20%) 2 days after the cells were treated for 1 h with B[a]PDE (>100 nM). In contrast, the cell number and viability were not altered in A549 human lung cancer cells by B[a]PDE treatment up to 10 microM with <5% apoptotic cells and <10 U/l LDH in the medium. SAE cells retain the features of basal cells in serum-free, low Ca2+ (4 nM) medium up to 4-5 passages, but in serum-supplemented or serum-free, high Ca2+ (1 mM) cultures, they differentiate into non-ciliated epithelial cells expressing Clara cell secretory protein (CCSP). A non-toxic, physiologically relevant dose of B[a]PDE (1 nM) partially inhibited serum and Ca2+-induced SAE cell differentiation. This effect was abolished by wortmannin, a phosphatidylinositol-3 kinase (PI-3K) inhibitor, and PD98059, a mitogen activated protein kinase (MAPK) kinase-1 (MEK1) inhibitor, but not by SB202190, a p38 MAPK inhibitor, or melittin, a protein kinase C inhibitor. Myo-inositol (10-100 microM) did not alter growth or differentiation of untreated SAE or A549 cells, but reversed the inhibitory effect of B[a]PDE on serum and Ca2+-induced SAE cell differentiation when supplemented to the culture after B[a]PDE treatment. This myo-inositol action was not altered by PD98059, wortmannin or melittin, but was partially suppressed by SB202190. Collectively, these results indicate that B[a]PDE inhibits serum-induced SAE cell differentiation, possibly involving activating signals through a PI-3K/MEK1 mediated MAPK pathway, whereas myo-inositol protects SAE cells against this inhibitory effect of B[a]PDE perhaps through both PI-3K/MEK1 and p38 MAPK pathways.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1999

Thapsigargin has similar effect on p53 protein response to benzo[a]pyrene-DNA adducts as TPA in mouse skin.

The level of p53 tumor suppressor protein increases in response to DNA damage caused by benzo[a]pyrene (B[a]P). The most used tumor promoter in the two step mouse skin carcinogenesis model, 12-O-tetradecanoylphorbol-13-acetate (TPA) decreases this response in mouse skin. In this study the effect of another promoter, thapsigargin was tested on B[a]P-induced p53 response using immunohistochemistry, western blotting and immunoelectron microscopy. We also studied the localization of p53 protein after treatments with BP and TPA or thapsigargin. Thapsigargin had a TPA-like effect on the acute induction of p53 protein related to benzo[a]pyrene-7, 8-diol-9,10-epoxide-DNA adducts in the skin of C57BL/6 mouse. After B[a]P treatment, there was slightly more putatively wild-type p53 protein in nuclei than in cytoplasm of the cells. Neither TPA nor thapsigargin affected the localization of p53 protein. Since both compounds increase the level of intracellular calcium, the inhibition of the p53 response may depend on the level of intracellular calcium. Inhibition of the putatively genome-protecting increase in p53 protein may be one of the critical effects of tumor promoters.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed2000

Correlation between DNA or protein adducts and benzo[a]pyrene diol epoxide I-triglyceride adduct detected in vitro and in vivo.

In this study, we demonstrated the in vitro and in vivo formation of carcinogen-lipid adduct and its correlation with DNA or protein adducts. The lipids from serum or hepatocyte membranes of Sprague-Dawley rats, human serum and standard major lipids were in vitro reacted with benzo[a]pyrene (B[a]P) and B[a]P metabolites. 7, 8-Dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene(BPDE-I), an ultimate carcinogenic form of B[a]P, was covalently bound to triglyceride (TG). BPDE-I-TG adducts isolated by thin-layer chromatography (TLC) were further detected by high-performance liquid chromatography. TGs, including triolein, tripalmitin and tristearin, showed positive reactions with BPDE-I. However, cholesterol, phospholipids (phosphatidylcholine, phosphatidyl-ethanolamine, phosphatidyl-inositol and sphingomyelin) and non-esterified fatty acids (palmitic acid, oleic acid, linoleic acid and stearic acid) did not react with BPDE-I. In addition, other B[a]P metabolites (B[a]P-phenols and -diols) did not react with TG. TG appeared to be the most reactive lipid yet studied with respect to its ability to form an adduct with BPDE-I. There was a clear-cut dose-related formation of [1,3-(3)H]BPDE-I-lipid adducts in vitro between TG and [1,3-(3)H]BPDE-I. In an animal study, BPDE-I-TG was also formed in the serum of rats orally treated with B[a]P (25 mg/rat). Also, obvious correlations between [(3)H]B[a]P related-biomolecule adducts (DNA or protein) or lipid damage and the BPDE-I-TG adducts were obtained in various tissues of mice i.p. treated with [(3)H]B[a]P. These data suggest that TG can form an adduct with BPDE-I, as do other macromolecules (DNA, RNA and protein). Therefore, a carcinogen-lipid adduct would be a useful biomarker for chemical carcinogenesis research and cancer risk assessment.

Adult↗
PubMed2000

LacI mutation spectra following benzo[a]pyrene treatment of Big Blue mice.

The mutation spectrum of the lacI gene from the liver of C57Bl6 Big Blue transgenic mice treated with benzo[a]pyrene (B[a]P) has been compared with the spectrum of spontaneous mutations observed in the liver of untreated Big Blue mice. Mice were treated with B[a]P for 3 days followed by a partial hepatectomy one day after the last injection. Liver tissue was removed for analysis at hepatectomy and, again, 3 days later at the time of sacrifice. Earlier, we reported that the lacI mutant frequency in these B[a]P-treated mice was elevated in the liver both at the time of hepatectomy and at sacrifice; however, a statistically significant increase in the mutant frequency was observed only at sacrifice. In this study, the DNA sequence spectra of lacI mutations observed in the liver of B[a]P-treated Big Blue mice at hepatectomy and at time of sacrifice were compared with each other and with the spectrum of spontaneous liver mutations. No differences were observed between the two B[a]P-treatment spectra. However, mutation frequencies of both GC-->TA and GC-->CG at the time of hepatectomy and at sacrifice were significantly elevated compared with the spontaneous frequency of these same transversions. Also, the frequency of AT-->TA transversions was significantly higher than the spontaneous frequency at the time of hepatectomy but not at sacrifice. The frequency of all other classes of mutations scored was not significantly different from the frequency of these same events in the spontaneous spectra. These data support the view that B[a]P treatment results in the induction of GC-->TA and GC-->CG transversions within 1 day of the last injection and they provide insights regarding the relative roles of benzo[a]pyrene-7,8-diol-9, 10-epoxide and radical cations of B[a]P in B[a]P-induced mutagenesis in vivo. Finally, these data provide evidence for B[a]P-induced mutagenesis under conditions where no statistical increase in mutant frequency could be shown.

Animals↗
PubMed2002

Effect of soluble and particulate nickel compounds on the formation and repair of stable benzo[a]pyrene DNA adducts in human lung cells.

Nickel compounds are well-known human carcinogens, but the underlying mechanisms are still not fully understood. Even though only weakly mutagenic, nickel chloride has been shown previously to impair the repair of UV-induced DNA damage as well as oxidative DNA damage. However, the carcinogenic potential depends largely on solubility, with poorly water-soluble nickel subsulfide and nickel oxide being strong carcinogens. Within the present study we investigated the effects of particulate black NiO and soluble NiCl(2) on the induction and removal of stable DNA adducts formed by benzo[a]pyrene (B[a]P) measured by a highly sensitive high performance liquid chromatography (HPLC)/fluorescence assay. With respect to adduct formation, NiO but not NiCl(2) reduced the generation of DNA lesions by approximately 30%. Regarding their repair, in the absence of nickel compounds, most lesions were removed within 24 h; nevertheless, between 20 and 35% of induced adducts remained even 48 h after treatment. NiCl(2) and NiO reduced the removal of adducts in a dose-dependent manner. Thus, 100 microM NiCl(2) led to approximately 80% residual repair capacity; after 500 microM the repair was reduced to approximately 36%. Also, even at the completely non-cytotoxic concentration of 0.5 microg/cm(2) black NiO, lesion removal was reduced to approximately 35% of control and to 15% at 2.0 microg/cm(2). Furthermore, both nickel compounds increased the benzo[a]pyrene-7,8-diol 9,10-epoxide (BPDE)-induced cytotoxicity. Taken together, our results indicate that the nucleotide excision repair pathway is affected in general by water-soluble and particulate nickel compounds and provide further evidence that DNA repair inhibition may be one predominant mechanism in nickel-induced carcinogenicity.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed2002

Effects of benzyl isothiocyanate and phenethyl isothiocyanate on DNA adduct formation by a mixture of benzo[a]pyrene and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in A/J mouse lung.

Dietary phenethyl isothiocyanate (PEITC) and a mixture of dietary PEITC and benzyl isothiocyanate (BITC) inhibit lung tumorigenesis in A/J mice induced by a mixture of the tobacco smoke carcinogens benzo[a]pyrene (B[a]P) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). In this study, we tested the hypothesis that inhibition of tumorigenesis by these isothiocyanates was due to inhibition of DNA adduct formation. We quantified the following pulmonary DNA adducts: N2-[7,8,9-trihydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene-10-yl]deoxyguanosine (BPDE-N2-dG) from B[a]P; and O(6)-methylguanine (O(6)-mG) and 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB)-releasing adducts from NNK. Initial experiments demonstrated that there were no effects of B[a]P on NNK-DNA adduct formation, or vice versa, and established by way of a time course study the appropriate sacrifice intervals for the main experiment. Dietary PEITC, or dietary BITC plus PEITC, inhibited the formation of HPB-releasing DNA adducts of NNK at several of the time points examined. There were no effects of dietary isothiocyanates on levels of O(6)-mG or BPDE-N2-dG. These results, which are consistent with previous studies in rats and with tumor inhibition data in mice, support a role for inhibition of HPB-releasing DNA adducts of NNK as a mechanism of inhibition of tumorigenesis by dietary PEITC and BITC plus PEITC. However, the observed inhibition was modest, suggesting that other effects of isothiocyanates are also involved in chemoprevention in this model.

Animals↗
PubMed2003

Simulated sunlight and benzo[a]pyrene diol epoxide induced mutagenesis in the human p53 gene evaluated by the yeast functional assay: lack of correspondence to tumor mutation spectra.

Many mutations in the p53 gene destroy the transcriptional transactivation function of the p53 protein. This function of p53 can be determined in a yeast assay using a p53 responsive reporter gene. The yeast assay could hold promise for the identification of mutagens implicated in human cancer if the p53 mutational spectra obtained with this assay would match human tumor mutation data. Ultraviolet (UV) light from the sun and polycyclic aromatic hydrocarbons, such as benzo[a]pyrene, are strongly implicated in the spectrum of p53 mutations found in human non-melanoma skin cancers and smoking-associated lung cancers, respectively. We have used these two model mutagens to assess the feasibility of using the p53 yeast assay in cancer epidemiology. After treatment of CpG methylated p53 DNA with a solar UV simulator or with benzo[a]pyrene diol epoxide (BPDE), the modified p53 sequences were assayed in yeast for mutational outcome. As expected, BPDE produced predominantly G to T transversions and simulated sunlight produced mostly C to T transitions at dipyrimidine sites in the p53 coding sequence. However, the preferentially mutated p53 sequences (hotspots) in the yeast assay were completely different from those in the mutational spectra found in human lung and skin cancers. The data indicate that this assay is not a reliable measurement of p53 mutagenesis in human tissues and that, perhaps, transcriptional activation is not the primary function of p53 in tumor suppression.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1982

Geno- and cytotoxicity of nitrosamines, aflatoxin B1, and benzo[a]-pyrene in continuous cultures of rat hepatoma cells.

Two closely related hepatoma cell lines were examined for their response to carcinogens requiring metabolic activation: H5, a dedifferentiated line expressing cytochrome P-448-dependent monooxygenase(s); and HF1-4, a differentiated line which also expresses cytochrome P-450-dependent monooxygenase(s). The hepatocarcinogens dimethyl- and diethylnitrosamine and aflatoxin B1, preferred substrates for cytochrome P-450-dependent monooxygenase(s), and the non-hepatocarcinogen benzo[a]pyrene, which is preferentially metabolized by cytochrome P-448-dependent monooxygenase forms, were used as test agents. Their effects were compared to those of the directly alkylating agents N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and N-ethyl-N-nitrosourea (ENU). The cytotoxicity was evaluated by plating efficiency, the genotoxicity by the appearance of alkaline labile DNA sites. The nitrosamines had a cytotoxic and genotoxic effect on the differentiated HF1-4 cells, but had no effect on H5 cells. Aflatoxin B1 affected both cell lines, but was approximately 10-times more potent in the HF1-4 than in the H5 cells. In contrast to the nitrosamines and the mycotoxin, benzo[a]-pyrene exerted a stronger effect on the dedifferentiated cell line. Pretreatment of cultures with dexamethasone increased both the cytotoxicity and genotoxicity of the hepatotoxic agents. MNNG and ENU induced a similar degree of DNA-damage after short-term (2 h) exposure in the two cell lines. When cells were allowed to recover for 16 h HF1-4 cells, but not H5 cells, regained their full growth potential suggesting a marked capacity for the repair of MNNG- and ENU-induced lesions in the HF1-4 cells. The results indicate that continuous lines of mammalian cells may retain a considerable degree of organ-specific response to chemical carcinogens. Hepatoma cells of the type described above may be useful for screening the wide spectrum of chemicals which are potentially genotoxic in liver and in extrahepatic tissues and for analyzing their metabolic activation and mechanism of action.

Aflatoxin B1↗
PubMed1982

Mutation in mammalian cells by stereoisomers of anti-benzo[a] pyrene-diolepoxide in relation to the extent and nature of the DNA reaction products.

Monolayer cultures of V79 cells were treated with tritium labelled (+) and (-) stereoisomers of anti-benzo[a]pyrene diolepoxide. Cell survival and induction of 8-azaguanine resistant mutants by the two stereoisomers were related to the extent of reaction with cellular DNA and to the nature of the reaction products. At equal extents of DNA reaction both isomers were equally cytotoxic but the (+) anti-isomer was considerably more mutagenic. This difference of mutagenicity could not be related to any particular product of DNA reaction or to differential excision repair by the V79 cells. It is proposed that mutagenicity in V79 cells, which correlates closely with reported carcinogenicity data in mice, is a consequence of reaction with DNA at the amino-group of guanine and that the difference found between the (+) and (-) stereoisomers results from differences in the spatial orientation of the benzo[a]pyrene residue at this site.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1982

Metabolism and DNA binding of benzo[a]pyrene in cultured human bladder and bronchus.

The metabolism of benzo[a]pyrene (BP) was examined in explant cultures of human bladder and bronchus. Three-day cultures were exposed to radiolabeled BP for 24 h, and the metabolism was determined by analysis of the level of binding of reactive metabolites to DNA, and by the release of metabolites into the medium. For a given individual, the DNA binding level and extent of metabolism was usually higher in the bladder than in the bronchus. In specimens obtained from 16 individuals, the average DNA-binding levels for BP-DNA adducts following a 24 h exposure to 1 microM BP were 6.4 +/- 5.0 mumol BP/mol deoxyribonucleotide for the bladder and 3.1 +/- 1.9 mumol BP/mol deoxyribonucleotide for the bronchus. The major BP-DNA adduct in both tissues co-chromatographed with one of the adducts formed by reaction of r-7, t-8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene with deoxyguanosine using high-pressure liquid chromatography. In tissues obtained from the same individual, the binding levels of BP metabolites to bladder cell DNA was not strongly correlated to that of bronchial cell DNA (r = 0.55). The medium of both tissues contained small amounts of free, unconjugated metabolites of BP (less than 3% of the total) and large amounts (30-86% of the total) of unidentified, highly polar material. Human bladder appears to be the most active explant tissue yet studied with respect to its ability to activate BP to DNA binding forms. The relevance of this observation to human bladder cancer is, as yet, unknown.

Adolescent↗
PubMed1982

Modulation of microsome-mediated benzo[a]pyrene-metabolism by serum.

The effects of serum on the metabolism of benzo[a]pyrene (BP) by liver microsomes from 3-methylcholanthrene-treated rats were studied. In the presence of serum, the aryl hydrocarbon hydroxylase activities were enhanced to 160-570% of the control value. Enhancement of BP-metabolism by serum was also revealed by high performance liquid chromatography, but the relative amounts of a series of BP-metabolites were not changed appreciably by addition of serum. Binding of BP-metabolites to DNA was influenced by serum: adducts derived from two stereo-isomeric BP-7,8-di-hydrodiol-9,10-oxides were increased, while those from 9-hydroxybenzo[a]pyrene-4,5-oxide were reduced.

Animals↗
PubMed1982

Anticarcinogenic and cocarcinogenic effects of benzo[e]pyrene and dibenz[a,c]anthracene on skin tumor initiation by polycyclic hydrocarbons.

In the present study, we have examined the effects of benzo[e]pyrene (B[e]P) and dibenz[a,c]anthracene (DB[a,c]A) on the skin tumor-initiating activities of methylated and non-methylated polycyclic aromatic hydrocarbons (PAH). B[e]P, when applied 5 min prior to initiation with seven different PAH skin carcinogens, effectively inhibited the tumor-initiating activities of 7,12-dimethylbenz[a]anthracene (DMBA) and dibenz[a,h]anthracene (DB[a,h]A) but had little or no effect on the tumor-initiating activities of 3-methyl-cholanthrene (MCA), 7-methylbenz[a]anthracene (7-MBA), 12-methylbenz[a]anthracene (12-MBA), and 5-methyl-chrysene (5-MeC). B[e]P potentiated the tumor-initiating activity of benzo[a]pyrene (B[a]P) by approximately 30%, DB[a,c]A, when applied 5 min prior to initiation, inhibited the tumor-initiating activities of DMBA, MCA, and DB[a,h]A but had little or no effect on the tumor-initiating activities of B[a]P, 7-MBA, 12-MBA, and 5-MeC. DB[a,c]A, when applied 12, 24, or 36 h prior to initiation with B[a]P, which allowed time for induction of epidermal monooxygenase enzymes, inhibited tumor initiation. The covalent binding of DMBA and B[a]P to epidermal DNA was examined under the influence of B[e]P. Doses of 20 and 200 nmol B[e]P given 5 min prior to 10 nmol [3H]DMBA reduced binding to 47 and 22%, respectively, of the control value. In contrast, doses of 200 or 2000 nmol B[e]P given 5 min prior to 200 nmol [3H]B[a]P had little or no effect on total binding. The data indicate that one cannot predict anti and cocarcinogenic effects of B[e]P and DB[a,c]A on the basis of a presence or absence of a methyl substituent. In addition, fundamental differences exist in the processing and metabolism of DMBA and B[a]P by mouse epidermal cells.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1982

Cell-mediated mutagenesis and tumor-initiating activity of the ubiquitous polycyclic hydrocarbon, cyclopenta[c,d]pyrene.

The ubiquitous polycyclic aromatic hydrocarbon (PAH), cyclopenta[c,d]pyrene (CPP), was tested to determine its mutagenicity for 6-thioguanine and ouabain resistance in Chinese hamster V79 cells and its tumor-initiating activity in the skin of the tumor susceptible Sencar mice. The potent carcinogen/mutagen, benzo[a]pyrene (BP), was included for comparison. Inasmuch as V79 cells do not metabolize PAHs, mutagenesis was tested both in the presence and in the absence of X-irradiated golden hamster embryo fibroblasts capable of metabolizing PAH. Neither CPP nor BP showed mutagenicity for V79 cells in the absence of the embryo cells. In the presence of these cells (in the cell-mediated assay) both PAHs elicited, in a dose dependent manner, a cytotoxic and mutagenic response in V79 cells. CPP was however less active than BP in inducing both of these responses. At the optimal expression time and at the dose range of 0.1-1 microgram/ml, CPP induced 2-8 6-thioguanine resistant mutants per 10(5) colony forming cells compared to 9-50 mutants induced by BP. Similarly, these doses of CPP induced 1-9 ouabain resistant mutants per 10(6) colony forming cells compared to 7-75 mutants induced by BP. CPP was also active in initiating skin tumors in approximately 60% of the mice at 200 micrograms, the highest dose tested. BP was more efficient in tumor initiation and yielded a similar response with 10 micrograms. These results indicate that CPP and BP elicit, in the cell mediated assay, a mutagenic response similar to the activity of these PAH in the skin of Sencar mice.

Animals↗
PubMed1983

A comparison between the activation of benzo[a]pyrene in organ cultures and microsomes from the tracheal epithelium of rats and hamsters.

Epidermoid cancers of tracheal origin produced in Syrian golden hamsters and Fischer strain 344 rats are models for human bronchogenic carcinomas. These two species differ, however, in the sensitivity of their tracheal epithelia to tumor induction elicited by intratracheal benzo[a]pyrene (BP)-ferric oxide administration. The tracheas of hamsters are quite sensitive to the carcinogenic effects of BP-ferric oxide, but rat tracheas are apparently resistant to effects of comparable treatments by this route of administration. Rat tracheas are not completely resistant to polynuclear hydrocarbon carcinogenesis because in the heterotopic tracheal graft model, epidermoid carcinomas have been produced frequently. To determine whether differences in BP metabolism could explain this difference between species, quantitative kinetic and chromatographic studies of benzo[a]pyrene monoxygenase activity were carried out in epithelial microsomes and cells from organ cultures of rat and hamster tracheas. The Vmax was 2-fold greater in hamster tracheal cells than in rat tracheal cells whereas the Km values were identical. H.p.l.c. profiles from microsomes of rat and hamster tracheal epithelial cells incubated with BP exhibited extreme differences. Hamster tracheal microsomes produced large proportions of BP-quinones, BP-phenols, and BP-diols but rat tracheal microsomes produced mostly 3-OH BP. The total metabolic rate for BP in rat tracheal organ cultures was half that in cultures of hamster tracheas. The metabolites isolated in organ cultures of hamster and rat tracheas well reflected secondary reactions of conjugation and recycling. When evaluated with respect to the amount of tissue used, the most striking difference between rat and hamster tracheal organ cultures was in the amount of products which co-chromatographed with bay-region BP-tetrols. The amount of BP-tetrols produced by hamster tracheas was 0.22 pmol/mg tissue/24 h, and by rat, 0.012 pmol/mg tissue/24 h. The level of BP-DNA binding (in pmol/microgram DNA/24 h) catalyzed by hamster tracheal cells was 26.6 +/- 11.4, and by rat tracheas was 1.55 +/- 1.29. These interspecies differences associated with the formation of BP-diol epoxide, a presumed ultimate carcinogenic form of BP, are consistent with the differences between these two rodent species in susceptibility to carcinogenesis in this tissue.

Animals↗