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PubMed1982

New coal tar extract and coal tar shampoos. Evaluation by epidermal cell DNA synthesis suppression assay.

Coal tar therapy has been used for many years in the treatment of scaling skin diseases, including psoriasis and eczema. Previous studies of the potential effectiveness of tar have utilized phototoxic erythema assays with long-wave ultraviolet light (UV-A). However, in clinical use, coal tar is rarely used with UV-A, particularly for scalp disease. Therefore, we investigated a nonphototoxic approach to evaluate different coal tar products. Coal tar was found to suppress epidermal cell DNA synthesis in the hairless mouse model, and this is the basis for the assay presented. Using the epidermal cell DNA synthesis suppression assay, we observed that crude coal tar and a new extract of crude coal tar were equally effective and that a concentration gradient effect was achieved. In addition, four commercial coal tar shampoos assayed varied greatly in their ability to suppress epidermal cell DNA synthesis. One shampoo was washed after ten minutes and no significant alteration of suppressive effect was seen.

Animals↗

PubMed1994

Aqueous extracts of cigarette tar containing the tar free radical cause DNA nicks in mammalian cells.

The ability of aqueous extracts of cigarette tar to nick DNA was investigated using viable mammalian cells. Tar extracts contain a radical with a stable electron spin resonance (ESR) signal at g = 2.0036 characteristic of a semiquinone. The association of the tar component that carries the ESR signal with DNA was demonstrated using viable rat alveolar macrophages. The formation of single-strand DNA breaks caused by cigarette tar extracts in viable rat thymocytes follows saturation kinetics, indicating a tar component associates with DNA and then nicks it. These studies support our hypothesis that tar components that contain the cigarette tar radical can enter cells, associate with, and then nick DNA.

Animals↗

PubMed2005

Design, synthesis and bioactivities of TAR RNA targeting beta-carboline derivatives based on Tat-TAR interaction.

A series of new beta-carboline derivatives 3-14 bearing guanidinium group or amino group-terminated side chain targeting the TAR RNA were designed and synthesized. Molecular modeling studies indicated that the minimal interaction energy was obtained for compound 11, which contained the optimal linker of three methylene groups and the terminal guanidinium group interacted with the three-base bulge of TAR element by hydrogen bonds, which were the main contributor to the stability of drug-TAR RNA complex. To evaluate the ability of compounds 3-14 to block Tat-TAR interaction, we established a rapid, sensitive quantitative bioassay based on transient cotransfection of a Tat expression vector and a long terminal repeat region-chloramphenicol acetyltransferase (LTR-CAT) reporter construct in eukaryotic cells, monitoring the influence of the compounds on CAT expression levels with ELISA. Compounds 11 and 12 were the most active compounds of all in inhibiting Tat-TAR interaction bearing the terminal guanidinium group, and the optimal linker of the three methylene groups. Both compounds also exhibited anti-HIV-1 activity in MT4 cells, and their LD50 values of intraperitoneal acute toxicity for mice were 320.0 and 104.3 mg/kg, respectively. Furthermore, the results of capillary electrophoresis (CE) suggest that it is through targeting TAR RNA that this series of compounds block the Tat-TAR interaction.

Animals↗

PubMed1986

No difference between urinary mutagenicity in smokers of low-tar and medium-tar cigarettes: a double-blind cross-over study.

Urinary mutagenicity, blood carboxyhemoglobin and serum thiocyanate levels were measured in young, healthy volunteers smoking a fixed number of either low-tar (5 mg/cig.) or medium-tar (15 mg/cig.) cigarettes. The experiment was performed in a double-blind cross-over fashion. The volunteers were under daily control, and their diet and environment were standardized. The urinary mutagenic activity responded dose-dependently to the number of cigarettes smoked (0, 5, 10 or 20 per day), but there was no difference between the smokers of low-tar and medium-tar cigarettes. Neither were any significant differences found in blood carboxyhemoglobin nor serum thiocyanate. These results suggest that there is no substantial difference between the low-tar and medium-tar cigarette as to the inhalation of hazardous compounds in the real smoking situation.

Adult↗

PubMed1983

Urinary excretion of thioethers among low-tar and medium-tar cigarette smokers.

The urinary excretion of thioethers was studied among smokers of medium-tar cigarettes (16.3 mg/cig.) and low-tar cigarettes (5.4 mg/cig.). The test persons (26 smokers and 11 nonsmokers) were healthy young men in the military service. The smokers had an increased excretion of thioethers into the urine (P = 0.002 with Mann-Whitney U-test) when compared with the nonsmokers. No differences in the amount of urinary thioethers were detected between the low-tar and medium-tar cigarette smokers. The smokers (varying from 2.0 to 8.5 mmol/mol creatinine) had more individual variation than the nonsmokers (varying from 1.5 to 4.5 mmol/mol creatinine). Furthermore, the individual variation in the group of low-tar cigarette smokers did not markedly differ from the individual variation of medium-tar cigarette smokers.

Adult↗

PubMed2000

Comparative anti-dandruff efficacy between a tar and a non-tar shampoo.

A randomized double-blind clinical study was conducted on two groups of 30 volunteers using either a non-tar shampoo (2% salicylic acid, 0.75% piroctone olamine and 0.5% elubiol) or a 0.5% coal tar shampoo. Subjects were diagnosed as having moderate to marked dandruff. The study consisted of a 3-week washout, followed by a 4-week treatment and a 4-week posttreatment regression phase. The clinical evaluations and subject self-assessments showed that the non-tar shampoo was as effective as the tar shampoo. Both received high approval ratings (> or =70%). Biometrological methods proved to be more sensitive than clinical evaluations to assess the efficacy of the shampoos. The non-tar shampoo yielded a significantly better reduction of Malassezia spp. counts (p<0.02) during the treatment phase and reduced the spontaneous increase in squamometry values (p< 0.01) during the posttreatment phase. It is concluded that a formulation associating salicylic acid, piroctone olamine and elubiol exhibited increased beneficial effects compared to the coal tar shampoo.

Adult↗

PubMed1985

[Effect of coal tar on cignolin erythema--1 hour treatment of psoriasis with high-dose cignolin with and without tar].

Coal tar applied simultaneously showed a suppressive effect on anthralin erythema. This effect was demonstrated by an epicutaneous test 24 hours (27 patients) and 1 hour (46 patients) after application of various concentrations of anthralin combined with tar 3%. In a clinical study on 9 patients, anthralin 3% alone or combined with tar 10% were administered in a right and left comparison on symmetrical chronic psoriatic lesions for 1 hour daily. Anthralin plus tar exhibited a stronger anti-psoriatic effect than anthralin alone did. Tar reduced the anthralin erythema in the perilesional skin. These findings favor the combination of coal tar and anthralin in the 1-hour treatment schedule of psoriasis.

Adult↗

PubMed1986

[Effect of various kinds of tar and tar concentrations on anthralin erythema].

The effect of tar on anthralin-induced erythema was epicutaneously tested in ten patients. 3%, 5%, or 10% crude coal tar or coal tar solution was added to vaseline containing anthralin. A 5% or 10% tar preparation significantly suppressed the anthralin erythema induced by 0.5 to 1.0% anthralin having been applied for 24 hrs. In these concentrations, coal tar solution was at least as effective as coal tar itself.

Adolescent↗

PubMed1984

Detection of exposure to mutagenic compounds in low-tar and medium-tar cigarette smokers.

A volunteer study was carried out on groups smoking low-tar (5.4 mg/cig.) and medium-tar (16.3 mg/cig.) cigarettes and on non-smokers. The number of cigarettes smoked was recorded daily throughout a 51-day study period, and the effects of smoking were measured in the beginning and after 3-week terms of smoking medium-tar or low-tar cigarettes. The parameters measured were blood carboxyhemoglobin concentration, thioethers excreted into the urine, mutagenic activity in the urine, and the frequency of sister-chromatid exchanges in blood lymphocytes. For all four parameters, the differences between the smokers and the non-smokers were significant. However, within the study design no differences could be detected between low-tar or medium-tar cigarette smoking in the biological-monitoring tests used.

Adult↗

PubMed2002

Structure of TAR RNA complexed with a Tat-TAR interaction nanomolar inhibitor that was identified by computational screening.

HIV-1 TAR RNA functions critically in viral replication by binding the transactivating regulatory protein Tat. We recently identified several compounds that experimentally inhibit the Tat-TAR interaction completely at a 100 nM concentration. We used computational screening of the 181,000-compound Available Chemicals Directory against the three-dimensional structure of TAR [1]. Here we report the NMR-derived structure of TAR complexed with acetylpromazine. This structure represents a new class of compounds with good bioavailability and low toxicity that bind with high affinity to TAR. NMR data unambiguously show that acetylpromazine binds only to the unique 5' bulge site to which the Tat protein binds. Specificity and affinity of binding are conferred primarily by a network of base stacking and hydrophobic interactions. Acetylpromazine alters the structure of free TAR less than Tat peptides and neomycin do.

Acepromazine↗

PubMed1992

Conserved nucleotides in the TAR RNA stem of human immunodeficiency virus type 1 are critical for Tat binding and trans activation: model for TAR RNA tertiary structure.

Interaction between the human immunodeficiency virus type 1 (HIV-1) trans-activator Tat and its cis-acting responsive RNA element TAR is necessary for activation of HIV-1 gene expression. We investigated the hypothesis that the essential uridine residue at position 23 in the bulge of TAR RNA is involved in intramolecular hydrogen bonding to stabilize an unique RNA structure required for recognition by Tat. Nucleotide substitutions in the two base pairs of the TAR stem directly above the essential trinucleotide bulge that maintain base pairing but change sequence prevent complex formation with Tat in vitro. Corresponding mutations tested in a trans-activation assay strongly affect the biological activity of TAR in vivo, suggesting an important role for these nucleotides in the Tat-TAR interaction. On the basis of these data, a model is proposed which implicates uridine 23 in a stable tertiary interaction with the GC pair directly above the bulge. This interaction would cause widening of the major groove of the RNA, thereby exposing its hydrogen-bonding surfaces for possible interaction with Tat. The model also predicts a gap between uridine 23 and the first base pair in the stem above, which would require one or more unpaired nucleotides to close, but does not predict any other role for such nucleotides. In accordance with this prediction, synthetic propyl phosphate linkers of equivalent length to 1 or 2 nucleotides, were found to be fully acceptable substitutes in the bulge above uridine 23, demonstrating that neither the bases nor the ribose moieties at these positions are implicated in the recognition of TAR RNA by Tat.

Acquired Immunodeficiency Syndrome↗

PubMed1998

Fractionation of aqueous cigarette tar extracts: fractions that contain the tar radical cause DNA damage.

Previously, we have shown that aqueous cigarette tar (ACT) extracts contain a long-lived tar radical that associates with DNA in isolated rat alveolar macrophages and causes DNA damage in isolated rat thymocytes. These ACT solutions reduce oxygen to produce superoxide and, ultimately, hydrogen peroxide. In this study, we report the fractionation of ACT solutions prepared from the tar from five cigarettes using Sephadex columns. The fractions were analyzed by UV and electron paramagnetic resonance (EPR) spectroscopy and gas chromatography/mass spectrometry (GC/MS). The fractions containing polyphenolic species (principally catechol and hydroquinone, as determined by MS) caused most of the observed DNA damage in rat thymocytes. These DNA-damaging fractions produced superoxide, H2O2, and hydroxyl radicals. Stable free radicals were identified as o- and p-benzosemiquinone radicals by EPR spectroscopy. Hydroxyl radicals were detected by EPR spin-trapping with 5, 5-dimethyl-1-pyrroline N-oxide (DMPO). Catalase inhibited the EPR signal of the DMPO-OH adduct, indicating that H2O2 is the precursor of the hydroxyl radical spin adduct. The Sephadex separation resulted in a 90-fold concentration of the hydrogen peroxide-generating capacity of the fractions that contained polyphenols, relative to the unfractionated ACT solution. Another fraction, which contained nicotine, caused some DNA damage, but this damage was 28-fold less than the damage caused by the most damaging phenolic fraction. These results support our hypothesis that the tar radical system is an equilibrium mixture of semiquinones, hydroquinones, and quinones. The tar radical associates with DNA, causes DNA damage, and very likely is involved in the toxicity associated with cigarette smoking.

Animals↗

PubMed2006

HIV-1 TAR RNA subverts RNA interference in transfected cells through sequestration of TAR RNA-binding protein, TRBP.

TAR RNA-binding protein, TRBP, was recently discovered to be an essential partner for Dicer and a crucial component of the RNA-induced silencing complex (RISC), a critical element of the RNA interference (RNAi) of the cell apparatus. Human TRBP was originally characterized and cloned 15 years ago based on its high affinity for binding the HIV-1 encoded leader RNA, TAR. RNAi is used, in part, by cells to defend against infection by viruses. Here, we report that transfected TAR RNA can attenuate the RNAi machinery in human cells. Our data suggest that TAR RNA sequesters TRBP rendering it unavailable for downstream Dicer-RISC complexes. TAR-induced inhibition of Dicer-RISC activity in transfected cells was partially relieved by exogenous expression of TRBP.

HIV Long Terminal Repeat↗

PubMed1990

Binding of Tat protein to TAR region of human immunodeficiency virus type 1 blocks TAR-mediated activation of (2'-5')oligoadenylate synthetase.

The TAR sequence of the 5' leader of HIV-1 long terminal repeat-directed mRNA was found to be able to bind to and to activate double-stranded RNA-dependent (2'-5')A synthetase. Binding of TAR to the purified synthetase in vitro was abolished by addition of HIV-1 Tat protein, which binds to this sequence with a high affinity. Inhibition of TAR-mediated activation of (2'-5')A synthetase by Tat was prevented in the presence of the Zn2+ and Cd2+ chelators o-phenanthroline and penicillamine, which did not impair TAR-synthetase interaction. Transient expression assays of bacterial chloramphenicol acetyltransferase (CAT) gene in HeLa cells revealed that the levels of both CAT mRNA and CAT protein decreased after treatment of the cells with interferon, if CAT gene was linked to HIV-1 TAR segment. Cotransfection of the cells with a tat sequence containing plasmid rendered CAT gene expression insensible to the action of interferon.

2',5'-Oligoadenylate Synthetase↗

PubMed1998

Chimeric chemoreceptors in Escherichia coli: signaling properties of Tar-Tap and Tap-Tar hybrids.

The Tap (taxis toward peptides) receptor and the periplasmic dipeptide-binding protein (DBP) of Escherichia coli together mediate chemotactic responses to dipeptides. Tap is a low-abundance receptor. It is present in 5- to 10-fold-fewer copies than high-abundance receptors like Tar and Tsr. Cells expressing Tap as the sole receptor, even from a multicopy plasmid at 5- to 10-fold-overexpressed levels, do not generate sufficient clockwise (CW) signal to tumble and thus swim exclusively smoothly (run). To study the signaling properties of Tap in detail, we constructed reciprocal hybrids between Tap and Tar fused in the linker region between the periplasmic and cytoplasmic domains. The Tapr hybrid senses dipeptides and is a good CW-signal generator, whereas the Tarp hybrid senses aspartate but is a poor CW-signal generator. Thus, the poor CW signaling of Tap is a property of its cytoplasmic domain. Eighteen residues at the carboxyl terminus of high-abundance receptors, including the NWETF sequence that binds the CheR methylesterase, are missing in Tap. The Tart protein, created by removing these 18 residues from Tar, has diminished CW-signaling ability. The Tapl protein, made by adding the last 18 residues of Tar to the carboxyl terminus of Tap, also does not support CW flagellar rotation. However, Tart and Tapl cross-react well with antibody directed against the conserved cytoplasmic region of Tsr, whereas Tap does not cross-react with this antibody. Tap does cross-react, however, with antibody directed against the low-abundance chemoreceptor Trg. The hybrid, truncated, and extended receptors exhibit various levels of methylation. However, Tar and Tapl, which contain a consensus CheR-binding motif (NWETF) at their carboxyl termini, exhibit the highest basal levels of methylation, as expected. We conclude that no simple correlation exists between the abundance of a receptor, its methylation level, and its CW-signaling ability.

Bacterial Proteins↗

PubMed1971

Effect of cigarette tar upon tissue culture cells. Neoplastic transformation of hamster lung cells by tobacco tar in tissue culture.

Hamster lung fibroblastic cells were transformed into malignant cells in vitro by exposure to crude cigarette tar for 3 hours. Primary injuries of cells were observed between 2 and 48 hours after the treatment. Tar-treated cells showed nuclear pyknosis, cell necrosis, and enlarged, vacuolated cytoplasm. In one case giant cells were found at about 48 hours after treatment. Transformation occurred over 100 days after the treatment. The characteristics of transformed cells were random orientation of cells, with piling-up and criss-crossing, and continuous growth in vitro for over 300 days. Plating efficiency with treated cells was different from untreated cells. The transformed cells, cultured for 100 to 160 days, produced tumours when transplanted in cheek pouch of hamsters. The five of nine animals inoculated with 100 μg./ml. of tar treated cells (HT-100 strains) over 160 days in vitro died from tumours and others were killed for histological examinations and one of five animals transplanted with the cells of HT-10 strains within 121 days after the tar treatment. Histologically, the tumours were pleomorphic fibrosarcomas. Low doses (1 × 10(5) or less) of control cells failed to produce tumours after 270 days in culture. Contrarily, higher doses of 10(7) of control cells produced tumours when injected into the animals after 270 days in culture.

Animals↗

PubMed1983

The metabolism of prostaglandin E2 is decreased by high- and medium-tar but not by low-tar cigarette smoke in isolated rat lungs.

The effects of smoke from low-, medium- and high-tar cigarette brands on the metabolism of prostaglandin E2(PGE2) were investigated in isolated rat lungs. When isolated lungs were ventilated with smoke of high- or medium-tar cigarettes during an infusion of PGE2 into the pulmonary circulation, the amount of unmetabolized PGE2 was increased and that of 15-ketometabolites (15-keto-PGE2 and 13,14-dihydro-15-keto-PGE2 together) was decreased in the perfusion effluent compared to air ventilated control lungs. This decrease in the pulmonary metabolism of PGE2 was seen by both filter and non-filter high/medium-tar cigarettes. When isolated rat lungs were ventilated with smoke of low-tar cigarettes no change in the metabolism of PGE2 was detected. The pressor response of the vascular bed to the infusion of PGE2 was inhibited with smoke of both low- and high-tar cigarettes.

Animals↗

PubMed2003

The Australian tar derby: the origins and fate of a low tar harm reduction programme.

OBJECTIVE: To document the development of the low tar harm reduction programme in Australia, including tobacco industry responses. DATA SOURCES: Tobacco industry documents, retail tobacco journals, newspapers, medical journals, and Anti-Cancer Council of Victoria (ACCV) newsletters and archival records. STUDY SELECTION: Documents on the strategies and knowledge bases of the ACCV, other Australian health authorities, and the tobacco industry. RESULTS: The ACCV built a durable system for measuring and publicising the tar and nicotine yields of Australian cigarettes and influencing their development. The tobacco industry initially sought to block the development of this system but later appeared to cooperate with it, as is evidenced by the current market dominance of low tar brands. However, behind the scenes, the industry used its substantial knowledge advantage regarding compensatory smoking and its ability to re-engineer cigarettes to gain effective control of the system and subvert the ACCV's objectives. CONCLUSIONS: Replacement of the low tar programme with new means of minimising the harms from cigarette smoking should be a policy priority for the Australian government. This will require regulation, rather than further voluntary agreements, and stringent monitoring of successor programmes will be necessary.

Australia↗