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At least 19 recordsLinked to original sources

PubMed2005

Ruthenium(III) chloride catalyzed oxidation of pyrene and 2,7-disubstitued pyrenes: an efficient, one-step synthesis of pyrene-4,5-diones and pyrene-4,5,9,10-tetraones.

Pyrene and 2,7-disubstituted pyrenes have been oxidized with ruthenium(III) chloride (RuCl3) and sodium periodate (NaIO4) under very mild conditions to 4,5-diones or 4,5,9,10-tetraones. Thus, the oxidation has been controlled by varying the amount of oxidant and reaction temperature to proceed exclusively at the pyrene 4- and 5-positions or at the 4-, 5-, 9-, and 10-positions.

Journal Article↗

PubMed2001

Pyrene bioaccumulation, effects of pyrene exposure on particle-size selection, and fecal pyrene content in the oligochaete Limnodrilus hoffmeisteri (Tubificidae, Oligochaeta).

The oligochaete Limnodrilus hoffmeisteri Cleparéde was exposed to sediment-amended pyrene (0-1,196 nmol/g dry wt) for 2, 5, and 10 d to investigate sediment particle-size preference, tissue pyrene bioaccumulation (using biota-sediment accumulation factor, BSAF), fecal pyrene concentrations (using fecal-sediment accumulation factor, FSAF), and pyrene biotransformation. In non-pyrene-amended sediment, L. hoffmeisteri preferentially ingested finer sediment particles (< 3.5 microns). However, pyrene concentrations > 199 nmol/g dry weight resulted in a decreased preference for finer particles, presumably reducing pyrene exposure. Particle selectivity also changed with time such that after 10 d, worms showed an increased preference for finer particles. At high pyrene exposure, tissue pyrene concentrations rapidly attained equilibrium (maximum body residue 4.4 mumol/g wet wt, close to values cited for hydrocarbon critical body residues). Levels of biotransformation were low (mean 14%) and independent of time or pyrene concentration. Biota-sediment accumulation factor showed a negative relationship with sediment pyrene concentration; this trend may be due to reduced availability at high sediment pyrene concentrations or due to reductions in both ingestion rate and selectivity for fine, pyrene-rich particles. Fecal pyrene concentrations were depleted compared to sediment levels, suggesting removal of pyrene during gut passage by absorption. Fecal-sediment accumulation factor showed a negative relationship with increasing sediment pyrene levels.

Algorithms↗

PubMed1976

Enzymatic conversion of benzo(a)pyrene leading predominantly to the diol-epoxide r-7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene through a single enantiomer of r-7, t-8-dihydroxy-7,8-dihydrobenzo(a)pyrene.

Benzo(a)pyrene is metabolically and stereospecifically converted by mixed-function oxidases of rat liver microsomes and epoxide hydratase (glycol hydro-lyase (epoxide-forming), EC 4.2.1.63)to the single enantiomer (-)r-7,t-8-dihydroxy-7,8-dihydrobenzol (A) pyrene. This enantiomer is further metabolized stereoselectively by the mixed-function oxidases to predominantly the diol-epoxide, r-7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydrobenzol(a)pyrene in which the 7-hydroxyl and the 9,10-epoxide are trans. Other unidentified metabolites are also formed from the r-7,t-8-dihydroxy-7,8-dihydrobenzo(a)pyrene. Racemic r-7,t-8-dihydroxy-7,8-dihydrobenzo(a)-pyrene is converted metabolically to both r-7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene and r-7,t-8-dihydroxy-c-9,10-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene. The diol-epoxides are unstable in aqueous medium, and their identification and characterization as r-7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene and r-7,t-8-dihydroxy-c-9,10-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene were accomplished by the identity of their tetrahydroxytetrahydrobenzo(a)pyrenes hydrolysis products with those of the authentic synthetic compounds with respect to mobility on high-pressure liquid chromatography and mass and ultraviolet absorption spectral analysis. The diol-epoxides were also reduced in the presence of NADPH to distinct trihydroxypentahydrobenzo(a)pyrenes. Since the synthetic racemic r-7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene is very highly mutagenic in mammalian cells, we suggest that it is the metabolically formed diol-epoxide that may be an ultimate carcinogenic form of benzo(a)pyrene.

Animals↗

PubMedDate not supplied

Comparison of the urinary excretion time courses of pyrene-1,6-dione, pyrene-1,8-dione and 1-hydroxypyrene in rats intravenously exposed to pyrene.

The urinary excretion time courses of pyrene-1,6-dione (P16D), pyrene-1,8-dione (P18D) and 1-hydroxypyrene (1-OHP) were compared in Sprague-Dawley and Wistar rats. Groups of five male rats, of about 200 g of body weight, were injected intravenously with 0.05, 0.5, 5 and 50 micromol pyrene kg-1 of body weight. Urine was collected at 2, 4, 6, 8, 10, 12, 18, 24, 30, 42 and 48 h post-dosing. Pyrene metabolites were measured by high-performance liquid chromatography (HPLC)/fluorescence after enzymatic hydrolysis of the glucurono- and sulfo-conjugates, extraction on Sep-Pak C18 cartridges and, for the analysis of dione metabolites, derivatization to stable diacetoxypyrene molecules. Over the 48-h sampling period, on average 17.4-25.6% of the injected pyrene was excreted overall as P16D, 6.4-8.8% as P18D and 0.6-0.8% as 1-OHP in the urine of Sprague-Dawley rats. By comparison, on average 10.3-14.7% of the intravenous pyrene dose was recovered as P16D, 4.8-6.4% as P18D and 0.3-0.4% as 1-OHP in the urine of Wistar rats. In both strains of rats there was no clear effect of the dose on the 0-48-h cumulative urinary excretion of P18D and 1-OHP over the entire dose range, while the percentage of dose recovered overall as P16D in urine at the highest dose (50 micromol kg-1) was statistically lower than at the other doses. The 0-48-h cumulative percentage of pyrene dose excreted as metabolites in the urine of Sprague-Dawley rats was also significantly higher than in Wistar rats (p<0.01) exposed under identical conditions. As for the urinary excretion-time courses of the different metabolites, for a given dose and strain of rats, excretion curves of P16D, P18D and 1-OHP generally evolved in parallel. There was also no clear effect of the dose on the excretion rate, thus half-life, of pyrene metabolites, except for P16D in Sprague-Dawley rats at the highest dose where elimination tended to be slower compared with the other doses (p<0.01). The average first-order elimination half-life of P16D, P18D and 1-OHP was 4.0, 5.7 and 4.1 h, respectively, in Sprague-Dawley rats, and 5.1, 6.1 and 5.1 h, respectively, in Wistar rats (all doses combined but excluding the highest dose for P16D). This study showed the relative importance of metabolic pathways leading to diones compared with 1-OHP. These dioxygenated metabolites appear to be interesting biomarkers of pyrene exposure at environmentally and occupationally relevant doses. Their adequacy as biomarkers of human exposure has yet to be confirmed.

Animals↗

PubMed1982

Spectroscopic characterizations and comparisons of the structures of the covalent adducts derived from the reactions of 7, 8-dihydroxy-7,8,9,10-tetrahydrobenzo [a] pyrene-9,10-oxide, and the 9, 10-epoxides of 7,8,9,10-tetrahydrobenzo [a] pyrene and 9.10,11,12-tetrahydrobenzo [e] pyrene with DNA.

The conformation of covalent adducts derived from the reactions of racemic 7 beta,8 alpha-dihydroxy-9 alpha, 10 alpha-epoxy-7,8,9,10-tetrahydrobenzo [a] pyrene (BaPDE), 9,10-epoxy-7,8,9,10-tetrahydrobenzo [a] pyrene (BaPE), and 9,10-epoxy-9,10,11,12-tetrahydrobenzo [e] pyrene (BePE) with calf thymus DNA in aqueous buffer solution (25 degrees C, pH 7.0) were investigated and compared by means of absorption, fluorescence and electric linear dichroism techniques. Two types of conformations are recognized. Site I is characterized by a red shift (approximately 10 nm) in the absorption maximum of the pyrene nucleus, a significantly reduced fluorescence yield, and a negative electric linear dichroism signal (delta A); this site is presumed to involve a near-parallel (within 25 degrees) orientation of the planar pyrene residue with the planes of the DNA bases, and a relatively strong interaction between the phi electrons of the nucleic acid bases and the pyrene residue. In site II, there is only a small red-shift in the absorption maximum (approximately 2 nm), a non-zero fluorescence yield, and a positive delta A throughout the absorption region of the pyrene residue; in this conformation the pyrene residue is presumed to lie on the outside of the DNA molecule, possibly in one of the grooves. The BaPDE-DNA complex displays predominantly a site II-type conformation while the BaPE- and BePE-DNA complexes display both site I and site II adducts, with site I conformations predominating. The lack of hydroxyl groups in BaPE and BePE lead to a loss in stereospecificity in covalent adduct formation. The 7 and 8 hydroxyl groups in covalent adduct formation. The 7 and 8 hydroxyl groups in BaPDE appear to reduce the probability of formation of site I-type of covalent adducts, and appear to be, at least in part, responsible for the enantiomeric stereospecificity in the covalent reaction between BaPDE and DNA.

Benzopyrenes↗

PubMed1975

[Studies on the metabolism of benzo(a)pyren in alveolar-macrophages. I. Uptake of benzo(a)pyrene and induction of benzo(a)pyrene hydroxylase (author's transl)].

Alveolar macrophages play a significant role in the elimination of inhaled foreign compounds and particles from the lung. The question arises, if alveolar macrophages participate in the detoxification or activation of environmental carcinogenic compounds. In the first communication on this subject we describe experiments concerning the uptake of benzo(a)pyrene and the activity of the metobolizing enzymes. The alveolar macrophages are obtained by lung lavage from guinea pigs (Fig. 1,2,3). The cells are grown in monolayers in petri dishes or on the surface of cover slips or glass-vials. The uptake of benzo(a)pyrene in alveolar macrophages is measured by a microfluorimetric method in single cells and by using labelled substrate. The results obtained by both methods indicate that the uptake is terminated between 1-2 h (Fig. 4, 5). The kinetics of uptake and elimination (Fig. 8, 9). are influenced by the concentration of serum (Fig. 6) and benzo(a) pyrene (Fig. 7) in the medium. Two mechanism for the uptake in the alveolar macrophages are discussed: diffusion and pinocytose. The activity of the metabolizing enzymes (benzo(a)pyrene hydroxylase, aryl hydrocarbon hydroxylase)increases during incubation with benzo(a)pyrene (Fig. 10, 11) and is dependant on the concentration of benzo(a)pyrene in the growth medium (Fig. 12). The enzyme activity is inducible also by other polycyclic hydrocarbons (Tab. 1). The induction is inhibited by actinomycin D and cycloheximid (Tab. 2). The activity of the enzymes in guinea pig alveolar macrophages is comparable to the activity in leucocytes and alveolar-macrophages from humans (Tab. 3, 4).

Animals↗

PubMed1991

Metabolism of benzo[a]pyrene and benzo[a]pyrene-7,8-dihydrodiol in human mammary epithelial cells: feedback inhibition by 7-hydroxybenzo[a]pyrene.

The metabolism of benzo[a]pyrene (B[a]P) and (-)-transbenzo[a]pyrene-7,8-dihydrodiol (B[a]P-diol) was compared in human mammary epithelial cells (HMEC) grown in serum-free medium, MCDB-170. Conversion of B[a]P-diol to the carcinogen (+)-benzo[a]pyrene-7,8-dihydroxy-9,10-epoxide (BPDE), as measured by analysis of their tetraol hydrolysis products, occurred much more efficiently in cultures incubated with [3H]B[a]P-diol than in cultures incubated with [3H]B[a]P. In cultures pretreated with unlabeled B[a]P (24 h, 400 nM), the conversion of [3H]-B[a]P-diol to [3H]tetraols is inhibited 49%, while the conversion of [3H]B[a]P to [3H]B[a]P-diol- is not affected. These observations led to the identification of a major B[a]P-derived metabolite as 7-hydroxybenzo[a]pyrene (B[a]P-7-ol), which was found to be an extremely potent and selective inhibitor of the conversion of B[a]P-diol to BPDE, with a KI estimated at 3-12 nM. Thus B[a]P activation in HMEC appears to be significantly limited by a feedback inhibition pathway induced by B[a]P-7-ol. The potency and selectivity of the B[a]P-7-ol-induced inhibition suggests that the diol to diolepoxide conversion is affected by a selective oxygenase in HMEC, rather than a non-enzymatic, peroxy radical-induced mechanism. B[a]P-7-ol should prove to be a valuable tool in the study of B[a]P carcinogenesis.

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

PubMed1996

Molecular characterization of mutation and comparison of mutation profiles in the hprt gene of Chinese hamster ovary cells treated with benzo[a]pyrene trans-7,8-diol-anti-9,10-epoxide, 1-nitrobenzo[a]pyrene trans-7,8-diol-anti-9,10-epoxide, and 3-nitrobenzo[a]pyrene trans-7,8- diol-anti-9,10-epoxide.

Both 1- and 3-nitrobenzo[a]pyrene (nitro-BaP) are environmental contaminants, potent mutagens in Salmonella, and moderate mutagens in Chinese hamster ovary (CHO) cells. The mutagenicity of their oxidized metabolites,trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-epoxy -7,8,9,10-tetrahydro-1-nitrobenzo[a]pyrene (1-nitro-BaP-DE) and trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydro-3-nitrobenzo[a]- pyrene (3-nitro-BaPDE), together with trans-7,8-dihydroxy-anti-9, 10-ep- oxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BaP-DE), was determined in CHO-K1 cells, and the resulting mutations at the hprt locus were characterized by polymerase chain reaction (PCR) amplification of reverse-transcribed hprt mRNA, followed by DNA sequence analysis. The mutant frequencies, in mutants/10(6) clonable cells, at 30 and 100 ng/ml, were BaP-DE, 248 and 456; 1-nitro-BaP-DE, 68 and 260; 3-nitro-BaP-DE, 81 and 232, respectively. In general, the three diolepoxides exhibited similar mutational spectra: 1) 64% (23/36 sequenced mutants) of BaP-DE, 53% (19/36) of 1-nitro-BaP-DE, and 64% (23/36) of 3-nitro-BaP-DE mutants resulted from simple base pair substitution, with the predominant mutation being G-->T transversion; 2) 90%, 100%, and 100% of mutations at G:C had the mutated dG on the nontranscribed DNA strand; and 3) about one quarter of the mutants produced by each mutagen had one or more PCR products with partial or complete exon deletions. The mutagens induced few frameshifts or complex mutations. Among the differences in mutational specificity for the three diolepoxides, the proportion of substituted dGs with 3' purines was significant (P < 0.05) for BaP-DE (16/19, 84%) and 3-nitro-BaP-DE (17/20, 85%), but not significant for 1-nitro-BaP-DE-induced mutants (11/17, 65%, P > 0.05). Also, high proportions of BaP-DE and 3-nitro-BaP-DE base pair substitutions at G:C occurred in DNA sequence contexts of 5'-GG-3', 5'-GGA-3', and 5'-TGGA-3', while the proportions of 1-nitro-BaP-DE mutants in these contexts were often lower. The results indicate that nitro substitution at C1 or C3 of BaP-DE reduces mutational potency in CHO cells and appears to have only subtle effects upon the mutational pattern in the hprt gene.

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

PubMed1985

Secondary metabolites of benzo[a]pyrene: 3-hydroxy-trans-7,8-dihydro-7,8-dihydroxybenzo[a]pyrene, a biliary metabolite of 3-hydroxybenzo[a]pyrene in the rat.

Rats administered 3-hydroxybenzo[a]pyrene (50 mg/kg, i.p.), excrete via the bile metabolites which, after treatment with beta-glucuronidase and aryl sulphatase, yield, in addition to 3-hydroxybenzo[a]pyrene, 3-hydroxy-trans-7,8-dihydro-7,8-dihydroxybenzo[a]pyrene (3-OH-BP-7,8-diol) and a minor, highly labile, metabolite tentatively identified as 3,5-dihydroxybenzo[a]pyrene. These novel metabolites are readily isolated in a pure state via preparative layer chromatography. The structure of the 3-OH-BP-7,8-diol was revealed by its u.v., proton magnetic resonance and mass spectral properties. Its hydroxyl functions are in a predominantly quasi-diequatorial conformation.

Animals↗

PubMed2004

Differential c-myc expression profiles in normal human bronchial epithelial cells following treatment with benzo[a]pyrene, benzo[a]pyrene-4,5 epoxide, and benzo[a]pyrene-7,8-9,10 diol epoxide.

Bronchial epithelial cells are often exposed to airborne mutagens that have the potential to induce genetic changes involved in the development of lung cancer. Although lung tumors often display alterations in the expression of oncogenes and/or tumor suppressor genes, the role of specific chemicals and/or metabolites in causing these alterations is not well defined. The polycyclic aromatic hydrocarbon (PAH) benzo[a]pyrene (B[a]P), a by-product of combustion, is a prevalent airborne environmental mutagen and a constituent of cigarette smoke. The primary objective of this study was to compare the effect of B[a]P and two of its reactive metabolites, benzo[a]pyrene diol epoxide (BPDE or bay region epoxide) and benzo[a]pyrene-4,5-dihydroepoxide (BPE or K-region epoxide), on expression of the proto-oncogene c-myc in normal human bronchial epithelial (NHBE) cells using a quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) method. Changes in c-myc gene expression were compared with DNA adduct formation, growth inhibition, and cell-cycle progression as determined by (32)P-postlabelling, neutral red (NR), and flow cytometric analyses, respectively. None of the three test compounds altered the levels of 18S ribosomal RNA or beta-actin at the concentrations evaluated for c-myc expression, indicating that nonspecific changes in gene expression induced by cytotoxicity, for example, were not present at the concentrations evaluated. Cells exposed to B[a]P exhibited a dose-dependent increase in c-myc expression; conversely, a dose-dependent decrease in c-myc expression was observed following BPDE exposure. A marginal but concentration-dependent increase in c-myc mRNA levels was observed following exposure to the K-region epoxide. Our results demonstrated that, although B[a]P and its metabolites alter c-myc expression, the parent compound and its metabolites produce unequal and contrasting effects on the expression of this gene.

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

PubMed1987

Contrasting disposition and metabolism of topically applied benzo(a)pyrene, trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene, and 7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene in mouse epidermis in vivo.

Whereas extensive evidence indicates that 7 beta,8 alpha-dihydroxy-9 alpha, 10 alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene (anti-BPDE) is a major ultimate carcinogen of benzo(a)pyrene (BaP) in mouse skin, tumorigenicity studies have consistently shown that anti-BPDE is less active then BaP in this model system. In order to investigate factors responsible for this apparent contradiction, we have compared the disposition, metabolism, and DNA binding of [3H]BaP, (+/-)-trans-7,8-[14C]dihydroxy-7,8-dihydrobenzo(a)pyrene [(+/-)-[14C]BaP-7,8-diol), and (+/-)-anti-[3H]BPDE in mouse epidermis in vivo. There were remarkable differences in the total radioactivity recovered in epidermis at various times after topical application of BaP, BaP-7,8-diol, and anti-BPDE. BaP and its metabolites were removed from epidermis gradually (t1/2 approximately equal to 2 h). However, 60-65% of anti-BPDE disappeared from mouse epidermis within 3 min of application, while a second slower phase of removal of radioactivity was observed between 8 min and 2 h. The kinetics of removal of BaP-7,8-diol and its metabolites were intermediate between those of BaP and anti-BPDE. The half-life of anti-BPDE in mouse epidermis was measured by trapping it with 2-mercaptoethanol. The initial half-life was about 6 min, similar to that observed in vitro. However, following the initial rapid penetration of anti-BPDE through epidermis most of the remaining material became immobilized in an epidermal binding site in which its half-life was greater than 2 h. Qualitatively, the metabolite patterns of BaP, BaP-7,8-diol, and anti-BPDE were similar to expectations based on in vitro studies. However, the kinetics of metabolite formation from BaP were different from those of BaP-7,8-diol or anti-BPDE. The extents of formation of anti-BPDE-DNA adducts 24 h after application of BaP, BaP-7,8-diol, or anti-BPDE to mouse skin were similar despite the fact that the levels of anti-BPDE present in epidermis were about 50 to 100 times greater after application of BaP-7,8-diol or anti-BPDE than after application of BaP. The results of this study demonstrate that the quantitative aspects of BaP-7,8-diol and anti-BPDE metabolism and disposition in mouse skin are different from those of BaP and indicate that the relatively low tumorigenicity of BaP-7,8-diol and anti-BPDE in mouse skin may be partially attributable to differences between the disposition of these metabolites when topically applied compared to when they are generated intracellularly from BaP.

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

PubMed1982

Distinct local environments of the pyrene chromophores in the covalent deoxyribonucleic acid adducts of 9,10-epoxy-9,10,11,12-tetrahydrobenzo[e]pyrene and 7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene elucidated by optically detected magnetic resonance.

The optically detected magnetic resonance (ODMR) spectra of the covalent DNA adduct of 9,10-epoxy-9,10,11,12-tetrahydrobenzo[e]pyrene (BePE) reveal that the excited triplet state chromophore is perturbed by the nucleic acid and that this perturbation is diminished successively by denaturation and enzymatic hydrolysis of the modified DNA, indicating that the adduct resides in an environment with some quasi-intercalative character. In contrast the covalent adduct of 7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene shows little ODMR evidence of interaction with the nucleic acid, which, in view of ODMR's sensitivity demonstrated for the BePE adduct, suggests that the chromophore is situated in an environment resembling the bulk solvent. These results demonstrate that ODMR is more sensitive than conventional phosphorescence techniques to interactions between these pyrene-like chromophores and DNA.

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

PubMed2003

Role of cytochrome P4501B1 in benzo[a]pyrene bioactivation to DNA-binding metabolites in mouse vascular smooth muscle cells: evidence from 32P-postlabeling for formation of 3-hydroxybenzo[a]pyrene and benzo[a]pyrene-3,6-quinone as major proximate genotoxic intermediates.

Benzo[a]pyrene (BP), a polycylic aromatic hydrocarbon (PAH), is a potent atherogen and carcinogen in laboratory animals. Since genotoxic mechanisms may contribute to the development of atherosclerosis by PAHs, we have tested the hypotheses that: 1) BP induces DNA adducts in mouse aortic smooth muscle cells (SMCs); 2) 3-hydroxybenzo[a]pyrene (3-OH-BP) and benzo[a]pyrene-3,6-quinone (BPQ) are proximate genotoxic metabolites; and 3) cytochrome P4501B1 (CYP1B1) mediates the activation of BP and its metabolites to ultimate genotoxic intermediates. Cultured mouse aortic SMCs were treated with BP, 3-OH-BP, or BPQ for 24 h, and DNA adduct formation was analyzed by (32)P-postlabeling. In some experiments, cells were pretreated with the CYP1B1 inhibitor 1-ethynylpyrene (EP) prior to exposure to BP or its metabolites. BP, 3-OH-BP, and BPQ induced formation of several DNA adducts that were not observed in dimethylsulfoxide-treated cells. Re- and cochromatography experiments indicated that 3-OH-BP and BPQ were proximate genotoxic metabolites of BP. DNA adduct formation was strongly inhibited by EP, a specific inhibitor of CYP1B1. BP treatment of SMCs resulted in induction of aryl hydrocarbon hydroxylase (AHH) activity and CYP1B1, but not CYP1A1, apoprotein. EP also blocked AHH induction by BP. In conclusion, the results of this study support the hypothesis that in SMCs, which are target sites for the development of atherosclerosis, the major bioactivation pathway of BP entails CYP1B1-mediated formation of the 3-OH-BP and BPQ, which are proximate genotoxic metabolites that may in turn get transformed to ultimate DNA-binding metabolites, which may contribute to atherogenesis by PAHs.

Animals↗

PubMed1979

Carcinogenicity and polarographic behaviour of dibenzo[a,h]pyrene, 4,11-diazadibenzo[a,h]pyrene and 7,14-diazadibenzo[a,h]pyrene.

In a simultaneous test of carcinogenicity the writers have studied the activities of dibenzo[a,h]pyrene (I), 4,11-diazadibenzo[a,h]pyrene (II) and 7,14-diazadibenzo[a,h]pyrene (III). These compounds were dispersed in paraffin disks and subcutaneously implanted in rats. Each experimental group consisted of 30 animals. The number of sarcomas induced by (I) and (II) was 23 and 16 respectively. The compound (III) has proved wholly inactive. Tumorigenicity of (I) and (II) was found to be proportional to their electron donation and inversely proportional to their electron acceptance in the performed polarographic test. Inactivity of (III) is being discussed from the aspect of molecular geometry.

Animals↗

PubMed1992

The time-dependent increase in the binding of benzo[a]pyrene to DNA through (+)-anti-benzo[a]pyrene-7,8-diol-9,10-epoxide in primary rat hepatocyte cultures results from induction of cytochrome P450IA1 by benzo[a]pyrene treatment.

The proportion and amount of benzo[a]pyrene (B[a]P) that binds to DNA through the carcinogenic (+)-anti-benzo[a]pyrene-7,8-diol-9,10-epoxide [(+)-anti-BPDE] increases with time of exposure to B[a]P in cell cultures derived from a number of species. Pretreatment of primary rat hepatocyte cultures for 12 h with 1 microgram B[a]P/ml medium increased the subsequent metabolism of [3H]B[a]P by 47% and [3H]B[a]P-DNA binding by 53% compared with acetone-pretreated hepatocytes. The amount of (+)-anti-BPDE bound to DNA in the B[a]P-pretreated hepatocytes increased 175%. B[a]P pretreatment also increased DNA-binding 2-fold in hepatocytes treated with [3H]7,8-dihydroxy-7,8-dihydro-B[a]P but had no effect on DNA binding in cells treated with anti-B[a]P-7,8-diol-9,10-epoxide. Western blotting showed that cytochrome P450IA1, which was not detectable prior to B[a]P treatment, was selectively increased by B[a]P treatment. A monoclonal antibody that specifically inhibits cytochrome P450IA1 reduced the binding of B[a]P to DNA by greater than 90% in microsomal preparations from B[a]P-pretreated hepatocytes. These results indicate that the time-dependent increase in the formation of (+)-anti-BPDE-DNA adducts results from an increase in the amount and proportion of B[a]P metabolized to this ultimate carcinogen by P450IA1 that is induced by the B[a]P treatment. The importance of P450IA1 induction by the B[a]P for its activation to this ultimate carcinogenic metabolite suggests that long-term exposure of cells to B[a]P could result in activation of a higher proportion of the B[a]P to the carcinogenic (+)-anti-BPDE.

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

PubMed1991

Comparative dose-response tumorigenicity studies of dibenzo[alpha,l]pyrene versus 7,12-dimethylbenz[alpha]anthracene, benzo[alpha]pyrene and two dibenzo[alpha,l]pyrene dihydrodiols in mouse skin and rat mammary gland.

Comparative studies were conducted of the tumor-initiating activity in mouse skin and carcinogenicity in rat mammary gland of dibenzo[a,l]pyrene (DB[a,l]P) versus 7,12-dimethyl-benz[a]anthracene (DMBA), the most potent recognized carcinogenic polycyclic aromatic hydrocarbon (PAH); benzo[a]pyrene (B[a]P), the most potent recognized carcinogenic environmental PAH; DB[a,l]P 8,9-dihydrodiol, the K-region dihydrodiol; and DB[a,l]P 11,12-dihydrodiol, precursor to the bay-region diolepoxide. The tumor-initiating activity of DB[a,l]P and B[a]P was compared in the skin of female SENCAR mice at doses of 300, 100 and 33.3 nmol. The mice were promoted with 12-O-tetradecanoylphorbol-13-acetate (TPA) twice-weekly for 13 weeks. DB[a,l]P at all doses induced significantly more tumors than B[a]P at the corresponding dose, with a significantly shorter latency. Subsequently, the tumor-initiating activity of DB[a,l]P was compared in the skin of female SENCAR mice to that of DMBA, B[a]P, DB[a,l]P 8,9-dihydrodiol and DB[a,l]P 11,12-dihydrodiol at doses of 100, 20 and 4 nmol. The mice were promoted with TPA twice-weekly for 24 weeks. In addition, groups of mice were initiated with 100 nmol of DB[a,l]P, DMBA, B[a]P, DB[a,l]P 8,9-dihydrodiol or DB[a,l]P 11,12-dihydrodiol and kept without promotion. This experiment showed that in the mouse skin, DB[a,l]P and DB[a,l]P 11,12-dihydrodiol displayed similar tumor-initiating activity with a response inversely proportional to the dose, presumably due to the toxicity of the compounds. At the high dose they elicited tumors earlier than DMBA, though DMBA produced a much higher tumor multiplicity. At the low dose, DMBA, DB[a,l]P and DB[a,l]P 11,12-dihydrodiol exhibited similar tumorigenicities. DB[a,l]P 8,9-dihydrodiol was a marginal tumor initiator. Once again, DB[a,l]P was by far a much stronger tumor initiator than B[a]P. Female Sprague-Dawley rats were treated with 1.0 or 0.25 mumol of DB[a,l]P, DMBA or B[a]P by intramammillary injection at eight teats. DB[a,l]P at both doses was a more potent carcinogen than DMBA at the corresponding dose in the rat mammary gland. B[a]P was a marginal mammary carcinogen, eliciting only a few fibrosarcomas. Thus, these data suggest that DB[a,l]P is the strongest PAH carcinogen ever tested.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1997

Comparison of the morphological transforming activities of dibenzo[a,l]pyrene and benzo[a]pyrene in C3H10T1/2CL8 cells and characterization of the dibenzo[a,l]pyrene-DNA adducts.

C3H10T1/2CL8 (C3H10T1/2) mouse embryo fibroblasts were used to study the in vitro carcinogenic activities of dibenzo[a,l]pyrene (DB[a,l]P) and benzo[a]pyrene (B[a]P). The morphological transforming activities of these rodent carcinogens were compared using replicate concentration-response studies. In concentration ranges where both polycyclic aromatic hydrocarbons (PAHs) were active, DB[a,l]P proved to be four to 12 times as potent as B[a]P based on concentration. At lower concentrations DB[a,l]P was active at 0.10 and 0.20 microM, concentrations where B[a]P was inactive. This makes DB[a,l]P the most potent non-methylated PAH evaluated to date in C3H10T1/2 cells. DNA adducts of DB[a,l]P in C3H10T1/2 cells were analyzed by both TLC and TLC/HPLC 32P-postlabeling methods using mononucleotide 3'-phosphate adduct standards derived from the reactions of anti-DB[a,l]P-11,12-diol-13,14-epoxide (anti-DB[a,l]PDE) and syn-DB[a,l]P-11,12-diol-13,14-epoxide (syn-DB[a,l]PDE) with deoxyadenosine 3'-monophosphate and deoxyguanosine 3'-monophosphate. All of the DNA adducts observed in C3H10T1/2 cells treated with DB[a,l]P were identified as being derived from the metabolism of DB[a,l]P to its fjord region diol epoxides through DB[a,l]P-11,12-diol. The predominant adduct was identified as an anti-DB[a,l]PDE-deoxyadenosine adduct. Other major adducts were anti-DB[a,l]PDE-deoxyguanosine and syn-DB[a,l]PDE-deoxyadenosine adducts with minor amounts of syn-DB[a,l]PDE-deoxyguanosine adducts. These DNA adduct data are consistent with similar findings of DB[a,l]PDE-deoxyadenosine adducts in mouse skin studies and human mammary cells in culture.

Animals↗

PubMed1988

Detection of benzo[a]pyrene-DNA adducts in cultured cells treated with benzo[a]pyrene diol-epoxide by quantitative immunofluorescence microscopy and 32P-postlabelling; immunofluorescence analysis of benzo[a]pyrene-DNA adducts in bronchial cells from smoking individuals.

Monoclonal antibodies were raised against the reaction product of benzo[a]pyrene diol-epoxide (BPDE) and deoxyguanosine-5'-monophosphate. The antibodies were used for detection of DNA adducts in situ in BPDE-treated cultured human fibroblasts by immunofluorescence microscopy. Analogue-digital conversion of the fluorescence signal and further image processing allowed measurement of the immunospecific fluorescence in the nuclei of these cells. The results are compared with the adduct levels measured in isolated DNA by 32P-postlabelling. Preliminary results are shown of the application of the immunofluorescence method to the analysis of DNA adducts in bronchial cells obtained from smoking individuals.

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