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PubMed2000

Synthesis of oligonucleotide derivatives containing a bis-pyrene residue in the main chain.

The oligonucleotide having the bis-pyrene residue in the main chain was synthesized. The preparation of the bis-pyrene was started from the conversion of 2,2-bis-(bromomethyl)-1,3-propanediol into the protected bis-amino derivative. The reaction of the bis-amino derivative with 1-pyrenebutyric acid using DCC/HOBT afforded the desired bis-pyrene. This compound was then converted to the protected phosphormidite. The oligonucleotides possessing the bis-pyrene were synthesized by using the amidite. The oligonucleotides having the bis-pyrene residue can bind to DNA sequence in an aqueous solution to give the duplex with comparable thermal stability as that of the unmodified DNA/DNA duplex. The significantly enhanced pyrene-excimer fluorescence was observed upon hybridization of the bis-pyrene modified oligonucleotides with DNA.

Base Sequence↗
PubMed2005

Induction of fibroblast growth factor-9 and interleukin-1alpha gene expression by motorcycle exhaust particulate extracts and benzo(a)pyrene in human lung adenocarcinoma cells.

Motorcycle exhaust particulates (MEP) contain carcinogenic polycyclic aromatic hydrocarbons including benzo(a)pyrene. This study has determined the ability of MEP to alter the expression of select genes from drug metabolism, cytokine, oncogene, tumor suppressor, and estrogen signaling families of human lung adenocarcinoma CL5 cells. cDNA microarray analyses and confirmation studies were performed using CL5 cells treated with 100 microg/ml MEP extract for 6 h. The results showed that MEP increased the mRNA levels of metabolic enzymes CYP1A1 and CYP1B1, proinflammatory cytokines interleukin (IL)-1alpha, IL-6, and IL-11, fibroblast growth factor (FGF)-6 and FGF-9, vascular endothelial growth factor (VEGF)-D, oncogene fra-1, and tumor suppressor p21. In contrast, MEP decreased tumor suppressor Rb mRNA in CL5 lung epithelial cells. Treatment with 10 microM benzo(a)pyrene for 6 h altered gene expression profiles, in a manner similar to those by MEP. Induction of IL-1alpha, IL-6, IL-11, and FGF-9 mRNA by MEP and benzo(a)pyrene was concentration and time dependent. Cotreatment with 2 mM N-acetylcysteine blocked the MEP- and benzo(a)pyrene-mediated induction. Treatment with MEP or benzo(a)pyrene increased IL-6 and IL-11 releases to CL5 cell medium. Incubation of human lung fibroblast WI-38 with MEP- or benzo(a)pyrene-induced CL5 conditioned medium for 4 days stimulated cell growth of the fibroblasts. Inhalation exposure of rats to 1:10 diluted motorcycle exhaust 2 h daily for 4 weeks increased CYP1A1, FGF-9, and IL-1alpha mRNA in lung. This present study shows that MEP and benzo(a)pyrene can induce metabolic enzyme, inflammatory cytokine, and growth factor gene expression in CL5 cells and stimulate lung epithelium-fibroblast interaction.

Adenocarcinoma↗
PubMed1986

Clotrimazole, an inhibitor of benzo[a]pyrene metabolism and its subsequent glucuronidation, sulfation, and macromolecular binding in BALB/c mouse cultured keratinocytes.

The effect of the antifungal imidazole compound, clotrimazole, on the metabolism of benzo[a]pyrene (BP) was studied in cultured keratinocytes prepared from BALB/c mouse epidermis. Varying concentrations of clotrimazole added to the cultured keratinocytes resulted in a dose-dependent inhibition of the activities of the microsomal cytochrome P-450-dependent monooxygenases aryl hydrocarbon hydroxylase and 7-ethoxycoumarin O-deethylase. The major organic solvent-soluble metabolites of BP identified in the cultured cells were trans-7,8-dihydro-7,8-dihydroxybenzo[a]pyrene (BP-7,8-diol), 9-hydroxybenzo[a]pyrene (9-OH-BP), and 3-hydroxybenzo[a]pyrene (3-OH-BP), although small amounts of trans-4,5-dihydro-4,5-dihydroxybenzo[a]pyrene, BP-quinones, and trans-9,10-dihydroxybenzo[a]pyrene were also present. The major organic solvent-extractable metabolites of BP found in the extracellular culture medium were primarily the diols with smaller quantities of phenols and quinones. The major water-soluble metabolites of BP present both intracellularly and extracellularly were glucuronide conjugates of 3-OH-BP, 9-OH-BP, and benzo[a]pyrene-3,6-dione and to a lesser extent sulfate conjugates (primarily of the BP-7,8-diol). Clotrimazole inhibited the generation of organic solvent-soluble and water-soluble conjugates in a dose-dependent manner. The in vitro metabolism of BP by microsomes prepared from control and benz[a]anthracene (BA)-induced cultured keratinocytes was also inhibited by clotrimazole with greater inhibitory effect on BA-induced keratinocytes especially with respect to the formation of diols and quinones. The enzyme-mediated covalent binding of BP to mouse keratinocyte DNA and protein was also substantially diminished by clotrimazole in a dose-dependent fashion. These results indicate that clotrimazole, a widely used drug for the management of a variety of superficial dermatophyte infections of the skin, is a potent inhibitor of cytochrome P-450-dependent transformation of polycyclic aromatic hydrocarbons in cultured murine keratinocytes. This system offers a convenient approach for studies as inhibitors of carcinogen metabolism in the epidermis.

Animals↗
PubMed1988

Microbial metabolism of polycyclic aromatic hydrocarbons: isolation and characterization of a pyrene-degrading bacterium.

Microbiological analyses of sediments located near a point source for petrogenic chemicals resulted in the isolation of a pyrene-mineralizing bacterium. This isolate was identified as a Mycobacterium sp. on the basis of its cellular and colony morphology, gram-positive and strong acid-fast reactions, diagnostic biochemical tests, 66.6% G + C content of the DNA, and high-molecular-weight mycolic acids (C58 to C64). The mycobacterium mineralized pyrene when grown in a mineral salts medium supplemented with nutrients but was unable to utilize pyrene as a sole source of carbon and energy. The mycobacterium grew well at 24 and 30 degrees C and minimally at 35 degrees C. No growth was observed at 5 or 42 degrees C. The mycobacterium grew well at salt concentrations up to 4%. Pyrene-induced Mycobacterium cultures mineralized 5% of the pyrene after 6 h and reached a maximum of 48% mineralization within 72 h. Treatment of induced and noninduced cultures with chloramphenicol showed that pyrene-degrading enzymes were inducible in this Mycobacterium sp. This bacterium could also mineralize other polycyclic aromatic hydrocarbons and alkyl- and nitro-substituted polycyclic aromatic hydrocarbons including naphthalene, phenanthrene, fluoranthene, 3-methylcholanthrene, 1-nitropyrene, and 6-nitrochrysene. This is the first report of a bacterium able to extensively mineralize pyrene and other polycyclic aromatic hydrocarbons containing four aromatic rings.

Biodegradation, Environmental↗
PubMed1999

Cross-induction of pyrene and phenanthrene in a Mycobacterium sp. isolated from polycyclic aromatic hydrocarbon contaminated river sediments.

A polycyclic aromatic hydrocarbon (PAH)-degrading culture enriched from contaminated river sediments and a Mycobacterium sp. isolated from the enrichment were tested to investigate the possible synergistic and antagonistic interactions affecting the degradation of pyrene in the presence of low molecular weight PAHs. The Mycobacterium sp. was able to mineralize 63% of the added pyrene when it was present as a sole source of carbon and energy. When the enrichment culture and the isolated bacterium were exposed to phenanthrene, de novo protein synthesis was not required for the rapid mineralization of pyrene, which reached 52% in chloramphenicol-treated cultures and 44% in the absence of the protein inhibitor. In the presence of chloramphenicol, < 1% of the added pyrene was mineralized by the mixed culture after exposure to anthracene and naphthalene. These compounds did not inhibit pyrene utilization when present at the same time as pyrene. Concurrent mineralization of pyrene and phenanthrene after exposure to either compound was observed. Cross-acclimation between ring classes of PAHs may be a potentially important interaction influencing the biodegradation of aromatic compounds in contaminated environments.

Biodegradation, Environmental↗
PubMed2001

Phototoxicity of anthracene and pyrene to glochidia of the freshwater mussel Utterbackia imbecillis.

The acute toxicity of photoactivated anthracene and pyrene to the glochidial larvae of the paper pondshell (Utterbackia imbecillis) was characterized in the laboratory using two sets of experiments. Acute toxicity tests designed to determine the overall sensitivity of glochidia to anthracene and pyrene were conducted under simulated sunlight (ultraviolet [UV]-A = 70+/-0.5 microW/cm2 [mean +/- standard deviation]). The median lethal concentration (LC50) and median lethal dose (LD50) of anthracene at 24 h were 1.93 (95% CI, 0.87-3.02) microg/L and 1.94 (1.87-2.00) microg/g glochidia, respectively. The LC50 and LD50 for pyrene at 24 h were 2.63 (2.38-2.90) microg/L and 6.36 (5.82-6.94) microg/g glochidia, respectively. Acute toxicity tests designed to delineate the relationship between the rate of mortality and UV intensity were conducted under one of four different UV intensities (UV-A = 15, 31, 50, and 68 microW/cm2). Regression analyses revealed that time to death decreased as tissue residue concentrations and UV intensity increased for both compounds. Based on measured tissue residues, anthracene was 1.5-fold more potent than pyrene and 3-fold more potent than fluoranthene. The lower potency of fluoranthene is in agreement with previously developed structure-activity relationships; however, these relationships predict equal potency between anthracene and pyrene. These findings suggest that glochidia of freshwater mussels are sensitive to photoactivated anthracene and pyrene at environmentally relevant concentrations, that the time-dependent mortality of glochidia can be accurately predicted through evaluating the product of tissue residue and light intensity, and that species-dependent factors may alter the predicted relative potencies of anthracene and pyrene.

Animals↗
PubMed2003

Screening pyrene metabolites in the hemolymph of dungeness crabs (Cancer magister) with synchronous fluorescence spectrometry: method development and application.

The present study examined the metabolic pathways of pyrene in dungeness crabs (Cancer magister) in the laboratory and the potential of using synchronous fluorescence spectrometry (SFS) to determine pyrene metabolite concentrations in the hemolymph of crabs exposed to polycyclic aromatic hydrocarbons (PAHs) in the field. Pyrene was metabolized by crabs mainly to 1-hydroxypyrene and pyrene-1-glucoside. Both pyrene metabolites could be detected by SFS in the hemolymph of crabs. A nondestructive hemolymph collection procedure was developed and used in conjunction with the SFS assay to assess the exposure of crabs to PAHs in Kitimat Arm (British Columbia, Canada). Our results showed that crabs obtained near the source of PAH contamination had the highest level of pyrene-related fluorescence in the hemolymph, whereas concentrations were lower at other sites downstream from the pollution source. In a separate study, the hepatopancreases of crabs were analyzed for parent PAHs by using gas chromatography-mass spectrometry. Pyrene-associated fluorescent responses of the hemolymph were found to correlate positively with the concentration of total PAHs in the hepatopancreas (r = 0.39, p < 0.05).

Animals↗
PubMed2002

Removal of pyrene by different microalgal species.

The efficiency of seven microalgal species, namely, Chlamydomonas sp., Chlorella miniata, Chlorella vulgaris, Scenedesmus platydiscus, Scenedesmus quadricauda, Selenastrum capricornutum, and Synechosystis sp. to remove pyrene from solution varied from species to species. According to the 6-hour, 12-hour, and 7-day exposure data, S. capricornutum was the most efficient species in the removal of pyrene, followed by S. platydiscus (a local isolate), and the least effective species was C. vulgaris. For all species, the removal was very rapid in the first 3 to 6 hours of treatment, and no significant difference was found between live and dead cells of C. miniata, C. vulgaris and S. capricornutum, indicating that the initial removal was due to passive physico-chemical biosorption. More than 65% of the pyrene adsorbed was bound on cell wall materials of S. capricornutum, suggesting the major binding sites were on cell walls. The pyrene removal was also dependent on the concentration of algal biomass used, the more the biomass the higher the removal percentages. In addition to biosorption, pyrene was accumulated and transformed inside live cells. In 7-day S. capricornutum culture, pyrene was not detected in either culture medium or algal pellets, and pyrene might have been completely transformed by this species. The degree of bioaccumulation and biotransformation was species specific.

Adsorption↗
PubMedDate not supplied

Covalent binding of benzo(a)pyrene in perfused rat lung following systemic and intratracheal administration.

Covalent binding of benzo(a)pyrene to DNA, RNA, and protein of perfused rat lung after intratracheal administration of the substrate was about 50% of that obtained by direct addition of the substrate into the perfusate. Systemic availability of benzo(a)pyrene by absorption from the intratracheal sites was found to be 25%. During single pass perfusion of rat lung as well as in the combined liver-lung recirculating perfusion system, covalent binding after intratracheal exposure to benzo(a)pyrene was reduced to 50-75%. These experiments point out the relative importance of systemic versus inhalation exposure to benzo(a)pyrene in the development of lesions on the lung macromolecules. The elimination capacity of the perfused lung was found to be relatively high as compared to the liver. At constant benzo(a)pyrene infusion by a single pass medium, clearance values of the 5,6-benzoflavone-induced lung with 7.8 ml/min reach almost half of those of a 5,6-benzoflavone-induced liver (15.9 ml/min). The extraction ratios in lung both during bolus administration in the recirculating system and during constant infusion in the nonrecirculating system are 0.25 and 0.29, respectively, and thus amount to half of those measured in the liver (0.45 and 0.53, respectively). Though the liver is able to exert a protective effect against covalent binding of benzo(a)pyrene in the lung, this protection is not complete, and significant amounts of benzo(a)pyrene are expected to escape metabolic transformation by the liver representing a risk for the lung from the circulatory site in addition to that from the respiratory site.

Animals↗
PubMed1981

Specificity in the activation and inhibition by flavonoids of benzo[a]pyrene hydroxylation by cytochrome P-450 isozymes from rabbit liver microsomes.

The effect of flavone and 7,8-benzoflavone on the metabolism of benzo[a]pyrene to fluorescent phenols by five cytochrome P-450 isozymes obtained from rabbit liver microsomes was determined. Benzo[a]pyrene metabolism was stimulated more than 5-fold by the addition of 600 microM flavone to a reconstituted monooxygenase system consisting of NADPH, cytochrome P-450 reductase, dilauroylphosphatidylcholine, and cytochrome P-450LM3c or cytochrome P-450LM4. In contrast, an inhibitory effect of flavone on benzo[a]pyrene metabolism was observed when cytochrome P-450LM2, cytochrome P-450LM3b, or cytochrome P-450LM6 was used in the reconstituted system. 7,8-Benzoflavone (50-100 microM) stimulated benzo[a]pyrene metabolism by the reconstituted monooxygenase system about 10-fold when cytochrome P-450LM3c was used, but benzo[a]pyrene hydroxylation was strongly inhibited when 7,8-benzoflavone was added to the cytochrome P-450LM6-dependent system. Smaller effects of 7,8-benzoflavone were observed on the metabolism of benzo[a]pyrene by the cytochrome P-450LM2-, cytochrome P-450LM3b-, and cytochrome P-450LM4-dependent monooxygenase systems. These results demonstrate that the activating and inhibiting effects of flavone and 7,8-benzoflavone on benzo[a]pyrene metabolism depend on the type of cytochrome P-450 used in the reconstituted monooxygenase system.

Animals↗
PubMed1981

Nuclear uptake and subsequent nuclear metabolism of benzo(a)pyrene complexed to cytosolic proteins.

The binding of [3H]benzo(a)pyrene to proteins of rat liver cytosol, the nuclear uptake of cytosolic protein-bound [3H]-benzo(a)pyrene, and the subsequent nuclear metabolism of the polycyclic hydrocarbon were investigated. The binding of [3H]benzo(a)pyrene to cytosol had a saturable high affinity component with a Kd of 2.54 nM and a capacity of 530 fmol/mg protein. Specific binding of [3H]benzo(a)pyrene to cytosol was also assayed using sucrose density gradient analysis. Nuclear uptake of protein-bound [3H]benzo(a)pyrene was demonstrated both directly and by sucrose density gradient analysis. The nuclear benzo(a)pyrene was readily converted to metabolites which were qualitatively and quantitatively no different from nuclear metabolites of exogenously (not protein associated) added [3H]benzo(a)pyrene.

Animals↗
PubMed1982

Metabolic activation of benzo(a)pyrene by transformable and nontransformable C3H mouse fibroblasts in culture.

Incubation of 2.5 microM benzo(a)pyrene (BaP) with C3H/10T 1/2 or CVP3SC6 (CVP) mouse fibroblasts for 48 hr resulted in the metabolism of 36 to 42% of the BaP to organic soluble derivatives, which cochromatographed with 7,8-trans-dihydroxy-7,8-dihydrobenzo(a)pyrene, 9,10-trans-dihydroxy-9,10-dihydrobenzo(a)pyrene, 3-hydroxybenzo(a)pyrene, and 9-hydroxybenzo(a)pyrene, or to water-soluble derivatives. The formation of both organic and water-soluble metabolites during the 48-hr period increased proportionally with time, except in the case of BaP phenols, which increased initially but then remained the same or decreased. The distribution of organic soluble metabolites in the extracellular culture medium consisted primarily of BaP diols and was significantly different from that found inside the cells. The intracellular profile of organic soluble metabolites produced by both cell lines consisted predominantly of BaP phenolic derivatives and was qualitatively similar to the spectrum of metabolites produced by the incubation of BaP with C3H/10T 1/2 or CVP cell microsomes. The nature of the BaP water-soluble derivatives produced by the C3H/10T 1/2 and CVP cell lines was investigated by hydrolysis of culture medium with beta-glucuronidase and arylsulfatase. Although sulfation was not a major conjugation pathway for BaP in these cells, glucuronidation of BaP phenols was found to account for 30% of the total water-soluble derivatives. The similarity in the kinetics and qualitative nature of the metabolism of BaP by C3H/10T 1/2 and CVP cells indicates that both cell lines are equally capable of biosynthesizing the proximal carcinogen, 7,8-trans-dihydroxy-7,8-dihydrobenzo(a)pyrene. Analysis of the water-soluble metabolites produced by these cells suggests further that the nonresponsiveness of the CVP cells to BaP-induced transformation cannot be accounted for on the basis of an increased detoxication of 7,8-trans-dihydroxy-7,8-dihydrobenzo(a)pyrene.

Animals↗
PubMed1989

Role of nitroreduction in the synergistic mutational response induced by mixtures of 1- and 3-nitrobenzo[a]pyrene in Salmonella typhimurium.

Previous studies showed that binary mixtures of the environmental pollutants 1- and 3-nitrobenzo[a]pyrene produced a synergistic mutational response in the Salmonella reversion assay. Since nitroreduction is believed to mediate the direct-acting mutagenicity of the individual compounds, we have examined the role of nitroreduction in the mutagenicity of mixtures of 1- and 3-nitrobenzo[a]pyrene in the Salmonella plate incorporation assay. While mixtures of 1- and 3-nitrobenzo[a]pyrene induced up to 183% more revertants in strain TA98 than produced by equivalent amounts of the individual compounds, in the nitroreductase-deficient strain TA98NR the same mixtures only induced up to 57% more revertants than the individual compounds. Analysis of mixtures of 1- and 3-nitrosobenzo[a]pyrene (the two-electron reduction products of 1- and 3-nitrobenzo[a]pyrene) for mutation induction in TA98 yielded no evidence of a synergistic effect between the compounds. The mutagenicity of the mixtures was dependent upon the amount of the more mutagenic component. Salmonella cultures were also incubated with mixtures of 1- and 3-nitrobenzo[a]pyrene, as well as with equivalent amounts of the individual compounds. In two experiments, nitroreductive ability, as measured by the amount of 1-nitropyrene metabolized to 1-aminopyrene in 1 hr, was increased 9 to 105% in cultures pretreated with the mixtures as compared with cultures pretreated with the individual compounds. The results of this study support the hypothesis that nitroreduction is a major factor in the synergistic mutational response induced by 1- and 3-nitrobenzo[a]pyrene in Salmonella typhimurium.

Benzopyrenes↗
PubMed1997

The Effect of Ternary Complex Formation on the Partitioning of Pyrene and Anthracene in Aqueous Solutions Containing Sodium Dodecyl Sulfate and M-gamma-cyclodextrin

The partitioning behavior of pyrene and anthracene between n-decane and aqueous solutions containing a partially methylated gamma-cyclodextrin (M-gamma-CD) and sodium dodecyl sulfate (SDS) was studied by extraction experiments. At concentrations below the aqueous solubility of pyrene and anthracene both were found to form 1:1 complexes with M-gamma-CD. Formation constants were determined as 1843 M-1 for pyrene and 624 M-1 for anthracene. In micellar solutions of SDS pyrene was found to be better solubilized than anthracene. At constant concentrations of M-gamma-CD the dependence of the partition coefficients on increasing concentrations of SDS could be divided into three linear regions. At concentrations below a critical surfactant concentration (CSCSDS) the partition coefficients of both polyaromatic hydrocarbons as well as the fluorescence intensity of pyrene increased linearly with the addition of SDS. In the fluorescence spectra of anthracene the addition of SDS led to a shift of the maxima to higher wavelengths. These data suggest the formation of ternary complexes of M-gamma-CD with each of the polyaromatic hydrocarbons and SDS. The ternary complex with anthracene was found to be more stable than that of pyrene, which resulted in higher partition coefficients than seen with pyrene. Increasing the surfactant concentrations above the CSCSDS the partition coefficients remained constant until micelles were formed and another linear increase of the partition coefficients could be observed. CSCSDS and the critical micellization concentration (CMC) were found to increase linearly with cyclodextrin concentration. For CSCSDS a molar ratio of 3/1 was found for M-gamma-CD/SDS. Mixed micelles between SDS and gamma-CD are supposed to be formed above CSCSDS. Copyright 1997Academic Press

Journal Article↗
PubMed1978

Repair of DNA damaged by mutagenic metabolites of benzo(a)pyrene in human cells.

The repair of human DNA after damage by known and potential metabolites of benzo(a)pyrene has been examined utilizing the bromodeoxyuridine photolysis assay. Repair was characterized as either ultraviolet ("long") or ionizing radiation type ("short") repair utilizing normal cells and cells deficient in ultraviolet-type repair endonuclease from a patient with xeroderma pigmentosum (XP). We have found that only (+/-)-7beta,8alpha-dihydroxy-9beta,-10beta-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene (BP diol epoxide 1) and its disastereomer, (+/-)-7beta,8alpha,-dihydroxy-9alpha,10alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene (BP diol epoxide 2) elicit damage to DNA which is recognizable by the ultraviolet excision repair system in normal human cells. Benzo(a)pyrene 4,5-, 9,10-, 11,12-oxides do not elicit damage which is repairable by this repair system. The 1,2-diol-3,4-epoxides from naphthalene have no measurable activity in our assay. These results indicate that both the benzo(a)pyrene ring structure and the diol epoxide groups are important in causing the damage to DNA which is repairable by the ultraviolet excision repair system. These results parallel the reported high mutagenic activity of these compounds and support the concept that benzo(a)pyrene 7,8-diol-9,10-epoxides may be the ultimate, metabolically activated forms of benzo(a)pyrene.

Benzopyrenes↗
PubMed1980

Inhibition by norharman of metabolism of benzo[a]pyrene by the microsomal mixed function oxidase of rat liver.

The effect of norharman on the metabolism of ethyl acetate-soluble metabolic intermediates of benzo[a]pyrene (BP), 9,10-dihydro-9,10-dihydroxybenzo[a]pyrene (9,10-diol), 4,5-dihydro-4,5-dihydroxybenzo[a]pyrene (4,5-diol), 7,8-dihydro-7,8-dihydroxybenzo[a]pyrene (7,8-diol), benzo[a]pyrene diones, 3-hydroxybenzo[a]pyrene (3-OH-BP) and 9-hydroxybenzo[a]pyrene (9-OH-BP), were studied. These metabolic intermediates were converted by microsomal enzymes to other more polar ethyl acetate-soluble metabolites and then finally to the water-soluble metabolites. Norharman inhibited markedly the disappearance of each metabolite added as a substrate. With high-pressure liquid chromatographic (HPLC) separation it was revealed that formation of more polar metabolite was more efficiently inhibited by norharman than the formation of less polar metabolite. Formation of water-soluble metabolite was most efficiently inhibited by norharman. The mechanisms of the inhibitory effect of norharman on BP metabolism were studied by difference spectroscopy. On the addition of norharman, microsomes showed a type II difference spectrum, while on the addition of BP, they showed a type I difference spectrum. 3-OH-BP and 4,5-diol also gave a type I spectrum. Thus both BP and its metabolites bind to the active center of P-450, whereas norharman binds to the sixth ligand position of the iron ion of P-450. Kinetic studies showed that the Km-value of microsomes for BP was 6.25 microM in the presence and absence of norharman. This indicated that norharman inhibits the metabolism of BP non-competitively.

Alkaloids↗
PubMed2005

Evidence from surface tension and fluorescence data of a pyrene-assisted micelle-like assemblage of humic substances.

Surface activity and fluorescence of humic substances (HS) and HS/pyrene solutions were monitored under various pH conditions. For HS alone the surface tension of the solutions decreased with increasing acidity, with a minimum at around pH 4. This effect, which is a consequence of an increase in the amphiphilic character of structures, is much more pronounced in humic (HA) than in fulvic acids (FA). The addition of pyrene (0.1 micromolL(-1)) results, for HA, in a marked reduction in the migration of amphiphilic species to the solution surface. FA profiles are not modified in presence of pyrene at that concentration. A decrease in the pyrene I1/I3 ratio in HS solutions shows that below pH 9 pyrene molecules react progressively to the change to a more hydrophobic environment, the greatest effect being observed at around pH 6 to 7. These signals are followed by a significant increase in the pyrene excimer fluorescence (lambda(exc)/lambda(em)=334 nm/450 nm), which is a consequence of the proximity of pyrene molecules. For FA, the I1/I3 decrease is less significant and no excimers develop. This set of effects is explained in view of conformational adjustments of HS, mainly HA, which become arranged in micelle-like domains in aqueous solution, the aromatic moieties being assembled around the pyrene molecules.

Benzopyrans↗
PubMed1990

The strong hepatocarcinogenicity of the electrophilic and mutagenic metabolite 6-sulfooxymethylbenzo[a]pyrene and its formation of benzylic DNA adducts in the livers of infant male B6C3F1 mice.

6-Hydroxymethylbenzo[a]pyrene was activated to an electrophilic and mutagenic sulfuric acid ester metabolite by rat and mouse liver sulfotransferase activity. The intrinsic mutagenicity of this reactive ester, 6-sulfooxymethylbenzo[a]pyrene, was inhibited by glutathione and glutathione S-transferase. A single i.p. dose of 2.5 nmol/g body wt of 6-sulfooxymethylbenzo[a]pyrene in infant male B6C3F1 mice induced liver tumors in 35 of 36 mice at 10 months with an average multiplicity of 4.4. A comparable dose of the parent hydrocarbon, 6-hydroxymethylbenzo[a]pyrene, was only a tenth as active. The electrophilic sulfuric acid ester produced high levels of benzylic DNA adducts in the livers of these mice that accounted for about 80% of the total DNA adducts. These results strongly suggest that this sulfuric acid ester is an important ultimate electrophilic and carcinogenic metabolite in carcinogenesis by 6-hydroxymethylbenzo[a]pyrene and possibly even by 6-methylbenzo[a]pyrene and benzo[a]pyrene in mouse liver.

Animals↗