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PubMed2003

The effect of aging on pyrene transformation in sediments.

The effect of aging on pyrene transformation and pyrene association with fractions of the sedimentary organic matrix (SdOM) was evaluated using [4,9-(13)C2]pyrene. Sediments were collected from a site of previous petroleum hydrocarbon contamination (New Orleans, LA, USA). Aged sediments were autoclaved for 1 h, amended with pyrene, and then stored in the dark in a 0.05% NaN3 solution for 120 d. Both aged and nonaged sediments were incubated in aerated microcosms for 120 d. Microcosms were acidified to collect evolved carbon dioxide (CO2); sediments were fractionated and lipid extracted to quantify pyrene in SdOM fractions. Cross-polarization magic angle spinning 13C-nuclear magnetic resonance (CPMAS 13C-NMR) spectra indicated that synthetic aging techniques did alter SdOM structure to some degree, but these changes did not affect SdOM affinity for pyrene. Aging delayed pyrene mineralization and increased pyrene concentrations extracted from bulk sediment and humic fractions. Aging also reduced the toxicity of sediment humin. Pyrene-4,5-dione and pyrene cis-4,5-dihydrodiol were identified in extracts of aged sediments by 13C-NMR and gas chromatography mass spectrometry, respectively.

Biotransformation↗
PubMed1989

Effect of fatty acids on formation, distribution, storage, and release of benzo(a)pyrene phenols and glucuronides in the isolated perfused rat liver.

The hydroxylation of benzo(a)pyrene and conjugation, storage, and release of benzo(a)pyrene phenols and glucuronides by the perfused rat liver were studied in the presence and absence of acute addition of physiological concentrations of common dietary fatty acids. The actions of fatty acids on the oxidation and conjugation of benzo(a)pyrene in the intact liver were compared with their actions on microsomes isolated from rat liver. Rats were treated with beta-naphthoflavone to stimulate polycyclic aromatic hydrocarbon metabolism. Long-chain fatty acyl CoA compounds (palmitoyl CoA, oleoyl CoA, linolenoyl CoA; 50 microM) inhibited hydroxylation of benzo(a)pyrene by isolated microsomes by about 45%; however, long-chain fatty acids did not affect overall rates of hydroxylation of benzo(a)pyrene by the perfused liver at concentrations ranging up to 300 microM. The medium-chain acyl CoA compound, octanoyl CoA, also did not affect benzo(a)pyrene hydroxylation in microsomes or liver. Although fatty acids did not alter rates of hydroxylation, the ratio of free benzo(a)pyrene phenols to glucuronides (F/G ratio) increased about 60% (P less than 0.05) in livers perfused with long-chain fatty acids (palmitate, oleate, linolenate). Inhibition of glucuronidation was not observed with the medium-chain fatty acid, octanoate. Benzo(a)pyrene phenols and glucuronides accumulated linearly in the liver at rates of approximately 40 nmol/g/h. A second action of both long- and medium-chain length fatty acids was to increase rates of release of benzopyrene phenols into the perfusate by 50 to 80%. Fatty acids did not effect release of benzo(a)pyrene phenols and glucuronides into bile. Taken together, these data support the hypothesis that fatty acids displace carcinogenic metabolites of benzo(a)pyrene from binding sites in the liver which enter the circulation and travel to target tissues.

Acyl Coenzyme A↗
PubMed1976

The involvement of a diol-epoxide in the metabolic activation of benzo(a)pyrene in human bronchial mucosa and in mouse skin.

DNA has been isolated from human bronchial segments that have been treated in short-term organ culture with 3H-labelled benzo (a) pyrene. DNA has also been isolated from mouse skin treated with 3H-labelled samples of benzo (a) pyrene, with the related radioactive 4,5-, 7,8- and 9,10-dihydrodiols and with 3H-3-hydroxybenzo (a) pyrene. Sephadex LH20 column chromatography of hydrolysates of these DNA samples showed that the hydrocarbondeoxyribonucleoside products formed in benzo (a)-pyrene-treated human bronchial mucosa and mouse skin are indistinguishable from those that are formed when 7,8-dihydro-7,8-dihydroxybenzo (a) pyrene 9,10-oxide reacts with DNA in solution. These same hydrocarbon-deoxyribonucleoside products were also found in hydrolysates of DNA from mouse skin treated with 7,8-dihydro-7,8-dihydroxybenzo (a)-pyrene but products of this type were not detected in hydrolysates of DNA following treatment of mouse skin either with the 4,5- or 9,10-dihydrodiols or with 3-hydroxybenzo (a) pyrene. This results show that the metabolic activation of benzo (a) pyrene to a diolepoxide, 7,8-dihydro-7,8-dihydroxybenzo (a) pyrene 9,10-oxide, which reacts with DNA, is the same in human bronchial mucosa, a tissue in which this hydrocarbon is suspected of being carcinogenic, as it is in mouse skin and in hamster embryo cells, two situations in which benzo(a)pyrene is known to induce malignancy.

Animals↗
PubMed1978

Formation of DNA-binding products from isolated benzo[a]pyrene metabolites in rat liver nuclei.

Liver nuclei from 3-methylcholanthrene-treated rats in the presence of NADPH metabolized 3- and 9-hydroxybenzo[a]pyrene and 7,8-dihydro-7,8-dihydroxybenzo[a]pyrene to products that bound to DNA. Maximal binding was obtained with the dihydrodiol which was approximately 3-fold that with 9-hydroxybenzo[a]pyrene, and 60-fold that with 3-hydroxybenzo[a]pyrene, as substrates. Both 4,5-dihydro-4,5-dihydroxybenzo[a]pyrene and 9,10-dihydro-9,10-dihydroxybenzo[a]pyrene were also extensively metabolized by the nuclear fraction but did not give rise to DNA-binding products. The available evidence suggests that the DNA binding species derived from 9-hydroxy-benzo[a]pyrene is 9-hydroxy-benzo[a]pyrene-4,5-oxide and from 7,8-dihydro-7,8-dihydroxybenzo[a]pyrene, as previously observed in different systems, 7,8-dihydro-7,8-dihydroxy-benzo[a]pyrene-9,10-oxide.

Animals↗
PubMed1980

Transport of a carcinogen, benzo[a]pyrene, from particulates to lipid bilayers: a model for the fate of particle-adsorbed polynuclear aromatic hydrocarbons which are retained in the lungs.

Fluorescence spectroscopic methods were used to investigate the effects of adsorption of benzo[a]pyrene to particulate matter on its rate of uptake into model membranes composed of dipalmitoyl L-alpha-phosphatidylcholine. From these experiments we conclude the following: 1. Adsorption of benzo[a]pyrene to four types of asbestos (anthophyllite, crocidolite, chrysotile, and amosite) and a variety of non-fibrous particles (hematite, silica, titanium dioxide, porous glass and talc) results in increased rates of membrane uptake when compared with aqueous suspensions of benzo[a]pyrene microcrystals. Benzo[a]pyrene was not released from carbon black. 2. Asbestos-adsorbed benzo[a]pyrene was transferred to the membranes most rapidly. 3. Adsorption of benzo[a]pyrene to the surface of the particles is necessary for its enhanced transport into membranes. That is, simple mixtures of benzo[a]pyrene microcrystals and particulates do not show enhanced transport. 4. Particle-enhanced transport of benzo[a]pyrene is not correlated with the effects of the particles on vesicle integrity, binding of vesicles to the particles, or the concentrations of either particles or vesicles. The rate limiting step for transport of benzo[a]pyrene into vesicles appears to be its rate of desorption from the surface of the particle. Following desorption, membrane uptake of benzo[a]pyrene is rapid.

Adsorption↗
PubMed1988

Examination of differences between benzo[a]pyrene and steroid hydroxylases in guinea pig adrenal microsomes.

The effects of antibodies to cytochromes P-45017 alpha,lyase and P-450C21 on benzo[a]pyrene hydroxylase activity were measured in microsomes from guinea pig adrenals. Anti-cytochrome P-45017 alpha,lyase IgG inhibited about 30% of the benzo[a]pyrene hydroxylase activity of the microsomes in the presence of excess amounts of the IgG, but anti-cytochrome P-450C21 IgG did not affect the activity. In a reconstituted system, consisting of cytochrome P-450, NADPH-cytochrome-P-450 reductase and dilauroylphosphatidylcholine, cytochrome P-45017 alpha,lyase catalyzed, in addition to steroid hydroxylation, benzo[a]pyrene hydroxylation, but cytochrome P-450C21 did not hydroxylate benzo[a]pyrene. Since anti-cytochrome P-45017 alpha,lyase IgG inhibited benzo[a]pyrene hydroxylase activity completely in the reconstituted system with cytochrome P-45017 alpha,lyase, the presence of non-inhibited benzo[a]pyrene hydroxylase in the microsomes suggests that the residual activity in the microsomes may be due to some enzyme other than cytochrome P-45017 alpha,lyase. Benzo[a]pyrene hydroxylase activity was detected in detergent-solubilized microsomes from which cytochrome P-45017 alpha,lyase was removed by using an immobilized anti-cytochrome P-45017 alpha,lyase IgG-Sepharose column. This shows the existence in microsomes of a benzo[a]pyrene hydroxylase other than cytochrome P-45017 alpha,lyase. Benzo[a]pyrene hydroxylase in the solubilized microsomes required O2, NADPH and NADPH-cytochrome-P-450 reductase for its activity and was inhibited by CO. This suggests that benzo[a]pyrene hydroxylase is a cytochrome P-450-dependent monooxygenase. This novel enzyme was also active in xenobiotic metabolism, such as 2-nitropropane denitrification and aminopyrine demethylation.

Adrenal Glands↗
PubMed1986

Effects of the state of the succinimido-ring on the fluorescence and structural properties of pyrene maleimide-labeled alpha alpha-tropomyosin.

Rabbit skeletal alpha alpha-tropomyosin was labeled at Cys-190 with pyrene maleimide to form (S-[N-(1-pyrene)succinimido])2-tropomyosin (pyreneI-Tm). The product with cleaved succinimido-rings, pyreneII-Tm was also prepared by incubation of pyreneI-Tm at pH greater than 7.5. The pH dependence of the rate of cleavage indicated that hydrolysis rather than aminolysis was the more likely reaction. PyreneI-Tm exhibited a loss in helix content and end-to-end polymerization compared with unlabeled Tm, which increased upon formation of pyreneII-Tm. The cleavage resulted in increased interchain excited state excimer fluorescence originating from pyrene-pyrene interaction between the chains. Thus, increased pyrene-pyrene interaction at Cys 190 leads to an increase in unfolding, the effects of which appear to be transmitted to the ends of tropomyosin. The fluorescence properties of the two types of pyrene-succinimide adducts of dithiothreitol were very similar to the corresponding adducts of pyrene-Tm indicating excimer formation through ground state pyrene-pyrene interaction.

Animals↗
PubMed2000

Pyrene excimer fluorescence: a spatially sensitive probe to monitor lipid-induced helical rearrangement of apolipophorin III.

Manduca sexta apolipophorin III (apoLp-III), an 18-kDa, monomeric, insect hemolymph apolipoprotein, is comprised of five amphipathic alpha-helices arranged as a globular bundle in the lipid-free state. Upon lipid binding, it is postulated that the bundle opens, exposing a continuous hydrophobic surface which becomes available for lipid interaction. To investigate lipid binding-induced helical rearrangements, we exploited the unique fluorescence characteristics of N-(1-pyrene)maleimide. Pyrene is a spatially sensitive extrinsic fluorescent probe, which forms excited-state dimers (excimers) upon close encounter with another pyrene molecule. Cysteine residues were introduced into apoLp-III (which otherwise lacks cysteine) at Asn 40 (helix 2) and/or Leu 90 (helix 3), creating two single-cysteine mutants (N40C-apoLp-III and L90C-apoLp-III) and N40C/L90C-apoLp-III, a double-cysteine mutant, which were labeled with pyrene maleimide. Pyrene-labeled N40C/L90C-apoLp-III, but not the pyrene-labeled single-cysteine mutants, exhibited strong excimer fluorescence in the lipid-free, monomeric state. Guanidine hydrochloride titration and temperature studies revealed a loss in excimer fluorescence, accompanied by a loss in the molar ellipticity of the protein. When apoLp-III interacts with phospholipid vesicles to form disklike complexes, a significant loss in excimer fluorescence was noted, indicating that the helices bearing the pyrene moieties diverge from each other. Pyrene excimer fluorescence was further employed to examine the relative orientation of lipid-bound apoLp-III molecules. Pyrene-labeled N40C- or L90C-apoLp-III displayed no excimer fluorescence in the disk complexes, while complexes prepared with an equal mixture of both single-labeled mutants did emit excimer fluorescence, indicating apoLp-III adopts a preferred nonrandom orientation around the perimeter of the bilayer disk. These studies establish pyrene excimer fluorescence as a useful spectroscopic tool to address intra- and intermolecular interactions of exchangeable apolipoproteins upon binding to lipid.

Animals↗
PubMed1999

Synthesis of anti-7,8-dihydroxy-9,10-epoxy-7,8,9, 10-tetrahydro-11-methylbenzo[a]pyrene and its reaction with DNA.

Substitution of a methyl group in the bay region can enhance the tumorigenicity of polycyclic aromatic hydrocarbons such as chrysene, benz[a]anthracene, and others. This phenomenon has been related to facile DNA adduct formation of bay region diol epoxides with a methyl group and epoxide ring in the same bay. While anti-7, 8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene and its DNA adduct formation have been studied extensively, it is not known whether a methyl substituent in the bay region alters the reactivity of DNA in this system. This is of interest because 11-methylbenzo[a]pyrene, which has a bay region methyl group, is more tumorigenic than benzo[a]pyrene. To examine the question, we have devised and employed an efficient synthesis based on photochemical cyclization, and prepared anti-7,8-dihydroxy-9, 10-epoxy-7,8,9,10-tetrahydro-11-methylbenzo[a]pyrene, the likely ultimate carcinogen of 11-methylbenzo[a]pyrene. We have then reacted anti-7,8-dihydroxy-9,10-epoxy-7,8,9, 10-tetrahydro-11-methylbenzo[a]pyrene with calf thymus DNA and found that it gives three major adducts. These were identified as having resulted from cis- and trans-ring opening of the (S,R,R, S)-enantiomer and from trans-ring opening of the (R,S,S, R)-enantiomer. The standard deoxyguanosine adduct markers were prepared, and their structures were tentatively assigned on the basis of their CD and 1H NMR spectra. The adduct distribution of anti-7,8-dihydroxy-9,10-epoxy-7,8,9, 10-tetrahydro-11-methylbenzo[a]pyrene is quite different from that observed in the reaction of DNA with the corresponding diol epoxides of benzo[a]pyrene or with 5-methylchrysene. The heterogeneity of adducts obtained with anti-7,8-dihydroxy-9,10-epoxy-7,8,9, 10-tetrahydro-11-methylbenzo[a]pyrene thus may be related to the enhanced tumorigenicity of 11-methylbenzo[a]pyrene.

Benzopyrans↗
PubMed1975

Mutagenic and cytotoxic activity of benzol[a]pyrene 4,5-, 7,8-, and 9,10-oxides and the six corresponding phenols.

The benzo[a]pyrene 4,5-, 7,8-, and 9,10-oxides and the six corresponding phenols (4-, 5-, 7-, 8-, 9-, and 10-hydroxybenzo[a]pyrene) have been tested for mutagenic and cytotoxic activity in bacteria and in a mammalian cell culture system. Benzo[a]pyrene 4,5-oxide (K-region) was highly mutagenic in two histidine-dependent strains (TA1537 and TA1538) of Salmonella typhimurium which detect frameshift mutagens. In contrast, benzo[a]pyrene 7,8- and 9,10-oxides were less than 1% as mutagenic as the 4,5-oxide. Benzo[a]pyrene 7,8- and 9,10-oxides were unstable in aqueous media, whereas the 4,5-oxide was stable for several hours. This difference in stability could not account for the different mutagenic activities of the three arene oxides. The benzo[a]pyrene oxides were inactive in a strain (TA1535) that is reverted by base pair mutagens such as N-methyl-N'-nitro-N-nitrosoguanidine or in a strain (TA1536) that detects framshift mutagens similar to the acridine half-mustard ICR-191. Benzo-[a]-pyrene and the six phenols were all stable in aqueous media, but they had little or no mutagenic activity in any of the four Salmonella strains. Conversion of 8-azaguanine-sensitive Chinese hamster V79 cells to 8-azaguanine-resistant variants was increased by benzo[a]pyrene 4,5-oxide, whereas the 9,10-oxide was considerably less active. Benzo[a]pyrene and the other derivatives had little or no effect. Benzo[a]yrene 4,5-oxide was more cytotoxic to the Chinese hamster V79 cells than the 7,8- and 9,10-oxides, while 8-hydroxybenzo[a]pyrene was the most cytotoxic of the six phenols.

Benzopyrenes↗
PubMed1976

Identification of mutagenic metabolites of benzo(a)pyrene in mammalian cells.

The mutagenicity of benzo[a]pyrene and 15 of its derivatives, which included phenols, the benzo[a]yrene-4,5-epoxide (the K-region epoxide), dihydrodiols, two isomeric 7,8-diol-9,10-epoxides, a 6-methyl derivative, and a 6-hydroxymethyl derivative, were tested with Chinese hamster V79 cells in order to identify the mutagenic metabolites of benzo[a]pyrene. Mutations were characterized by resistance to ouabain or 8-azaguanine. Since V79 cells do not metabolize polycyclic hydrocarbons, mutagenesis was tested both in the presence and absence of benzo[a]pyrene-metabolizing normal golden hamster cells. All the tested phenols, 4,5-diols, trans-9,10-diol, 6-methyl, and 6-hydroxymethyl derivatives of benzo[a]pyrene showed little or no mutagenicity for both genetic markers. The (+/-)7alpha,8beta-dihydroxy-9alpha,10alpha-epoxy-7,8;9,10-tetrahydrobenzo[a]pyrene and K-region 4,5-epoxide exhibited similar and moderate mutagenicity in the absence of benzo[a]pyrene-metabolizing cells, but the (+/-)7alpha,8beta-dihydroxy-9beta,10beta-epoxy-7,8,9,10-tetrahydrobenzo[a]-pyrene showed a 2000- and 270-fold higher mutation frequency for ouabain and 8-azaguanine resistance, respectively, than did the K-region 4,5-epoxide. The trans-7,8-diol which was not mutagenic in the absence of benzo[a]pyrene-metabolizing cells was more mutagenic than benzo[a]pyrene after metabolism and mutagenesis by trans-7,8-diol in these cells was inhibited by 7,8-benzoflavone, an inhibitor of mixed-function oxidases. Metabolically formed trans-7,8-diol was isolated and incubated with rat liver microsomes in the presence of co-factors. High-pressure liquid chromatography analysis indicated that the major metabolite of trans-7,8-diol is 7alpha,8beta-dihydroxy-9beta,10beta-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene. The results indicate that the latter compound is metabolically formed and the major mutagenic intermediate of benzo[a]yrene metabolism.

Benzopyrenes↗
PubMed1980

Metabolism and macromolecular binding of carcinogenic and noncarcinogenic metabolites of benzo(a)pyrene by hamster embryo cells.

The metabolism and macromolecular binding of four metabolites of benzo(a)pyrene in hamster embryo fibroblasts has been studied. Two noncarcinogenic phenolic derivatives, 3-hydroxybenz(a)pyrene and 9-hydroxybenzo(a)pyrene, are rapidly metabolized, primarily to their respective glucuronic acid conjugates and other H2O-soluble conjugates (78.4 to 80.8% of total radioactivity). Water-soluble conjugates were also formed from the carcinogenic phenol, 2-hydroxybenzo(a)pyrene, and from 7,8-dihydro-7,8-dihydroxybenzo(a)pyrene, but in lower amounts (36.8 to 43.8% of total radioactivity. With each of the compounds, from 10 to 20% of the radioactivity was converted to ethyl acetate-soluble metabolites. The amount of unmetabolized 2-hydroxybenzo(a)pyrene recovered intracellularly was 20-fold higher than that recovered in incubations with the other phenols. Covalent binding to nuclear macromolecules was monitored after isopyknic separation. Binding of the three phenols tested was similar and was lower than the binding of benzo(a)pyrene to nuclear DNA, RNA, and protein. In contrast to the results with the monohydroxybenzo(a)pyrenes, high levels of covalent binding were observed with 7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene; binding to DNA was 8-fold higher (315 pmol bound per mg DNA) than binding of benzo(a)pyrene to DNA.

Animals↗
PubMed2005

Pyrene mineralization capacity increases with compost maturity.

Experiments were conducted to determine the effects of composting or simple addition of compost to the mineralization of n-hexadecane, pyrene and benzo(a)pyrene in soil. Soil (contaminated or clean) was composted with maple leaves and alfalfa. Samples from different composting phases were spiked with radiolabeled and cold n-hexadecane, pyrene or benzo(a)pyrene, placed in aerated microcosms at different temperatures, and monitored for mineralization. It was determined that neither composting nor the addition of compost had any effect on n-alkane or benzo(a)pyrene mineralization. In contrast, the pyrene mineralization rate increased dramatically with the amount of time that soil had been composted. Highest pyrene mineralization rates and extents (more than 60% after 20 days) were obtained when pyrene was in contact with composted soil from the curing stage. Neither thermophiles (55 degrees C) nor fungi were responsible for pyrene mineralization.

Air↗
PubMed1985

A comparison of the intercalative binding of non-reactive benzo[a]pyrene metabolites and metabolite model compounds to DNA.

The reversible DNA physical binding of a series of non-reactive metabolites and metabolite model compounds derived from benzo[a]pyrene (BP) has been examined in UV absorption and in fluorescence emission and fluorescence lifetime studies. Members of this series have steric and pi electronic properties similar to the highly carcinogenic metabolite trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE) and the less potent metabolite 4,5-epoxy-4,5-dihydrobenzo(a)pyrene (4,5-BPE). The molecules examined are trans-7,8-dihydroxy-7,8-dihydrobenzo[a]-pyrene (7,8-di(OH)H2BP), 7,8,9,10-tetrahydroxytetrahydrobenzo[a]pyrene (tetrol) 7,8,9,10-tetrahydrobenzo[a]pyrene (7,8,9,10-H4BP), pyrene, trans-4,5-dihydroxy-4,5-dihydrobenzo[a]pyrene (4,5-di(OH)H2BP) and 4,5-dihydrobenzo[a]pyrene (4,5-H2BP). In 15% methanol at 23 degrees C the intercalation binding constants of the molecules studied lie in the range 0.79-6.1 X 10(3) M-1. Of all the molecules examined the proximate carcinogen 7,8-di(OH)-H2BP is the best intercalating agent. The proximate carcinogen has a binding constant which in UV absorption studies is found to be 2.8-6.0 times greater than that of the other hydroxylated metabolites. Intercalation is the major mode of binding for 7,8-di(OH)H2BP and accounts for more than 95% of the total binding. Details concerning the specific role of physical bonding in BP carcinogenesis remain to be elucidated. However, the present studies demonstrate that the reversible binding constants for BP metabolites are of the same magnitude as reversible binding constants which arise from naturally occurring base-base hydrogen bonding and pi stacking interactions in DNA. Furthermore, previous autoradiographic studies indicate that in human skin fibroblasts incubated in BP, pooling of the unmetabolized hydrocarbons occurs at the nucleus. The high affinity of 7,8-di(OH)H2BP for DNA may play a role in similarly elevating in vivo nuclear concentrations of the non-reactive proximate carcinogen.

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

Biological monitoring exposure of workers from plant producing carbon electrodes: quantification of benzo[a]pyrene DNA-adducts in leukocytes, by a 32P-postlabelling method and an immunoassay.

The levels of benzo[a]pyrene were monitored for blood DNA-benzo[a]pyrene adducts in 17 workers from a plant producing carbon electrodes, with high exposure to benzo[a]pyrene (575-902-1149 ng m(-3)). Two different techniques, a 32P-postlabelling method and a competitive immunoassay using polyclonal antibodies obtained from rabbits immunised with DNA modified by benzo[a]pyrene-trans-7,8-dihydrodiol-9,10-epoxide were used. For each worker, urinary 1-hydroxypyrene, a potential indicator of exposure to polycyclic aromatic hydrocarbons, was measured. The effect of tobacco by urinary cotinine measurement was also considered. The postlabelling and immunoassay detection limits for DNA-benzo[a]pyrene adducts were respectively 0.15 and 10 fmol 50 microg(-1) of DNA. The results obtained by the two methods demonstrated a good detection of DNA-benzo[a]pyrene adducts, but no direct relationship between the quantity of adducts and the concentration of benzo[a]pyrene in air-borne was noted in the studied plant. The levels of DNA-benzo[a]pyrene adducts obtained by immunoassay were significantly higher than those obtained by the 32P-postlabelling (P < 0.001). For several workers, variations due to professional or non professional factors must be taken into account in interpreting the results. In conclusion, the two methods used proved very efficient in determining DNA-benzo[a]pyrene adducts, and may be useful in monitoring human exposure to known and previously unidentified environmental genotoxic agents.

Adult↗
PubMed1992

An improved fluorometric assay for dosimetry of benzo(a)pyrene diol-epoxide-DNA adducts in smokers' lung: comparisons with total bulky adducts and aryl hydrocarbon hydroxylase activity.

An improved high-performance liquid chromatography/fluorometric assay has been established to quantitate the benzo(a)pyrene (BP) tetrols released after acid hydrolysis of lung DNA from lung cancer patients, so that the formation of benzo(a)pyrene diol-epoxide-DNA adducts can be measured. The r-7,c-10,t-8,t-9-tetrahydroxy-7,8,9,10-tetrahydro-BP isolated by high-performance liquid chromatography was determined by chromatography in two different solvent systems and fluorescence spectroscopy. This assay has a detection limit of 2 pg of r-7,c-10,t-8,t-9-tetrahydroxy- 7,8,9,10-tetrahydro-BP, requires 100-500 micrograms of DNA, and can measure 1 adduct/10(8) unmodified nucleotides. As this assay does not use immunoaffinity chromatography or solvent extraction, it allows a > 90% recovery of benzo(a)pyrene diol-epoxide-DNA adducts. This procedure has been tested on 13 DNA samples prepared from nontumorous lung parenchyma taken from lung cancer patients at surgery and revealed the presence of DNA adducts of the anti-benzo(a)pyrene diol-epoxide in 9 of 11 samples from smokers and in 2 of 2 ex-smokers. In only two samples from smokers the formation of adducts derived from syn-benzo(a)pyrene diol-epoxide was detected. A 15-fold variation in DNA adduct level was found in 11 of 13 DNA samples, with a range of 0.6-9.9 adducts of benzo(a)pyrene diol-epoxide/10(8) nucleotides. In samples containing both anti- and syn-benzo(a)pyrene diolepoxide-DNA adducts, the anti/syn adduct ratio is 2:1. A highly significant correlation was found between pulmonary microsomal aryl hydrocarbon hydroxylase activity and the level of benzo(a)pyrene diolepoxide-DNA adduct (r = 0.91; P < 0.001; n = 13). A crude linear correlation between the amounts of these adducts and those of bulky DNA adducts determined by 32P-postlabeling assay was observed in the same samples (r = 0.78; P < 0.02; n = 13). Thus this highly sensitive and specific procedure is suitable for measuring benzo(a)pyrene diolepoxide-DNA adducts in human tissues from environmentally exposed subjects and could be adapted to measure polycyclic aromatic hydrocarbons other than BP.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1984

Influence of red blood cells, serum albumin, and serum lipoproteins on the clearance of benzo[alpha]pyrene by isolated livers of 3-methylcholanthrene-treated rats.

Red blood cells, serum albumin, and serum lipoproteins transport benzo[alpha]pyrene and other xenobiotic compounds in the circulation. The distribution of benzo[alpha]pyrene and its metabolites among these blood components was examined, and the effect of their presence in the perfusion medium on the ability of isolated livers from 3-methylcholanthrene-pretreated rats to clear circulating benzo[alpha]pyrene was determined. A large fraction (45%) of the benzo[alpha]pyrene in rat blood was associated with the serum lipoproteins. However, only 8% of the benzo[alpha]pyrene metabolites was associated with this component. Forty to forty-five percent of each was associated with red blood cells. Benzo[alpha]pyrene clearance by isolated rat livers was 1.8 +/- 0.2 ml/min when the medium contained only red blood cells and buffer. Addition of serum lipoproteins or serum albumin increased benzo[alpha]pyrene clearance to 5.1 +/- 0.5 or 8.5 +/- 0.9 ml/min respectively. Appearance of benzo[alpha]pyrene metabolites in perfusions medium and bile was similarly altered by the changes in medium composition. These results indicate that the clearance of benzo[alpha]pyrene by rat liver depends on the composition of the medium perfusing the organ and suggest that alterations in blood components in vivo may influence the metabolic disposition of this carcinogen.

Animals↗
PubMed1991

A biologically based toxicokinetic model for pyrene in rainbow trout.

A biologically based toxicokinetic model was developed to stimulate the metabolic disposition of pyrene in trout with an average body weight of 450 g and dosed with a single bolus injection of the chemical (10 mg/kg). The model consists of a membrane-limited muscle compartment and six flow-limited compartments including the gills, liver, gut, kidney, carcass, and blood. The compartments are represented by mass balance equations including terms for the binding of pyrene to tissue and blood proteins, biotransformation, penetration rate into the muscle, blood flow rate, tissue mass, etc. The model also provides for nonsaturable and saturable clearances of pyrene by the liver and kidney. Michaelis-Menten constants for pyrene metabolism (Km, Vmax) were determined from in vitro experiments using isolated liver cells. Renal clearance of pyrene was very close to the glomerulus filtration rate of trout. Solution of the system of equations yielded the time courses of pyrene concentration in the tissues. Predicted concentrations of pyrene in the gills, liver, gut, kidney, muscle, and blood were consistent with experimental observations for at least 6 days. The model was validated by comparing the model predicted and experimental results of trout weighing 285 g and dosed with a single intraarterial dose (3 mg/kg) of pyrene. The predicted pyrene concentrations also were in adequate agreement with the empirical data.

Animals↗