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PubMed1997

Rate of pyrene metabolism in rat liver post-mitochondrial fractions.

The objective of the present study was to estimate the maximal velocity (Vmax) and Michaelis affinity constant (Km) for the oxidation of pyrene to 1-hydroxypyrene using rat liver post-mitochondrial fractions. The approach involved the determination of the concentrations of 1-hydroxypyrene formed during 5 min incubations of pyrene (initial concentrations: 0.0025-0.5 microM), and correcting for the rate of 1-hydroxypyrene disappearance (2.16 x 10(-5) per (mg protein/l)/min) during the incubation period. The Vmax and Km for pyrene metabolism in the rat corresponded to 0.0577 +/- 0.0108 micromol/min per g liver and 27.73 +/- 13.54 microM, respectively. The intrinsic clearance (CL(int)) of pyrene in the rat estimated in the present study (0.041-0.111 l/min per kg) was within the range of the previously reported CL(int) in humans (0.037-0.125 l/min per kg). The results of this study suggest that CL(int) of pyrene in humans can be predicted from such data obtained in the rat.

Animals↗
PubMed1999

Cytochrome P450 isoforms catalyzing benzo[a]pyrene metabolism in the Chinese hamster liver.

Cytochrome P450 isoforms involved in the benzo[a]pyrene metabolism in the Chinese hamster liver were characterized. The activity of benzo[a]pyrene hydroxylase in male hamster livers increased markedly by treatment with 3-methylcholanthrene (25 mg/kg per day, i.p., 3 days) and moderately with phenobarbital (60 mg/kg per day) and dexamethasone (100 mg/kg per day). In contrast, the ability for the mutagenic activation of benzo[a]pyrene determined by the mutagenicity test was increased most markedly by treatment with phenobarbital and significantly with 3-methylcholanthrene, but not with dexamethasone. These observations are similar to those in the rat rather than in the Syrian hamster. Western blot analysis and assay of the enzymes associated with cytochrome P450 isoforms showed that the 3-methylcholanthrene treatment elevated markedly the level of CYP1A2, but not that of CYP1A1, while the phenobarbital treatment elevated markedly the level of CYP2A and CYP3A, but not that of CYP2B. Further, immunoinhibition study demonstrated that, in Chinese hamster livers, CYP2A and CYP1A2 were mainly involved in the mutagenic activation of benzo[a]pyrene and CYP3A in the benzo[a]pyrene hydroxylase activity, respectively.

Animals↗
PubMed2000

Evaluation of benzo(a)pyrene-induced DNA damage in human endothelial cells using alkaline single cell gel electrophoresis.

The alkaline version of the 'comet assay' was used to evaluate DNA damage in human umbilical vein endothelial cells (HUVEC) exposed to 0.1, 1.0, or 10 microM benzo(a)pyrene for 90min. The genotoxicity was monitored in HUVEC pretreated with the Ah-receptor agonist beta-naphthoflavone (BNF), previously shown to induce cytochrome P4501A1 (CYP1A1) activity in these cells, and in vehicle-treated HUVEC with only constitutive levels of this enzyme. Increased DNA damage was observed only in cells that had been exposed to 10 microM benzo(a)pyrene, cells exposed to BNF being subjected to the most extensive damage. The CYP1A/B-inhibitor alpha-naphthoflavone (ANF) reduced the benzo(a)pyrene-induced DNA-damage in the BNF-treated HUVEC to the same level as in the uninduced cells. The fact that benzo(a)pyrene induced DNA damage in vehicle-treated HUVEC suggests that there may be at least one alternative route of bioactivation for benzo(a)pyrene in these cells. Consequently, judging from the present results it seems as if tobacco-related polycyclic aromatic hydrocarbons (PAHs) may disrupt the function of the endothelial lining in blood vessels with low monooxygenase activity. It is proposed that exposure to Ah receptor agonists via, for example, tobacco smoke, may enhance the DNA-damaging effects of smoke-related genotoxic PAHs in human endothelial cells. The role of PAHs in endothelial dysfunction of tobacco smokers should therefore be further studied.

Animals↗
PubMed2001

Probing the lateral organization of membranes: fluorescence repercussions of pyrene probe distribution.

Phospholipids pyrene labeled are widely used to investigate dynamics and organizations of membranes. We studied pyrene probe lateral distribution by analyzing the variations of the molar absorption coefficient (epsilon) versus probe concentrations, in small unilamellar vesicles (SUV) made of phospholipids and/or glycolipids, with pyrene labeled phosphatidylcholine (PyPC) or phosphatidylglycerol (PyPG). The results were interpreted according to an infinite associative model. They indicated that an effective self-association process corresponding to K ranging from 30 to 100 M(-1) occurred with those probes incorporated in dimannosyl diacylglycerol (DMDG). In contrast, after SUV labeling of egg yolk phosphatidylcholine (EggPC) or phosphatidylglycerol (EggPG), K values < 1 M(-1) were determined. The corresponding percentages of various stacked forms of pyrene probes were calculated. They indicated that, for a 3% PyPG labeling, the monomer represented 21% of n-mers in DMDG and 94% in EggPC. The analysis of fluorescence experiments carried out on the same samples indicated that: (i) the fluorescence process of pyrene probes was generated by the monomers: and (ii) the excimer forming resulted from a diffusional encounter between one excited and one non-excited monomer. A correction of fluorescence data allowing a more correct interpretation of fluorescence measurements was proposed.

Cell Membrane↗
PubMed1994

Solution conformation of the (+)-trans-anti-[BP]dG adduct opposite a deletion site in a DNA duplex: intercalation of the covalently attached benzo[a]pyrene into the helix with base displacement of the modified deoxyguanosine into the major groove.

This paper reports on the solution structure of the (+)-trans-anti-[BP]dG adduct positioned opposite a deletion site in a DNA oligomer duplex which defines the alignment of this covalent benzo[a]pyrene-N2-deoxyguanosine stereosiomer relative to the deletion site. The combined NMR-molecular mechanics computation studies were undertaken on the (+)-trans-anti-[BP]dG adduct embedded in the d(C5-[BP]G6-C7).d(G16-G17) sequence context in a duplex containing 11 residues on the modified strand and 10 on the partner, with no base opposite the modification. The exchangeable and nonexchangeable protons of the benzo[a]pyrenyl moiety and the nucleic acid were assigned following analysis of two-dimensional NMR data sets in H2O and D2O solution. The solution conformation of the (+)-trans-anti-[BP]dG.del 11-mer duplex has been determined by incorporating intramolecular and intermolecular proton-proton distances defined by lower and upper bounds deduced from NOESY spectra as restraints in molecular mechanics computations in torsion angle space. The benzo[a]pyrene ring of [BP]dG6 is intercalated between intact Watson-Crick dC5.dG17 and dC7.dG16 base pairs with the deoxyguanosine base of [BP]dG6 displaced into the major groove. The intercalation site is wedge shaped, being narrower toward the dG16-dG17 step on the deletion-containing strand. The deoxyguanosine base of [BP]dG6 which is positioned in the major groove is inclined relative to the helix axis and stacks over the 5'-flanking dC5 residue in the solution structure. The intercalative-base displacement structure of the (+)-trans-anti-[BP]dG.del 11-mer duplex exhibits several unusually shifted proton resonances which can be readily accounted for by the ring current contribution of the deoxyguanosyl and pyrenyl rings of the [BP]dG6 adduct. This solution structure of the (+)-trans-anti-[BP]dG.del 11-mer duplex where the pyrene ring intercalates into the helix with displacement of the modified deoxyguanosine into the major groove strikingly contrasts with our previous study on the (+)-trans-anti-[BP]dG.dC 11-mer duplex [Cosman, M., et al. (1992) Proc. Natl. Acad. Sci. U.S.A. 89, 1914-1918] where the benzo[a]pyrene ring is positioned in the minor groove without disruption of the Watson-Crick pairing at the [BP]dG.dC modification site. Thus, generation of the deletion site following removal of the dC opposite the (+)-trans-anti-[BP]dG results in a displacement of the entire [BP]dG residue toward the major groove and intercalation of the benzo[a]pyrene ring into the helix.

Base Sequence↗
PubMed1983

Fluorescent properties of pyrene bound at specific acylation sites of chicken liver fatty acid synthase.

The covalent modification of chicken liver fatty acid synthase by 4-(1-pyrenyl)butyryl-CoA (PBA-CoA), a fluorescent analogue of acetyl- and malonyl-CoA, has been studied. The binding isotherms and the kinetics of inactivation suggest 2 mol of PBA-CoA/mol of enzyme is specifically incorporated into the enzyme. Two classes of binding sites have been identified by determining the fluorescence lifetimes of enzyme-bound pyrene, by the quenching of enzyme-bound pyrene fluorescence with iodide, and by neutral hydroxaminolysis of both the native and denatured PBA-CoA-modified enzymes. Hydroxaminolysis of the denatured enzyme indicates that 4-(1-pyrenyl)butyric acid is esterified to both hydroxyl and thiol groups. The portion esterified to the hydroxyl is readily removed from the native enzyme by treatment with neutral hydroxylamine, indicating that the oxygen ester is unstable to hydroxylamine in the native enzyme. Iodide and acrylamide quenching of the enzyme-bound pyrene fluorescence shows that solvent access to both classes of pyrene binding sites is restricted. Iodide preferentially quenches one class of sites in the native enzyme, but these sites are not differentiated in the monomeric or denatured enzyme. The steady-state anisotropy, 0.083, indicates the enzyme-bound pyrene has considerable rotational freedom. The dynamic anisotropy can be characterized solely by a viscosity-dependent rotational correlation time of 610 ns, which is ascribed to the rotational motion of the dimeric enzyme.

Acyl Coenzyme A↗
PubMed2002

Fluorescence studies of pyrene maleimide-labeled translin: excimer fluorescence indicates subunits associate in a tail-to-tail configuration to form octamer.

Translin is an octameric single-stranded DNA binding protein consisting of 228 amino acid residues per monomer. This protein contains two cysteine residues per monomer. Studies of reactions with DTNB show that both cysteines are reactive and exhibit biphasic reaction kinetics. Further studies with two site-directed mutants, C58S and C225S, confirm that Cys-58 reacts slowly while Cys-225 reacts quickly. Pyrene excimer emission was observed for pyrene maleimide-labeled C58S mutant. This was not observed, however, with the pyrene maleimide-labeled C225S mutant. DAS (decay associated spectra) revealed that all excited pyrene labels on C225 residues can form excimers with pyrenes of adjacent subunits within a few nanoseconds. Time-resolved emission anisotropy detects a rotational correlation time appropriate for octameric but not dimeric species. These results indicate proximity for the Cys-225 residues on adjacent monomers and that the subunits must interact in a tail-to-tail orientation. Moreover, disulfide bonds are not required for the formation of an octamer.

Base Sequence↗
PubMed2004

Role of base stacking and sequence context in the inhibition of yeast DNA polymerase eta by pyrene nucleotide.

The Y family DNA polymerase yeast pol eta inserts pyrene deoxyribose monophosphate (dPMP) in preference to A opposite an abasic site, the 3'-T of a thymine dimer, and a normal T with almost equal efficiency. In contrast, pol A family polymerases such as Klenow fragment and T7 DNA polymerase only insert dPMP efficiently opposite an abasic site and the 3'-T of a thymine dimer but not opposite undamaged DNA. Pyrene nucleotide is also an efficient chain-terminating inhibitor of DNA synthesis by pol eta but not by Klenow fragment or T7 DNA polymerase. To better understand the origin of the efficiency and sequence specificity of dPMP insertion by pol eta, the kinetics of dPMP insertion opposite various templates have been determined. In one sequence context, the efficiency of dPMP insertion increases 4.6-fold opposite G < A << T < C, suggesting that the templating nucleotide modulates dPMP insertion efficiency by having to destack prior to dPTP binding. The efficiency of insertion of dPMP opposite T in the same sequence context increases 7-fold for primers terminating in G < A < C < T and is similar to that observed for nontemplated blunt-end extension, suggesting that stacking interactions between the pyrene and the primer terminus are also important. On heterogeneous templates, the average selectivity for dPMP insertion relative to the complementary dNMP decreases in the order of dAMP > dGMP > dTMP > dCMP, from a high of 5.8 when dAMP is to be inserted following a T to a low of 0.5 when dCMP is to be inserted following a C. The relative preference for dPMP insertion at a given site can be largely explained by the energetic cost of destacking the templating base and stacking of pyrene nucleotide relative to that of stacking and base pairing the complementary nucleotide. Thus, pyrene nucleotide represents a novel class of nucleotide-based chain-terminating DNA synthesis inhibitors whose base portion consists of a hydrophobic, non-hydrogen bonding, base-pair mimic.

Apurinic Acid↗
PubMed2005

Sorption and displacement of pyrene in soils and sediments.

Sorption isotherms of pyrene on soils and sediments were examined to understand its sorption behavior. All systems examined exhibited nonlinear sorption. Sorption nonlinearity was found to be a function of the polarity index of soil/sediment organic matter (SOM), suggesting that the degree of condensation of SOM, characterized by its polarity index, was correlated with the sorption behavior of pyrene. The polarity index of SOM could be a new factor for explaining the sorption nonlinearity. The sorption affinity of two soils and two sediments for pyrene increased with decreasing SOM polarity. A higher sorption affinity in the two soils was associated with a higher degree of condensation of SOM compared to that of the two sediments. A displacement test was performed after pyrene sorption using phenanthrene as a displacer. Pyrene was displaced in all systems examined, and nonlinearity became less pronounced after displacement. Such an increase in isotherm linearity implied that sorption site energies became more homogeneous after displacement. Furthermore, the site energy distribution IE*) derived from the Freundlich model parameters showed that energy reduction of high-energy sites was more significant than that of low-energy sites after displacement. In addition, a decrease in sorption capacity after displacement could be ascribed to the partial depletion of sorption sites by the displacer. The displacement data indicated that the cocontaminant can have potential effects on the fate and bioavailability of anthropogenic organic pollutants sorbed in soils and sediments, thus affecting their exposure risks.

Geologic Sediments↗
PubMed2002

Conformational heterogeneity observed in simulations of a pyrene-substituted DNA.

NMR studies previously carried out for a DNA system with a pyrene-substituted base did not observe NOEs involving the adenine located 5' to the pyrene, and thus the conformation of the adenine was poorly defined in the resulting family of refined structures. However, chemical shift data suggested that an AT base pair may be present. We have carried out fully unrestrained molecular dynamics simulations starting from several members of the family of structures, and these simulations support the existence of an AT base pair for this region. Simulations in both explicit and implicit solvent were carried out, with each converging to either anti or syn conformation for adenine and base pairing in all cases. During these simulations, large and dramatic conformational changes are observed that suggest pathways for complex conformational changes in the highly packed DNA interior. Our analysis reveals little difference in the energies of these syn and anti conformations, in contrast to control calculations carried out for standard DNA (in the absence of a neighboring pyrene). While no interconversion between the conformations was observed in standard simulations, reversible anti/syn exchange was directly simulated using the locally enhanced sampling approach. No exchange was seen in the non-pyrene control sequence. Together, these results suggest that an increased flexibility is introduced as a consequence of the pyrene substitution, offering an explanation that is consistent with the available experimental data. These results increase our optimism that simulations in atomic detail may provide accurate models for experimental observations in complex systems.

Computer Simulation↗
PubMed2006

Novel bifunctional viologen-linked pyrene conjugates: Synthesis and study of their interactions with nucleosides and DNA.

With the objective of developing efficient DNA oxidizing agents, a new series of viologen-linked pyrene conjugates with the general formula PYLnV(2+), having a different number of methylene spacer units (Ln) was synthesized, and their interactions with nucleosides and DNA have been investigated through photophysical and biophysical techniques. The viologen-linked pyrene derivatives PYL1V(2+) (n =equals; 1), PYL7V(2+) (n = 7), and PYL12V(2+) (n = 12) exhibited characteristic fluorescence emission of the pyrene chromophore centered around 380 nm but with significantly reduced yields when compared to those of the model compound PYL1Et(3)(+). The fluorescence quenching observed in these systems is explained through an electron-transfer mechanism based on a calculated favorable change in free energy (DeltaG(ET) = -1.59 eV), and the redox species characterized through laser flash photolysis studies. Intramolecular electron-transfer rate constants (k(ET)) were calculated from the observed fluorescence yields, and the singlet lifetimes of the model compound and are found to decrease with increasing spacer length. The DNA binding studies of these systems through photophysical, chiroptical, and viscometric techniques demonstrated that these systems effectively undergo DNA intercalation with association constants (KDNA) in the range of 1.1-2.6 x 10(4) M(-1) and exhibit 2:1 sequence selectivity for poly(dG) x poly(dC) over poly(dA) x poly(dT). Photoactivation of these systems initiates electron transfer from the singlet excited state of the pyrene chromophore to the viologen moiety followed by an electron transfer from DNA to the oxidized pyrene. This results in the formation of stable charge-separated species such as radical cations of both DNA and reduced viologen as characterized by laser flash photolysis studies and subsequently the oxidized DNA modifications. These novel systems are soluble in buffer media, stable under irradiation conditions, and oxidize DNA efficiently and selectively through a cosensitization mechanism and hence can be useful as photoactivated DNA cleaving agents.

Animals↗
PubMedDate not supplied

Enantiospecificity of covalent adduct formation by benzo[a]pyrene anti-diol epoxide with human serum albumin.

Human serum albumin was reacted with the (+)- and (-)-enantiomers of r-7,t-8-dihydroxy-t-9,t-10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene to determine if the chiral nature of the protein influences adduct formation. The alkylated proteins were analyzed directly by fluorescence line narrowing spectroscopy, and their spectra were compared to those of the model synthetic adducts N tau-(7,8,9-trihydroxy-r-7,t-8,t-9,c-10-tetrahydrobenzo[a]pyren-10- yl)histidine and 7,8,9-trihydroxy-r-7,t-8,t-9,c-10-tetrahydrobenzo[a]pyren- 10-yl N-t-BOC-alaninate ester. The results from these analyses indicated that different adducts were formed by the enantiomers of the diol epoxide. The adducted proteins were also enzymatically digested, and the 8,9-cis-dihydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene-containing adducts and hydrolysis products were isolated by boronate affinity chromatography. Diode array UV, fast atom bombardment, and on-line atmospheric pressure ionization-mass spectral analysis of the HPLC purified products indicated that the more mutagenic and tumorigenic (+)-enantiomer forms carboxylic ester adducts with the protein at either Asp(187) or Glu(188), while the (-)-enantiomer forms N tau-histidine adducts at His(146). This previously unrealized enantiospecificity of the reaction of benzo[a]pyrene anti-diol epoxide with human serum albumin has important consequences for the application of the adducts as biomarkers of internal exposure.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed2005

Competing roles of cytochrome P450 1A1/1B1 and aldo-keto reductase 1A1 in the metabolic activation of (+/-)-7,8-dihydroxy-7,8-dihydro-benzo[a]pyrene in human bronchoalveolar cell extracts.

(+/-)-7,8-Dihydroxy-7,8-dihydrobenzo[a]pyrene (BP-7,8-diol), a proximate carcinogen derived from benzo[a]pyrene (BP) requires further metabolic activation to exert its carcinogenic effects. Two principal pathways have been implicated, and these involve either the formation of (+/-)-trans-7,8-dihydroxy-9alpha,10alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (anti-BPDE) catalyzed by P450 1A1/P450 1B1 (NADPH-dependent monoxygenases) or the formation of benzo[a]pyrene-7,8-dione (BP-7,8-dione) catalyzed by human aldo-keto reductases AKR1A1 and AKR1C1-AKR1C4 [NAD(P)(H)-dependent oxidoreductases]. The relative contributions of the two pathways to PAH activation are unknown. In this study, BP-7,8-diol metabolism was studied in human bronchoalveolar H358 cell extracts. Parental H358 cells do not constitutively express P450 1A1/P450 1B1 or AKRs but were manipulated by induction with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to express P450 1A1/P450 1B1 or by stable transfection to express AKR1A1 (aldehyde reductase). TCDD induction of AKR1A1 transfectants provided a cell line that expressed both pathways. Extracts derived from parental H358 cells plus TCDD (P450 induction) produced electrophilic anti-BPDE, which hydrolyzed to benzo[a]pyrene tetrahydrotetrols (BP-tetrols), extracts derived from AKR1A1-transfected cells (AKR1A1 expression) produced reactive and redox-active BP-7,8-dione, which was trapped in situ as its mono(thioether) conjugate, and extracts derived from AKR1A1 transfectants plus TCDD (coexpression of P450 1A1/P450 1B1 and AKR1A1) produced both anti-BPDE and BP-7,8-dione. The competing activation of BP-7,8-diol by P450 1A1/P450 1B1 and AKR1A1 was studied with varied NADPH:NAD+ ratios. The system with a relatively higher concentration of NADPH favored formation of anti-BPDE via P450 1A1/P450 1B1, while the system with the higher concentration of NAD+ favored formation of BP-7,8-dione via AKR1A1. Under conditions that mimic the cellular redox state, 10 microM NADPH and 1 mM NAD+, equal amounts of BP-tetrols and BP-7,8-dione were formed. This suggests that P450 1A1/P450 1B1 and AKR1A1 play competing roles in the metabolic activation of BP-7,8-diol and that the dominant pathway of BP-7,8-diol activation depends on the redox state of the cells. These model systems provide a cellular context in which the dominant DNA adducts/lesions formed by either pathway may be compared.

Alcohol Oxidoreductases↗
PubMed2004

Crystal and molecular structure of a benzo[a]pyrene 7,8-diol 9,10-epoxide N2-deoxyguanosine adduct: absolute configuration and conformation.

Benzo[a]pyrene 7,8-diol 9,10-epoxide adducts in DNA are implicated in mutagenesis, and their formation from the diol epoxides and subsequent incorrect replication by human DNA polymerases provide an attractive mechanism for the induction of cancer by this highly carcinogenic hydrocarbon and its diol epoxide metabolites. Here, we describe the crystal structure of such an adduct at the exocyclic amino group of a purine nucleoside. The present adduct derives from trans opening at C10 of the (-)-(7S,8R)-diol (9R,10S)-epoxide enantiomer by the exocyclic N(2)-amino group of deoxyguanosine. In the crystal, the pyrene rings of adjacent molecules stack with each other, but the guanine bases do not stack either intermolecularly with each other or intramolecularly with the pyrene. The most notable features of the molecular structure are (i) independent and unambiguous proof of the absolute configuration of the adduct based on the spatial relationship between the known chiral carbon atoms of the deoxyribose and the four asymmetric centers in the hydrocarbon moiety; (ii) visualization of the relative orientations of the pyrene and guanine ring systems as well as the conformation of the partially saturated hydrocarbon ring (comprising carbon atoms 7, 8, 9, and 10), both of which conformational features in the crystal are in good agreement with deductions from NMR and CD measurements in solution; and (iii) the presence in the crystal of a syn glycosidic torsion angle, a conformation that is unusual in B-DNA but that may be involved in error-prone replication of these benzo[a]pyrene 7,8-diol 9,10-epoxide deoxyguanosine adducts by DNA polymerases.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1988

Detection of benzo[a]pyrene diol epoxide-DNA adducts in human placenta.

Human placenta is a readily available organ that responds to maternal environmental insult and has been previously used to investigate metabolism and bioactivation of procarcinogens, for example, benzo[a]pyrene. HPLC in combination with synchronous fluorescence spectroscopy was used to examine 28 placentas for the presence of benzo[a]pyrene diol epoxide-DNA adducts, and 10 of these were found to be positive. DNA samples from these placentas were subsequently pooled and subjected to partial enzymatic digestion to oligonucleotide fragments. Concentration of those DNA fragments containing benzo[a]pyrene diol epoxide-DNA adducts was achieved by immunoaffinity chromatography with polyclonal antibodies raised against these adducts. Column eluates were hydrolyzed under mild acid conditions and extracted with an organic solvent. The presence of benzo[a]pyrene-7,10/8,9-tetrahydrotetrol residues in the extracts was determined by HPLC and synchronous fluorescence spectroscopy and was confirmed by GC/MS. The results unequivocally confirm bioactivation and formation of DNA adducts from benzo[a]pyrene in human placenta in vivo and establish a methodological approach to direct measurement of carcinogen-DNA adducts that are formed as a result of human environmental exposure.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMedDate not supplied

Association of benzo[a]pyrene-diol-epoxide-deoxyribonucleic acid (BPDE-DNA) adduct level with aging in male smokers and nonsmokers.

We used our new flow cytometric method to measure benzo[a]pyrene-diolepoxide-deoxyribonucleic acid adduct levels in peripheral lymphocytes from healthy male smokers and nonsmokers. Smokers who had pack-years of 20 or more had significantly higher mean benzo[a]pyrene-diol-epoxide-deoxyribonucleic acid adduct levels than nonsmokers. In smokers, the adduct levels were correlated significantly with age, years of smoking, and pack-years, whereas daily tobacco consumption was not correlated with adduct levels. We also found a positive relationship between age and benzo[a]pyrene-diol-epoxide-deoxyribonucleic acid adduct levels in nonsmokers. Passive exposure to tobacco smoke was not associated with adduct levels. The results of our study indicate that benzo[a]pyrene-diol-epoxide-deoxyribonucleic acid adduct levels may be closely related to aging and that tobacco smoking-as well as other environmental factors-may play a role in the benzo[a]pyrene-diol-epoxide-deoxyribonucleic acid adduct formation.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1998

Pharmacokinetics of benzo[a]pyrene in the rat.

Groups of 4 male Wistar rats were dosed intravenously with 14C-labeled benzo[a]pyrene dissolved in an Emulphor/water vehicle at 3 different dose levels and killed at 1 of 15 specific time intervals from 5 min to 32 h after dosing. 14C-Radiolabel concentration-time data were obtained for blood, brain, adipose, heart, kidney, liver, lung, spleen, and testes. Benzo[a]pyrene concentration-time data were obtained for blood, adipose, kidney, liver, and lung. Appropriate mathematical models were fitted to these data and to the data for metabolites derived as the residuals from 14C-radiolabel minus benzo[a]pyrene difference, where applicable. Nonlinear kinetics were found for 14C-radiolabel in liver, while the data from lung for both 14C-radiolabel and for benzo[a]pyrene per se supported the binding of benzo[a]pyrene in that tissue.

Adipose Tissue↗
PubMed1983

Pyrene as a sensitive probe for DNA conformational changes due to protonation.

Planar pyrene molecules can acquire optical activity upon binding to the disymmetric environment of duplex DNA. Positive induced Cotton effects are observed for pyrene in basic and neutral DNA solutions but revert to strongly negative CD bands in moderately acidic solutions. pH titrations indicate that this change over is strongly cooperative until acid denaturation sets in. The negative induced CD for pyrene results from its binding to a protonated duplex state which shows a striking 40 degrees C decrease in the melting temperature from its neutral counterpart with 0.18 M NaCl. Further studies with synthetic polynucleotides reveal that pyrene strongly prefers the guanine containing sequences in general and dG-dC (and/or dC-dG) sequence(s) in particular for this protonated duplex state, in distinct contrast to the dA-dT (and/or dT-dA) sequence specificity in the neutral solutions. The observed pyrene CD sign reversal upon protonation is thus the manifestation of DNA conformational change and the accompanied alteration in base sequence specificity.

Circular Dichroism↗