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PubMed2007

Benzo[a]pyrene diol-epoxide (B[a]PDE) upregulates COX-2 expression through MAPKs/AP-1 and IKKbeta/NF-kappaB in mouse epidermal Cl41 cells.

Benzo[alpha]pyrene-7,8-diol-9,10-epoxide (B[a]PDE), the major metabolite of benzo[a]pyrene (B[a]P), shows an ultimate complete carcinogen in various animals and is a causative agent for human cancers. However, its effects on the activation of signal pathways and the expression of genes involved in its carcinogenic effect remain largely unknown. In this study, the effects of B[a]PDE on induction of cyclooxygenase (COX)-2 and the signal pathways leading to the induction were investigated. Treatment of mouse epidermal Cl41 cells with B[a]PDE caused an increase in the expression of COX-2 at both transcription and protein levels, while its parental compound B[a]P did not show significant inductive effect. The COX-2 induction by B[a]PDE was dependent on the activation of mitogen-activated protein kinases (MAPK)s/activation protein (AP)-1 pathway, because inhibition of AP-1 by either overexpression of TAM67 (dominant negative mutant of c-jun), or pretreatment of cells with PD98059 (MEK1/2-ERKs pathway inhibitor) or SB202190 (p38K inhibitor), markedly inhibited B[a]PDE-induced COX-2 expression. In addition, impairment of NF-kappaB pathway by either NEMO-BDBP (an NF-kappaB specific inhibitor) or IkappaB kinase (IKK)beta-KM (dominant negative mutant of IKKbeta) also caused marked reduction of COX-2 induction by B[a]PDE. In contrast, inhibition of nuclear factor of activated T cells (NFAT) with FK506, did not show any effect on B[a]PDE-induced COX-2 expression. Collectively, these data indicate that exposure of Cl41 cells to B[a]PDE can induce COX-2 expression by increasing its transcription, which requires the activation of MAPKs/AP-1 and IKKbeta/NF-kappaB pathways, but not NFAT pathway. In view of the importance of COX-2 in carcinogenesis, we anticipate that the induction of COX-2 by B[a]PDE may coordinate its mutagenic effects to facilitate the development of skin cancer.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1991

A monoclonal antibody to rat liver cytochrome P450 IIC11 strongly and regiospecifically inhibits constitutive benzo[a]pyrene metabolism and DNA binding.

The monoclonal antibody MAb 1-68-11, prepared to constitutive cytochrome P450 IIC11 (2c/RLM5) from male Sprague-Dawley rat liver, was used to study the contribution of the class of cytochrome P450s epitopically related to P450 IIC11 to the regiospecific metabolism of benzo[a]pyrene (BP) and its binding to DNA. The effect of MAb 1-68-11 was determined on the conversion of BP to BP-9,10-dihydrodiol, BP-7,8-dihydrodiol, BP-4,5-dihydrodiol, BP phenols, and BP quinones, and on the P450-dependent DNA binding catalyzed by P450 in microsomes from uninduced male and female Wistar and Sprague-Dawley rat livers, as well as 3-methylcholanthrene- and phenobarbital (PB)-induced male Wistar rat livers. In liver microsomes from untreated male rats, MAb 1-68-11 inhibited BP-9,10-dihydrodiol formation by 80%; in liver microsomes from untreated female rats, the inhibition was 100%. BP-7,8-dihydrodiol formation was inhibited from 38 to 77% in microsomes from males and 50% in those from females. In microsomes from PB-induced rats, inhibition of the 9,10-dihydrodiol and the 7,8-dihydrodiol was 90% and 73%, respectively, whereas BP-4,5-dihydrodiol formation was enhanced 80%. In microsomes from 3-methylcholanthrene-treated rats, no inhibition of MAb 1-68-11 was observed on either the metabolism of BP or its binding to DNA. In contrast, the binding of BP to DNA was completely inhibited by MAb 1-68-11 in microsomes from uninduced male Wistar rats and 70% in PB-induced microsomes. 32P-postlabeling analysis showed that formation of the major stable adduct, BP diol epoxide bound at C-10 to the 2-amino of deoxyguanosine, was strongly inhibited in uninduced and PB-induced microsomes. Formation of the major labile BP-DNA adduct 7-(benzo[a]pyren-6-yl) guanine (BP-N7Gua) was inhibited about 60% in microsomes from untreated male Wistar rats. These results show that MAb 1-68-11 regiospecifically inhibits cytochrome P450 IIC11 and epitopically related P450s that metabolize BP at the 7,8 and 9,10 positions. MAb 1-68-11 also inhibits enzyme-catalyzed binding of BP to DNA in the specific formation of BP-N7Gua and adducts detected by the 32P-postlabeling technique.

Animals↗
PubMed1992

Induction of CYP1A1 gene expression in H4-II-E rat hepatoma cells by benzo[e]pyrene.

In the rat, expression of the CYP1A1 gene is closely associated with arylhydrocarbon hydroxylase (AHH) enzyme activity. AHH is an inducile enzyme activity known to play an important role in the bioactivation of polycyclic aromatic hydrocarbons (PAHs) to mutagenic and carcinogenic metabolites. PAH-induced expression of the CYP1A1 gene appears to be regulated by several trans-acting factors, including the Ah receptor and the 4S PAH-binding protein. In this study, we used the PAH isomers benzo[a]pyrene (BaP) and benzo[e]pyrene (BeP) to further evaluate the role of the 4S PAH-binding protein in induction of the CYP1A1 gene in H4-II-E rat hepatoma cells. Although BaP is believed to bind to both the Ah receptor and the 4S protein, BeP has been reported to bind exclusively to the 4S protein. The results of the study presented here indicate that BaP and BeP induce the expression of the CYP1A1 gene, as measured by ethoxyresorufin O-deethylase (EROD) activity, in a concentration-dependent manner. However, BaP is about 25 times as potent as BeP in inducing EROD activity in these cells. Slot-blot analysis of total RNA isolated from these cells indicated that BeP, BaP, and 3-methylcholanthrene increased the level of CYP1A1 mRNA expression. Sucrose-gradient analysis of BeP binding activity indicated that BeP bound with high affinity to the 4S PAH-binding protein, but not to the Ah receptor. These results suggest that the 4S protein may play a role in the PAH-induced expression of the CYP1A1 gene in rat H4-II-E cells.

Animals↗
PubMed1993

Ki-ras oncogene mutations in tumors and DNA adducts formed by benz[j]aceanthrylene and benzo[a]pyrene in the lungs of strain A/J mice.

Strain A/J mice received intraperitoneal injections of benz[j]aceanthrylene (B[j]A) or benzo[a]pyrene (B[a]P). At 24, 48, and 72 h, lung tissues were removed for analysis of B[a]P- or B[j]A-derived DNA adduct formation during the first 3 d of exposure. One group of mice exposed to these hydrocarbons was kept for 8 mo to determine lung tumor multiplicity, the occurrence of mutations in codons 12 and 61 of the Ki-ras gene in the tumors that arose, the relationship between Ki-ras oncogene mutations in tumors, and the presence and quantity of genomic DNA adducts. The major DNA adduct in the lungs of mice exposed to B[a]P was N2-(10 beta-[+B, 7 alpha, 9 alpha-trihydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene]yl)-deoxyguanosine (BPDE-I-dGuo) arising from bay-region diolepoxide activation of B[a]P and was consistent with the occurrence of tumors with mutations GGT-->TGT (56%), GGT-->GTT (25%), and GGT-->GAT (19%) in codon 12, all involving mutations of a guanine. B[j]A, a demethylated analogue of 3-methylcholanthrene (3-MCA) with an unsaturated cyclopenta ring, produced 16-to 60-fold more tumors at equivalent doses than did B[a]P; the mutations in tumors were GGT-->TGT (4%), GGT-->GTT (30%), and GGT-->CGT (65%). Analysis of adduction patterns in DNA suggested that B[j]A was activated to form DNA-binding derivatives in A/J mouse lungs primarily at the cyclopenta ring even though B[j]A contains a bay region. As reported in the published literature, the mutation spectrum induced by 3-MCA in Ki-ras codon 12 of mouse cells is similar to that of B[a]P but not to that of its close relative B[j]A. In contrast to B[j]A, 3-MCA is activated mostly via a bay-region diol-epoxide since its cyclopenta ring is saturated and not easily epoxidates. Therefore, we propose that the GGT-->CGT mutations produced by B[j]A in Ki-ras codon 12 were mostly the result of cyclopenta-ring-derived adducts.

Animals↗
PubMed2004

Selective digestion and novel cleanup techniques for detection of benzo[a]pyrene diol epoxide-DNA adducts by capillary electrophoresis/mass spectrometry.

Benzo[a]pyrene (BP) is a ubiquitous environmental polycyclic aromatic hydrocarbon (PAH) which, upon metabolic conversion to reactive benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE), has been found to attach covalently to DNA. Given the low level of DNA adducts typically present in vivo or in vitro, an essential first step prior to capillary electrophoresis/mass spectrometry (CE/MS) (or liquid chromatography/mass spectrometry (LC/MS)) analysis of the DNA digests is the removal of the bulk non-adducted nucleotides, enzymes or salts, and isolation of enriched adducts. This report focuses on the development of novel sample handling methods aimed at facilitating the analysis of BPDE-DNA adducts by CE/MS. This approach involves a simple variation on the digestion procedure, in combination with the use of metal affinity ZipTips for the more efficient cleanup of BPDE-DNA adducts formed in vitro for subsequent CE/MS analysis. The previously described digestion procedure, consisting of micrococcal nuclease, spleen phosphodiesterase and nuclease P1, allows for selective dephosphorylation of normal nucleotides, while leaving adducted nucleotides intact. Metal affinity ZipTips, typically used for selective extraction of phosphopeptides, were used here for extraction of adducted nucleotides. The utility of metal affinity SPE was tested on mixtures of dG and dGp, wherein nucleotide extracts contained no detectable nucleosides by CE/UV analysis. An in vitro BPDE-DNA incubation was then digested using the above procedure. Metal affinity solid-phase extraction (SPE) was subsequently used for the selective isolation of phosphorylated components, i.e., adducted nucleotides, from the mixture of enzymes and non-adducted nucleosides. SPE extracts were enriched in nucleotide adducts and analyzed using sample stacking and CE/MS. This method has several advantages over previously described cleanup procedures for dGp-BPDE adducts: fast, simple, uses commercially available materials, no need for excessive dilution (small scale), the suitability for use with automation, and possible applicability to other bulky hydrophobic adducts.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1995

Interference with protein kinase C-related signal transduction in vascular smooth muscle cells by benzo[a]pyrene.

Elucidation of the mechanisms involved in the deregulation of vascular smooth muscle cell (SMC) growth and differentiation during the course of atherogenesis and the putative role of toxic injury in this process have been a subject of considerable interest in recent years. In this regard, we have recently shown that in vitro exposure of vascular (aortic) SMCs to benzo[a]pyrene (BaP), an atherogenic polycyclic aromatic hydrocarbon, initially delays cell cycle progression and inhibits cell proliferation and then causes permanent modulation to a highly proliferative state. To define the molecular basis of this response, we have examined critical components of the protein kinase C (PKC) signal transduction system upon exposure to BaP. Marked inhibition of serum-stimulated inositol phospholipid turnover was observed in growth-arrested SMC cultures challenged with 30 microM BaP for 24 h and then stimulated with 10% fetal bovine serum for 120 or 1800 s. Benzo[a]pyrene inhibited PKC-mediated phosphorylation of exogenous and endogenous proteins in the cytosolic and particulate fraction of cycling, as well as quiescent cultures. The PKC inhibitory response was observed as early as 0.5 h following BaP treatment and maintained for at least 5 days. Exposure of quiescent SMCs to 30 microM BaP inhibited the ability of serum to induce c-fos mRNA expression and decreased AP-1 binding to a 12-O-tetradecanoyl phorbol-13-acetate responsive element. Inhibition of PKC-related signal transduction was not due to generalized interference with cell cycle events since peak expression of the c-myc and c-Ha-ras protooncogenes following serum stimulation of quiescent cultures was unchanged, or slightly enhanced, by 30 microM BaP. Collectively, these data suggest that the ability of BaP to modulate growth and differentiation programs in vascular SMCs involves early interference with PKC-related mitogenic signal transduction.

Animals↗
PubMed1998

Cloning, expression, and biochemical characterization of a functionally novel alpha class glutathione S-transferase with exceptional activity in the glutathione conjugation of (+)-anti-7,8-dihydroxy-9,10-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene.

The present study describes cDNA cloning, expression, and kinetic characterization of the two subunits of a murine alpha-class glutathione (GSH) S-transferase (GST) isoenzyme (previously designated as GST 9.5), which, unlike other alpha-class mammalian GSTs, is exceptionally efficient in the GSH conjugation of (+)-anti-7,8-dihydroxy-9,10-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene [(+)-anti-BPDE] [X. Hu, S. K. Srivastava, H. Xia, Y. C. Awasthi, and S. V. Singh (1996) J. Biol. Chem. 271, 32684-32688]. The cDNAs for both subunits of GST 9.5 (GST 9.5-1 and GST 9.5-2) were cloned by RT-PCR. The deduced amino acid sequences of GST 9.5-1 and GST 9.5-2 clones were identical to those of mGSTA1 and mGSTA2, respectively. Both these subunits were expressed in Escherichia coli to determine the relationships between recombinant mGSTA1-1 and mGSTA2-2 and corresponding subunits of tissue-isolated GST 9.5. The pI values of recombinant mGSTA1-1 and mGSTA2-2 (9.49 and 9.45, respectively) were similar to that of the tissue-isolated isoenzyme (pI 9.5). The reverse-phase HPLC elution profiles and immunological cross-reactivities of recombinant mGSTA1-1 and mGSTA2-2 were also similar to those of the corresponding subunits of tissue-isolated GST 9.5. The catalytic efficiency of recombinant mGSTA1-1 toward (+)-anti-BPDE, 131 mM-1.s-1, was approximately 9.5-to 655-fold higher compared with tissue-isolated mGSTP1-1, mGSTA3-3, mGSTM1-1, and mGSTA4-4. Moreover, the catalytic efficiency of mGSTA1-1 toward (+)-anti-BPDE was about 3.3-fold higher compared with recombinant mGSTA2-2. The mGSTA1 and/or mGSTA2 subunits were expressed to varying degrees in female A/J mouse tissues. For example, mGSTA1, but not mGSTA2, subunit expression was observed in the skin, which is a target organ for benzo(a)pyrene (BP)-induced cancer in mice. On the other hand, the expression of either mGSTA1 or mGSTA2 subunit could not be detected in the lung, which is another target organ for BP-induced cancer in mice. Interestingly, relatively large amounts of both mGSTA1 and mGSTA2 subunits were detected in the kidney. In conclusion, the results of the present study clearly indicate that the A1-type subunit of GST 9.5 is responsible for its exceptional catalytic efficiency in the GSH conjugation of (+)-anti-BPDE, which is the ultimate carcinogen of widespread environmental pollutant BP.

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

Metabolic fate of glutathione conjugate of benzo[a]pyrene-(7R,8S)-diol (9S,10R)-epoxide in human liver.

Benzo[a]pyrene-(7R,8S)-diol (9S,10R)-epoxide [(+)-anti-BPDE] is believed to be the activated form of the widely spread environmental pollutant benzo[a]pyrene. Glutathione (GSH) S-transferase (GST)-catalyzed conjugation of (+)-anti-BPDE with GSH is an important mechanism in its cellular detoxification. Here, we report that the GSH conjugate of (+)-anti-BPDE [(-)-anti-BPD-SG] is a potent inhibitor (K(i) 15 microM) of class Mu human GST isoenzyme, which, among human liver GSTs, is a highly efficient detoxifier of (+)-anti-BPDE. Thus, the inhibition of GST activity by (-)-anti-BPD-SG may hinder GSH conjugation of (+)-anti-BPDE, unless the conjugate is metabolized and/or eliminated. The results of the present study show that gamma-glutamyltranspeptidase (gamma-GT) can metabolize (-)-anti-BPD-SG at a rate of about 0.29 nmol/min/mg protein. Our studies also show that (-)-anti-BPD-SG is transported across the human canalicular liver plasma membrane (cLPM) in an ATP-dependent manner at a rate of about 0.33 nmol/min/mg protein. The ATP-dependent transport of (-)-anti-[(3)H]BPD-SG across human cLPM follows Michaelis-Menten kinetics (K(m) 84 microM; V(max) 0.33 nmol/min/mg). In conclusion, the results of the present study suggest that both gamma-GT-mediated metabolism and ATP-dependent canalicular transport may be important steps in overall detoxification of (+)-anti-BPDE in the human liver.

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

Mass spectrometric sequencing of site-specific carcinogen-modified oligodeoxyribonucleotides containing bulky benzo[a]pyrene diol epoxide-deoxyguanosyl adducts.

Site-specific carcinogen-modified oligonucleotides are often used in site-directed mutagenesis and other biological and biochemical studies of structure-function relationships. Postsynthetic analysis and confirmation of the sites of carcinogen binding in such oligonucleotides is an important step in the characterization of these site-specific carcinogen-DNA adducts. It is shown here that negative ion mode electrospray tandem mass spectrometry methods and collision-induced dissociation offer a rapid and convenient approach for the sequencing of products derived from the reaction of the carcinogenic and mutagenic metabolite of benzo[a]pyrene, the diol epoxide r7,t8-dihydroxy-t9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (anti-BPDE), with the 11-mer oligonucleotide d(CATGCGGCCTAC). The site of reaction of anti-BPDE with either one of the three dG residues in this oligonucleotide can be accurately established by comparing the mass/charge ratios of the observed collision-induced dissociation fragments with calculated values.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed2001

Identification and characterization of a novel benzo[a]pyrene-derived DNA adduct.

The aim of this study was to generate and identify a novel benzo[a]pyrene (BP)-derived DNA adduct found both in vitro and in vivo. To date, the majority of studies have focused on N(2)-[10 beta(7 beta,8a,9a-trihydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene)yl]-deoxyguanosine (anti-BPDE-dG), the major adduct generated following bioactivation of BP. However, a second adduct is also formed following bioactivation of BP which has been speculated to result from further metabolism of 9-OH-BP. In order to identify this second reaction pathway, the ultimate DNA binding species, and the DNA base involved, we have synthesized and characterized a dG-derived DNA adduct arising from further bioactivation of 9-OH-BP in the presence of rat liver microsomes. Analysis of the adducted nucleotides was conducted using both the (32)P-postlabeling assay and capillary electrophoresis-mass spectrometry (CE-MS).

Animals↗
PubMed2001

Effect of benzo[a]pyrene diol epoxide on expression of retinoic acid receptor-beta in immortalized esophageal epithelial cells and esophageal cancer cells.

Expression of retinoic acid receptor-beta (RAR-beta) is frequently lost in tobacco-related cancers. Benzo[a]pyrene diol epoxide (BPDE) is an active metabolite of tobacco procarcinogen benzo[a]pyrene and plays an important role in tobacco carcinogenesis. We therefore exposed SV-40 immortalized esophageal epithelial cells and esophageal cancer cells to BPDE to understand possible interactions between BPDE and RAR-beta expression. Our data showed that BPDE decreased RAR-beta mRNA and protein levels by suppression of transcription of RAR-beta. Retinoic acid was able to partially block the inhibitory effect of BPDE on RAR-beta expression and to increase G1 phase of cell cycles. Furthermore, induction of COX-2 expression by BPDE was associated with RAR-beta inhibition. This study suggests that one way by which BPDE causes esophageal carcinogenesis may be through the inhibition of RAR-beta.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1993

Differential sensitivity of human hepatoma cell line and primary rat hepatocyte culture to benzo(a)pyrene-induced unscheduled DNA synthesis and adduct formation.

We studied the genotoxic potential of a carcinogen in the human hepatoma cell line, HepG2, and in primary rat hepatocyte culture. HepG2 is a well differentiated human hepatoblastoma cell line with biotransforming capacity. Rat hepatocytes were obtained by the standard two-step in situ perfusion technique. Following benzo(a)pyrene treatment, both HepG2 and primary rat hepatocyte culture showed unscheduled DNA synthesis with different sensitivity. In 32P-postlabelling analysis, the chromatogram revealed quantitative and qualitative differences between HepG2 and primary rat hepatocyte cultures when treated with 10 microM benzo(a)pyrene for 18 hr. The results have demonstrated that the HepG2 cell line may be used in addition to primary rat hepatocytes in risk assessment for detection of environmental carcinogens.

Animals↗
PubMed2002

Retinal pigment epithelial cell DNA is damaged by exposure to benzo[a]pyrene, a constituent of cigarette smoke.

This study examined the effect of exogenous benzo[ a ]pyrene (BaP), an important constituent of cigarette smoke, on cultured bovine retinal pigment epithelial (RPE) cells. Evidence is presented for its metabolic conversion into benzo[ a ]pyrene diol epoxide (BPDE) and the consequent formation of potentially cytotoxic nucleobase adducts in DNA. Cultured RPE cells were treated with BaP at concentrations in the range of 0-100 microM. The presence of BaP was found to cause inhibition of cell growth and replication. BaP induced the expression of a phase I drug metabolizing enzyme which was identified as cytochrome P450 1A1 (CYP 1A1) by RT-PCR and by Western blotting. Coincident with the increased expression of CYP 1A1, covalent adducts between the mutagenic metabolite BPDE and DNA could be detected within RPE cells by immunocytochemical staining. Additional support for their formation was afforded by nuclease P1 enhanced (32)P-postlabelling assays on cellular DNA. Single-cell gel electrophoresis (comet) assays showed that exposure of RPE cells to BaP rendered them markedly more susceptible to DNA damage induced by broad band UVB or blue light laser irradiation. In the case of UVB, this is consistent with the photosensitization of DNA cleavage by nucleobase adducts of BPDE. Collectively, these findings imply that BaP has a significant impact on RPE cell pathophysiology and suggest mechanisms whereby exposure to cigarette smoke might cause RPE dysfunction and cell death, thus possibly contributing to degenerative disorders of the retina.

Animals↗
PubMed1995

Kinetics of hemoglobin and albumin adducts in rabbits subchronically exposed to benzo[a]pyrene.

Benzo[a]pyrene (BaP) can form adducts with proteins after activation to a diolepoxide. Benzo[a]pyrene-hemoglobin and BaP-albumin adducts were measured in rabbits exposed to 0.5 or 5 mumol.kg-1.week-1 for a total of 11 weeks (last injection on Day 75). Each dose group of nine rabbits was divided into three equal subgroups. For each dose, one subgroup received a single weekly injection (Mondays), the second had two equal weekly injections (Mondays and Thursdays), and the third had five weekly injections (Mondays through Fridays). Blood was collected prior to injection on Days 0, 7, 14, 21, 28, 35, 42, 49, 56, 77, 78, 80, 84, 92, 108, and 140 for adducts determinations, with Day 0 being a Monday. The measured concentration of hemoglobin adducts was independent of the frequency of administration for a given total weekly dose giving support to its value as a "biointegrator." In addition, animals injected with 0.5 and 5 mumol BaP.kg-1.week-1 had respective mean adduct concentrations of 0.3 and 3 pmol/g hemoglobin. The blood concentration of albumin adducts was related to the frequency of injection with the animals receiving one, two and five injections/week having the lowest, intermediate, and highest adduct concentrations, respectively. Animals injected with 0.5 and 5 mumol BaP.kg-1.week-1 had respective mean adduct concentrations of 5 and 20 pmol/g which are 17 and 7 times higher than their corresponding hemoglobin adducts' values. The corresponding albumin adducts' half-lives calculated from the day of cessation of exposure were 5.8 and 9.6 days, compared with a reported 5.7 days for the half-life of the intact protein.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2002

Surface pressure-area isotherms and fluorescent behavior of phospholipids containing labeled pyrene.

In this work, the surface and fluorescent behavior of three phospholipids containing a pyrene molecule in one of their hydrocarbon chains was studied. Differences between the isotherms provided by the different monolayers can be attributed to the orientation of the head group in the phospholipids at the air/water interface. This assertion is supported by the fluorescent behavior of monolayers of phospholipids containing labeled pyrene (Py-DPPE, Py-DPPC, and Py-DPPG).

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1994

Induction of CYP1A1 gene expression in mouse hepatoma cells by benzo[e]pyrene, a ligand of the 4S polycyclic hydrocarbon-binding protein.

Hepa 1c1c7 (WT), TAOc1BPrc1 (CI), and BPrc1 (CII) mouse hepatoma cells were exposed to benzo[e]pyrene (B[e]P) or benzo[a]pyrene (B[a]P). B[e]P induced activity of a rat CYP1A1 reporter gene construct (-3015 to +2545 bp) by 1.8- to 2-fold and 5-fold in WT and CI cells, respectively. B[e]P caused a 2-fold induction of a truncated CYP1A1 reporter gene construct (-658 to +2545 bp) in WT cells and induced ethoxyresorufin O-deethylase (EROD) activity by 24- and 13-fold in WT and CI cells. B[a]P also induced CYP1A1 reporter gene and EROD activity in these cells. WT and CII cells had both 8S (Ah) receptor and 4S polycyclic hydrocarbon (PAH)-binding activity, while CI cells exhibited a lower 4S binding activity; 8S binding activity was not detected in CI cells under two separate binding conditions. 8S binding activity in the presence of sodium molybdate was 60-fold greater in WT cells than in CII cells. The absence of sodium molybdate resulted in a dramatic decrease of 8S binding activity in WT cells. The ability of B[e]P to induce CYP1A1 promoter-reporter gene activity and EROD activity in WT and CI cells suggested a role for the 4S PAH-binding protein in the induction of CYP1A1. The lack of detectable 8S binding activity in CI cells was in concert with this role.

Animals↗
PubMed1997

Depletion of glutathione by benzo(a)pyrene metabolites, ionomycin, thapsigargin, and phorbol myristate in human peripheral blood mononuclear cells.

Previous studies in this laboratory have shown that polycyclic aromatic hydrocarbons (PAHs) alter Ca2+ homeostasis and inhibit activation of both B and T lymphocytes obtained from rodents and humans. In the present studies, we demonstrate that alpha-naphthoflavone (ANF), an inhibitor of cytochrome P4501A activity, reduced the Ca2+ elevation produced by BaP in human peripheral blood mononuclear cell (HPBMC) lymphocytes. These results suggested that BaP metabolites may play a role in intracellular Ca2+ homeostasis in human lymphocytes. Reactive oxidative intermediates of BaP produced in HPMBC are known to be highly carcinogenic and have also been shown to be immunosuppressive. We examined the effects of benzo(a)pyrene (BaP), 7,12-dimethylbenz(a)anthracene (DMBA), benzo(e)pyrene (BeP), and anthracene, as well as certain BaP metabolites, on the levels of intracellular Ca2+ and glutathione in HPBMC. While BaP, DMBA, BeP, and anthracene did not cause a statistically significant decrease in GSH in HPBMC at concentrations of 1 or 10 microM following a 6-, 48-, or 72-hr exposure, reactive BaP metabolites including 4,5-epoxide BaP and 7,8-diol-9,10-epoxide BaP consistently produced a 20-30% depletion of glutathione in HPBMC following a 6-hr treatment period. These BaP metabolites also elevated intracellular Ca2+ in HPBMC during a 6-hr incubation. Results of these experiments suggest that metabolism of BaP to certain epoxide metabolites may be responsible for sulfhydryl damage leading to transient GSH depletion and Ca2+ elevation. These results are consistent with the hypothesis that sulfhydryl damage by certain PAH metabolites may lead to altered Ca2+ homeostasis, leading to inhibition of cell activation and proliferation in HPBMC.

Benzo(a)pyrene↗
PubMed1993

Modulation by retinoic acid of spontaneous and benzo(a)pyrene-induced c-Ha-ras expression.

The effects of retinoic acid on the expression of the Ha-ras gene were studied in transformed rat hepatoma cells (H4IIE) and in rat aortic smooth muscle cells (ASMC) treated with benzo(a)pyrene (30 microM) in vitro. In H4IIE cells, a dose-dependent increase in steady state Ha-ras mRNA levels was observed upon exposure to retinoic acid for 24 hr. Exposure of ASMC to 10 microM retinoic acid under similar experimental conditions was also associated with increased Ha-ras expression. In contrast, retinoic acid (1 and 10 microM) inhibited benzo(a)pyrene-induced expression of Ha-ras in ASMC. These results suggest that retinoic acid modulates spontaneous and carcinogen-induced expression of Ha-ras in a differential manner.

Animals↗