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PubMed1995

The ESR properties, DNA nicking, and DNA association of aged solutions of catechol versus aqueous extracts of tar from cigarette smoke.

Previous studies in our laboratories have shown that extracts from mainstream or sidestream tobacco smoke nick DNA. These solutions contain the tar semiquinone free radical, and the tar radical becomes associated with cellular DNA. Aged solutions of catechol contain a semiquinone species that has ESR properties similar to those of the radical in cigarette tar extracts, and we have used these catechol solutions as a model for the tar radical. Both the radical in aged catechol solutions and the cigarette tar radical become associated with the DNA in mammalian cells and also nick DNA. The nicking of DNA caused by both tar and aged catechol solutions follows saturation kinetics. Aged catechol solutions thus allow the study of a model for the radical present in cigarette tar, without interference from the other toxic constituents in tar extracts.

Animals↗
PubMed2002

Highly increased urinary 1-hydroxypyrene excretion rate in patients with atopic dermatitis treated with topical coal tar.

Coal tar preparations, as used in dermatological practice, contain numerous polycyclic aromatic hydrocarbons of which many are proven animal carcinogens. Increased urinary 1-hydroxypyrene excretion in patients with atopic dermatitis treated with topical coal tar preparations has been demonstrated. Little is known about the relationship between the dermal uptake of polycyclic aromatic hydrocarbons on the one hand and the amount of tar applied to the skin, the total body area affected, the condition of the epidermal barrier and the severity of the dermatitis on the other. We compared urinary 1-hydroxypyrene excretion rate with these variables. The urinary 1-hydroxypyrene excretion rate was highly dependent on the total amount of tar applied to the skin and the total body area affected, and less on the severity of the atopic dermatitis or the condition of the epidermal barrier. Exposure to therapeutic doses of coal tar leads to much higher rates of urinary 1-hydroxypyrene excretion than occupational exposure. Because of the potential carcinogenicity of coal tar, as clearly demonstrated both in animal studies and from occupational exposure, careful consideration should be given to the use of coal tar preparations in dermatological practice. However, the risk of short-term high exposure is unknown. Restriction of the use of coal tar should be based on epidemiological studies and/or appropriate risk models taking into account its relative safety established over many years of clinical use.

Absorption↗
PubMed2004

Investigation of the wetting behavior of coal tar in three phase systems and its modification by poloxamine block copolymeric surfactants.

The removal of dense nonaqueous phase liquid mixtures (DNAPLs) from rocks and subsurface soils is an ongoing remedial challenge. Very often the wetting preferences of the system are not altered by exposure to the DNAPL. However, there are systems where the wetting properties of the solid phase have been altered from strongly water wetting by exposure to the DNAPL. In these cases some technique is necessary for reducing the work of adhesion between the DNAPL and the mineral surface. The focus of this report is the problems posed by coal tar in unconsolidated sands. It is shown that coal tar can alter the wetting properties of quartz, the principal component of sands, and is thus capable of adhering to the surface. In this investigation the ability of several members of the poloxamine family of polymeric surfactants to aid in the removal of coal tar from sand was evaluated. The poloxamines are tetrafunctional block copolymeric surfactants, which contain four poly(ethylene oxide)-block-poly(propylene oxide) chains joined to a central ethylenediamine moiety via the nitrogen atoms. Contact angle measurements of coal tar on a quartz surface immersed in aqueous surfactant solution and the interfacial tension between coal tar and aqueous surfactant solution have been measured. Coal tar/water interfacial tensions are reduced to values in the region of 2 mN m(-1) at surfactant concentrations of approximately 0.1 w/v %. Poloxamine surfactant impact on the static contact angle is more complex. In some cases the polymeric surfactants alter the wetting behavior from strongly water wetting to weakly water wetting. However, other poloxamines appear to have little if any impact on the contact angle, which remains strongly water wetting. The foregoing measurements have then been used to calculate the work of adhesion of the coal tar to quartz and the results qualitatively compared with the concentration of surfactant solution required to visually demonstrate the complete de-adhesion of coal tar to the quartz. It is shown that at surfactant concentrations below the critical micelle concentration (cmc) of the surfactant, the work of adhesion can be reduced sufficiently to ensure complete removal of coal tar from both quartz and sand.

Adsorption↗
PubMed1997

Synergistic induction of DNA strand breakage by cigarette tar and nitric oxide.

Cigarette smoking is a major cause of human cancer at a variety of sites, although its carcinogenic mechanisms remains unestablished. Cigarette smoke can be divided into two phases, gas phase and particulate matter (tar). Both phases contain high concentrations of oxidants and free radicals, especially nitric oxide (NO) and nitrogen oxides in the gas phase and quinone/hydroquinone complex in the tar. We have found that incubation of pBR322 plasmid DNA with aqueous extracts of cigarette tar and a NO-releasing compound (diethylamine NONOate) caused synergistic induction of DNA single-strand breakage, whereas either cigarette tar alone or NO alone induced much less strand breakage. This synergistic effect of cigarette tar and NO on DNA strand breakage was prevented by high concentrations of superoxide dismutase, carboxy-PTIO (an NO-trapping agent) or N-acetylcysteine, whereas hydroxyl radical scavengers such as dimethylsulfoxide, ethanol and D-mannitol did not show inhibitory effects. Possible mechanisms for this synergistic effect mediated by cigarette tar and NO are proposed, including involvement of peroxynitrite, which is a strong oxidant and nitrating agent formed rapidly by the reaction between NO and O2.-. NO is present in the gas phase of smoke and may be formed by a constitutive or inducible NO synthase in the lung, whereas O2.- is generated by auto-oxidation of polyhydroxyaromatic compounds such as catechol and 1,4-hydroquinone present in cigarette tar. Thus, potent reactive species including peroxynitrite formed by the interaction between cigarette tar and NO may play an important role in smoking-related diseases including lung cancer.

Copper↗
PubMed2000

7H-benzo[c]fluorene: a major DNA adduct-forming component of coal tar.

Coal tar is a complex mixture that exhibits high carcinogenic potency in lungs of animals when administered in the diet. Studies have noted that lung tumor induction does not correlate with the benzo[a]pyrene content of coal tar, suggesting that other hydrocarbons may be involved in the observed tumorigenicity. Our previous studies have demonstrated that a major 'unknown' chemical-DNA adduct is formed in the lung of mice exposed to coal tar. We have used an in vitro rat microsomal activation system to generate the 'unknown' adduct with neat coal tar and fractions of coal tar obtained by chemical fractionation and HPLC. Chemical-DNA adduct formation was evaluated by (32)P-postlabeling using both multi-dimensional TLC and HPLC. GC-MS analysis of the coal tar fractions obtained from HPLC, which produced the 'unknown' adduct in vitro, demonstrated that the adducting hydrocarbon had a mass of 216. A careful evaluation of candidate hydrocarbons led to the conclusion that a benzofluorene derivative may be responsible for forming the 'unknown' chemical-DNA adduct. Comparative in vitro and in vivo studies on the adducting properties of all three isomers of benzofluorene indicated that 7H-benzo[c]fluorene is responsible for producing the 'unknown' adduct observed in the lung of mice ingesting coal tar. Animal feeding studies also demonstrated that 7H-benzo[c]fluorene formed considerably more lung DNA adducts than 11H-benzo[a]fluorene and 11H-benzo[b]fluorene. These data indicate that the four-ring polycyclic aromatic hydrocarbon 7H-benzo[c]fluorene, a hydrocarbon not previously shown to form DNA adducts in lung, is in fact a potent lung DNA adductor and is a candidate PAH for causing lung tumors in animals treated with coal tar.

Animals↗
PubMed1983

Coal tar phototoxicity: kinetics and exposure parameters.

We examined two manifestations of coal tar phototoxicity: delayed erythema and skin pain (tar smarts) by quantifying the amount (dose) of UVA and exposure conditions required to induce these phenomena in normal human skin. The minimal UVA dose required to induce delayed erythema (minimal phototoxic dose or MPD) and the minimal UVA dose required to induce an immediate smarting reaction (minimal smarting dose or MSD) were recorded in 32 subjects in a variety of settings. A log-log dose-response model described the relation between the interval of time tar was left on the skin and lowering of MPD. We examined 4 different methods of tar removal and showed that several methods using more than water alone were equally effective--judging by resultant phototoxicity. The time between tar removal and UVA irradiation is important. Even 30 min was sufficient for the MPD to increase from 3.77 +/- 1.55 to 6.1 +/- 4.0 J/cm2 (p less than 0.02). The smarting reaction shows a similar dependence on the time interval between tar removal and exposure. The mean MSD was less than the mean MPD at all times tested. Both manifestations of coal tar phototoxicity, reduced delayed erythema threshold and susceptibility to the smarting reaction, persisted at least 30 h after tar removal.

Adult↗
PubMed1995

Is dermatologic usage of coal tar carcinogenic? A review of the literature.

BACKGROUND: Coal tar ointments have been used for decades in the treatment of various dermatoses, most notably eczema and psoriasis. Occupational exposure to coal tar poses an increased risk of developing cutaneous malignancies. The evidence of an increased risk of skin cancer in humans, as a result of dermatologic usage of tar, however, is conflicting. OBJECTIVE: A consensus on the carcinogenicity of tar is sought. METHODS: The existing literature (in vitro, animal, and human studies) on this subject is reviewed. RESULTS: The carcinogenicity of coal tar has clearly been demonstrated by in vitro and animal studies, and appears to be potentiated by concomitant use of ultraviolet radiation. Systemic absorption of mutagens from topically applied tar has been demonstrated in humans. Epidemiologic studies in humans, however, have not definitively shown an increase in skin cancer with therapeutic use of tar. CONCLUSIONS: Conclusive evidence for the carcinogenicity of tar used in dermatologic practice is lacking. Further controlled studies are necessary.

Animals↗
PubMed1987

Low-tar cigarettes: bane or benefit.

Modern cigarettes are generally low in tar (which includes many toxic products) and nicotine although not always in carbon monoxide delivery. The natural experiments available to epidemiologists, however, have not shown a very positive reduction in mortality that can be attributed to the lowering of tar. Campaigns by public health bodies have sometimes appeared to be effective in persuading the tobacco industry to lower tar generally (for example, Australia), but such low tar campaigns have been used by the tobacco industry to promote smoking itself and to sell the view that the habit is not as dangerous as it was (for example, U.K.). Outside the U.S., there has been very little advertising that features tar content. Comparisons made in sophisticated countries may not be relevant to developing countries. The matter of tar delivery by Third World smoking products needs attention. There is little argument that cigarettes should be lower in tar. There is, however, argument as to whether an optimal dose of nicotine reward is needed in order to prevent the development of compensatory smoking habits. There is also argument as to how the levels of tar and other toxic constituents in cigarettes should be lowered. Legislation and taxation are probably better weapons than public health advertising campaigns.

Advertising↗
PubMed1985

Increased risk of respiratory symptoms in young smokers of low tar cigarettes.

The effect of cigarettes yielding less than 10 mg tar was investigated in a representative sample (n = 4729) of 16 and 18 year old Finns. The rate of response was 80%. Cough and phlegm were significantly increased in young people smoking low tar cigarettes. When more than nine cigarettes were smoked daily respiratory symptoms were 2.4-6.2 times more prevalent among those who smoked low tar cigarettes than among those who never smoked. No differences were found between the smokers of low tar and medium tar cigarettes (yielding tar 10-18 mg). These data disagree with the hypothesis that the new low tar brands of cigarettes are less likely to cause respiratory symptoms than the old medium tar brands.

Adolescent↗
PubMed1989

Human immunodeficiency virus type 1 LTR TATA and TAR region sequences required for transcriptional regulation.

The human immunodeficiency virus (HIV) type 1 LTR is regulated at the transcriptional level by both cellular and viral proteins. Using HeLa cell extracts, multiple regions of the HIV LTR were found to serve as binding sites for cellular proteins. An untranslated region binding protein UBP-1 has been purified and fractions containing this protein bind to both the TAR and TATA regions. To investigate the role of cellular proteins binding to both the TATA and TAR regions and their potential interaction with other HIV DNA binding proteins, oligonucleotide-directed mutagenesis of both these regions was performed followed by DNase I footprinting and transient expression assays. In the TATA region, two direct repeats TC/AAGC/AT/AGCTGC surround the TATA sequence. Mutagenesis of both of these direct repeats or of the TATA sequence interrupted binding over the TATA region on the coding strand, but only a mutation of the TATA sequence affected in vivo assays for tat-activation. In addition to TAR serving as the site of binding of cellular proteins, RNA transcribed from TAR is capable of forming a stable stem-loop structure. To determine the relative importance of DNA binding proteins as compared to secondary structure, oligonucleotide-directed mutations in the TAR region were studied. Local mutations that disrupted either the stem or loop structure were defective in gene expression. However, compensatory mutations which restored base pairing in the stem resulted in complete tat-activation. This indicated a significant role for the stem-loop structure in HIV gene expression. To determine the role of TAR binding proteins, mutations were constructed which extensively changed the primary structure of the TAR region, yet left stem base pairing, stem energy and the loop sequence intact. These mutations resulted in decreased protein binding to TAR DNA and defects in tat-activation, and revealed factor binding specifically to the loop DNA sequence. Further mutagenesis which inverted this stem and loop mutation relative to the HIV LTR mRNA start site resulted in even larger decreases in tat-activation. This suggests that multiple determinants, including protein binding, the loop sequence, and RNA or DNA secondary structure, are important in tat-activation and suggests that tat may interact with cellular proteins binding to DNA to increase HIV gene expression.

Base Sequence↗
PubMed1995

The cellular factor TRP-185 regulates RNA polymerase II binding to HIV-1 TAR RNA.

Activation of HIV-1 gene expression by the transactivator Tat is dependent on an RNA regulatory element located downstream of the transcription initiation site known as TAR. To characterize cellular factors that bind to TAR RNA and are involved in the regulation of HIV-1 transcription, HeLa nuclear extract was fractionated and RNA gel-retardation analysis was performed. This analysis indicated that only two cellular factors, RNA polymerase II and the previously characterized TAR RNA loop binding protein TRP-185, were capable of binding specifically to TAR RNA. To elucidate the function of TRP-185, it was purified from HeLa nuclear extract, amino acid microsequence analysis was performed and a cDNA encoding TRP-185 was isolated. TRP-185 is a novel protein of 1621 amino acids which contains a leucine zipper and potentially a novel RNA binding motif. In gel-retardation assays, the binding of both recombinant TRP-185 and RNA polymerase II was dependent on the presence of an additional group of proteins designated cellular cofactors. Both the TAR RNA loop and bulge sequences were critical for RNA polymerase II binding, while TRP-185 binding was dependent only on TAR RNA loop sequences. Since binding of TRP-185 and RNA polymerase II to TAR RNA was found to be mutually exclusive, our results suggest that TRP-185 may function either alone or in conjunction with Tat to disengage RNA polymerase II which is stalled upon binding to nascently synthesized TAR RNA during transcriptional elongation.

Amino Acid Sequence↗
PubMed1999

Inversion of thermosensing property of the bacterial receptor Tar by mutations in the second transmembrane region.

The aspartate chemoreceptor Tar of Escherichia coli serves as a warm sensor that produces attractant and repellent signals upon increases and decreases in temperature, respectively. However, increased levels of methylation of the cytoplasmic domain of Tar resulting from aspartate binding convert Tar to a cold sensor with the opposite signaling behavior. Detailed analyses of the methylation sites, which are located in two separate alpha-helices (MH1 and MH2), have suggested that intra- and/or intersubunit interactions of MH1 and MH2 play a critical role in thermosensing. These interactions may be influenced by binding of aspartate, which could trigger some displacement of MH1 through the second transmembrane region (TM2). As an initial step toward understanding the role of TM2 in thermosensing, we have examined the thermosensing properties of 43 mutant Tar receptors with randomized TM2 sequences (residues 190-210). Among them, we identified one mutant receptor (Tar-I2) that functioned as a cold sensor in the absence of aspartate. This is the first example of attractant-independent inversion of thermosensing in Tar. Further analyses identified the minimal essential divergence from the wild-type Tar sequence (Q191V-W192R-Q193C) required for the inverted response. Thus, displacements of TM2 seem to influence the thermosensing function of Tar.

Amino Acid Sequence↗
PubMed1996

Inhibition of HIV-1 replication in viral mutants with altered TAR RNA stem structures.

Human immunodeficiency virus type 1 (HIV-1) Tat-mediated trans-activation requires the structural integrity of TAR RNA and the cooperative interaction of human host cell proteins. The TAR domain, minimally required for tat response, includes the Tat binding pyrimidine bulge, the TAR RNA upper stem, and the loop sequences. However, little is known about the significance of the 5'-stem structure of TAR in the regulation of viral growth. We designed viral mutations, specifically in the TAR RNA lower stem structure, and studied their effects on the kinetics of viral growth in T-lymphocyte cell lines and in activated human peripheral blood mononuclear cells. Mutations that destabilized the lower TAR stem structure inhibited viral growth to various degrees in different CD4+ T-cells. These results suggest that the structural integrity of the lower stem structure of TAR plays an important role in viral growth, presumably by binding to specific host cell proteins that stabilize Tat-TAR interactions.

Base Sequence↗
PubMed1992

Parvovirus H-1 P38 promoter requires the trans-activation region (tar), an SP1 site, and a TATA box for full activity.

In the parvovirus H-1 P38 promoter, there are sequences identified as a TATA box, an SP1 site, and a trans-activation responsive element (tar). It was previously shown that the parvovirus H-1 nonstructural protein NS1 positively regulates the expression of the P38 promoter for the viral capsid protein gene via the tar. To characterize the tar element further, a series of single-point mutations of the tar was constructed and the mutants were compared to wild-type for the trans-activation of the P38 promoter using a cat reporter gene. Most of the tar mutations had a negative effect on the P38 promoter and some of them reduced activity as much as 70%. However, when several mutants with multiple-point mutations in the tar were tested, no significant additive effect was observed. We examined the function of the SP1 site in the trans-activation of the P38 promoter by replacing the wild-type SP1 sequence with synthetic DNA fragments, OSP1 or 2SP1, containing no SP1 or two SP1 sites respectively, in a P38 construct with a cat reporter gene. The results indicate that P38 expression varies in proportion to the number of SP1 sites, suggesting a role for the SP1 site during trans-activation by NS1. The role of the TATA box on the P38 promoter was also examined by mutagenizing TATA to CACG. The activity of this promoter was reduced to 43%. When a construct mutated at both the SP1 and TATA box sites was tested for its activity, about 22% of the wild-type activity remained, implying that this remaining activity was contributed largely by the tar element. A model is proposed for how the tar element activates the wild-type and SP1-TATA minus promoters in the presence of NS1.

Base Sequence↗
PubMed1990

Overexpression of TAR sequences renders cells resistant to human immunodeficiency virus replication.

Overexpression of TAR-containing sequences (TAR decoys) was used to render cells resistant to HIV replication. A chimeric tRNA(meti)-TAR transcription unit contained in a double copy murine retroviral vector was used to express high levels of HIV-1 TAR-containing transcripts in CEM SS cells. Replication of HIV-1 was inhibited over 99% in cells expressing chimeric tRNA-TAR transcripts, but an amphotropic murine retrovirus replicated normally in these cells. Expression of TAR sequences in CEM SS cells had no adverse effects on cell viability, indicating that essential cellular factors are not being sequestered in these cells. TAR decoy RNA-mediated HIV inhibition may also be effective against natural HIV isolates in spite of their hypervariable nature, as suggested by the fact that replication of SIVmac was also inhibited in cells expressing HIV-1 TAR decoys.

Base Sequence↗
PubMed1987

The effect of the immune status of the TAR mouse on the growth and metastasis of tumour xenografts.

Mice thymectomised at 3-4 weeks of age and subsequently given whole-body irradiation (9 Gy) under cytosine arabinoside cover (TAR mice) provide an alternative model to the athymic nude (nu+/nu+) mouse for studying the biological characteristics of tumour xenografts. In the present study we have evaluated the repopulation events in the bone marrow and spleen following whole body irradiation of TAR mice, and analysed immune competence up to 98 days following irradiation. Repopulation of both bone marrow and spleen was evident in the weeks following whole body irradiation, and an initial increase in the relative proportion of T-lymphocytes present in the spleen was followed by a decrease in the percentage of lymphocytes expressing T-cell markers, which remained below the level observed in control mouse spleen cell preparations. TAR mice exhibited a decreased ability to respond to a non-specific T-cell mitogen and to elicit a T-cell dependent antibody response to influenza viral antigen. Both TAR and control mice possessed macrophages which could be activated to the tumouricidal state, and natural killer activity of TAR mice was enhanced greater than 3-fold above control values. The ability of TAR mice to accept tumour xenografts decreased with the increasing time interval between irradiation and subcutaneous implantation of tumour cells, and (in some instances) spontaneous regression was observed. In addition, a hamster tumour cell line possessing high metastatic potential in its syngeneic host was shown to metastasise to the regional lymph node, lungs, liver, kidneys and spleen of TAR mice from a cell inoculum implanted subcutaneously immediately after irradiation; however, with increasing time between irradiation and inoculation of tumour cells tumour metastasis decreased. The ability of TAR mice to support the growth and metastasis of tumour xenografts would appear to inversely correlate with the increase in natural killer cell activity following irradiation.

Animals↗
PubMed1997

HIV-1 Tat peptide binding to TAR RNA by electrospray ionization mass spectrometry.

Electrospray ionization mass spectrometry (ESI-MS) has been used to study the noncovalent complexes formed from the interaction between HIV-1 Tat peptide and Tat protein with TAR RNA. Both positive ion and negative ion ESI mass spectra showed a maximum stoichiometry of 3:1 between Tat peptide and TAR RNA. However, the higher order complexes only occurred at high relative concentrations of Tat peptide. The 1:1 Tat peptide-TAR RNA complex is believed to involve only specific interactions, whereas the higher order complexes involve nonspecific interactions. Relative binding affinities between Tat peptide and TAR RNA and its various mutants (TAR missing the three-nucleotide bulge, TAR with a poly(ethylene glycol) linker in the bulge region, and TAR with a poly(ethylene glycol) linker in the loop region) can be differentiated by competitive binding experiments and ESI-MS measurements. The gas phase mass spectrometry experiments are consistent with solution phase studies, as they show that mutations in the bulge region reduce TAR RNA affinity to Tat peptide.

Amino Acid Sequence↗
PubMed2001

Probing Tat peptide-TAR RNA interactions by psoralen photo-cross-linking.

Replication of human immunodeficiency virus type 1 (HIV-1) requires specific interactions of Tat protein with the trans-activation responsive region (TAR) RNA, a 59-base stem-loop structure located at the 5'-end of all HIV mRNAs. We have used a site-specific cross-linking method based on psoralen photochemistry to determine the effect of core residues from the Tat sequence on the protein orientation in the Tat-TAR complex and on the specificity of Tat-TAR binding. We synthesized two Tat fragments, Tat(42-72) and Tat(37-72), and incorporated a psoralen-modified amino acid at position 41 during solid-phase assembly of the peptides. We used these psoralen-Tat conjugates to form specific complexes with TAR RNA. Upon near-ultraviolet irradiation (360 nm), psoralen-Asp41-Tat(37-72) cross-linked to a single site in the TAR RNA sequence. The RNA-protein complex was purified and the cross-link site on TAR RNA was determined by primer extension analysis, which revealed that Asp41 of Tat is close to U42 of the lower stem region of TAR RNA. Specificity of the RNA-peptide cross-linking reactions was determined by competition experiments. Our results show that the addition of only four residues (Cys37-Thr40) from the Tat core region significantly enhanced the specificity of the Tat peptide-TAR interactions without altering the site or chemical nature of the cross-link. These studies provide new insights into RNA-protein recognition that could be useful in designing peptidomimetics for RNA targeting. Such psoralen-peptide conjugates provide a new class of probes for sequence-specific protein-nucleic acid interactions and could be used to selectively control gene expression or to induce site-directed mutations.

Amino Acid Sequence↗