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PubMed1997

[Impact of mycobacteria on nonspecific protective mechanisms associated with exchange of organic sulphur and nitrogen].

Guinea-pig experiments indicated that Mycobacteria tuberculosis (MBT) were actively involved in detoxification of the xenobiotics polycyclic aromatic hydrocarbons (PAH) and substantially altered the nonspecific protective mechanisms associated with activation of the body's antioxidative resources. MBT in the lung and liver tissues of animals long preexposed to PAH elevated the concentrations of sulphur-containing amino acids and glutathione with consumption of abundant nitrogen-rich adaptogenic antioxidants (arginine, urea) accumulated under the action of PAH. At the same time there is a upward trend for the body's antioxidative potentials both in a group infected with MBT and in group receiving PAH. Supplementing sodium glutamate potentiated the revealed adaptive rearrangements.

Animals↗
PubMed1982

Pharmacogenetics and human cancer.

Pharmacogenetics involves research into the hereditary basis for the different responses of different individuals to drugs or other environmental pollutants. Circumstantial evidence from a growing number of laboratory animal model systems suggests that human susceptibility to environmentally caused cancers may be influenced by an underlying genetic predisposition for metabolism of drugs and other foreign chemicals. The Ah locus is an example of a well-characterized model system for studying pharmacogenetics in mice. This complex controls the induction by polycyclic aromatic compounds of numerous drug-metabolizing enzyme 'activities'. Allelic differences at the Ah locus have been shown to be associated in the mouse with increased individual risk for cancer, mutation, DNA binding of reactive metabolites, drug toxicity, birth defects and enhanced detoxication. These differences appear to reflect changes in the steady-state level of reactive intermediates in target tissues. Tissue sites in direct contact with the carcinogen develop cancer more readily in responsive animals because of the presence of induced P1-450; tissues at distant sites of the body may develop malignancy more readily in nonresponsive animals because more carcinogen reaches that tissue, due to decreased P1-450 induction in proximal tissues and, therefore, a decrease in detoxication. Hence, not only the dose but the route of administration, the timing of the dosage, and the site of the tumour or toxicity--relative to the site of administered drug--are all very important in the interpretation of data from carcinogenicity or toxicity experiments involving P1-450 inducers, such as polycyclic hydrocarbons. These data emphasize the utility of studies in intact animals, in which differences in pharmacokinetics and enzyme induction may occur among various tissues; such subtleties cannot be detected in short-term testing with bacteria or tissue cultures. There is sufficient evidence that heritable variation of the Ah complex occurs in man. With the advent of recombinant DNA technology, this laboratory has recently cloned the P1-450 gene. In addition to a better understanding of P-450 induction and evolution of P-450 genes, we hope to develop a more sensitive assay for assessing the human Ah phenotype.

Aryl Hydrocarbon Hydroxylases↗
PubMed1982

MS/MS analysis of diesel emissions and fuels treated with NO2.

Correlations between direct-acting mutagens in diesel emissions and the activity of nitroaromatic compounds have been noted, but detection and identification of nitro-compounds in diesel particulates has remained an elusive problem. In the results reported here, MS/MS (tandem mass spectrometry) was found to detect nitroaromatic compounds in fractionated and unfractionated diesel soot extracts. The nitro-compounds detected ranged from two- to four-ring polynuclear aromatic hydrocarbon derivatives and were primarily mono-nitro derivatives. An aromatic fraction from diesel fuel reacted with NO2 resembled diesel exhaust extracts from an engine operating on the same fuel. Therefore, it is possible that nitroaromatic derivatives in diesel exhaust may be in part due to unburned fuel residues reacting with NO chi formed in the combustion process. The utility of MS/MS in comparing complex mixtures from different sources or subfractions thereof is discussed.

Fuel Oils↗
PubMed1983

Asbestos affects the in vitro uptake and detoxification of aromatic compounds.

A number of mineral dusts were tested for their ability to catalyze the transformation of benzo(a)pyrene from the microcrystalline state into lipid solution. The findings of Lakowicz and his co-workers, that fibrous dusts were more active than nonfibrous dusts, were confirmed. Macromolecular binding metabolites of BaP were formed in A549 cells to a similar extent whether the BaP was added in solution or adsorbed to fibers; however, the level of water-soluble metabolites was lower in cultures treated with adsorbed hydrocarbon. It was found that asbestos can also inhibit the accumulation of 1-naphthyl glucuronide in cultures treated with 1-naphthol. The significance of this in asbestos pathogenesis is briefly discussed.

Animals↗
PubMed2000

An anionic siloxane polymer as a pseudostationary phase for electrokinetic chromatography.

A novel polymeric pseudostationary phase for electrokinetic chromatography is introduced and characterized. Siloxane polymers are of interest for this application because of the range of chemistries that could be developed based on these backbones, and because successful development of siloxane polymers would make it possible to employ much of the stationary phase chemistry developed in the past thirty years. A commercially available water-soluble siloxane with a hydroxy-terminated alkyl group was converted to the sulfate derivative. This siloxane polymer is water-soluble, effectively eliminating this limitation associated with siloxane polymers. When employed as a pseudostationary phase, this compound provided rapid, efficient, and selective separations. The electrophoretic mobility of the polymer was less than sodium dodecyl sulfate (SDS) and poly(sodium 10-undecenylsulfate), providing a compressed migration time range, which is the main limiting factor for this polymer. The chemical selectivity of the siloxane sulfate was somewhat different than SDS micelles. The siloxane was employed in buffers modified with a large amount of acetonitrile to separate a number of polynuclear aromatic hydrocarbons. The addition of acetonitrile caused an apparent discontinuity in the electrophoretic mobility of the polymer, which may indicate a change in the structure with increasing organic solvent content.

Buffers↗
PubMed2005

CYP2S1: a short review.

A new member of the cytochrome P450 superfamily, CYP2S1, has recently been identified in human and mouse. In this paper, we review the data currently available for CYP2S1. The human CYP2S1 gene is located in chromosome 19q13.2 within a cluster including CYP2 family members CYP2A6, CYP2A13, CYP2B6, and CYP2F1. These genes also show the highest homology to the human CYP2S1. The gene has recently been found to harbor genetic polymorphism. CYP2S1 is inducible by dioxin, the induction being mediated by the Aryl Hydrocarbon Receptor (AHR) and Aryl Hydrocarbon Nuclear Translocator (ARNT) in a manner typical for CYP1 family members. In line with this, CYP2S1 has been shown to be inducible by coal tar, an abundant source of PAHs, and it was recently reported to metabolize naphthalene. This points to the involvement of CYP2S1 in the metabolism of toxic and carcinogenic compounds, similar to other dioxin-inducible CYPs. CYP2S1 is expressed in epithelial cells of a wide variety of extrahepatic tissues. The highest expression levels have been observed in the epithelial tissues frequently exposed to xenobiotics, e.g., the respiratory, gastrointestinal, and urinary tracts, and in the skin. The observed ubiquitous tissue distribution, as well as the expression of CYP2S1 throughout embryogenesis suggest that CYP2S1 is likely to metabolize important endogenous substrates; thus far, retinoic acid has been identified. In conclusion, CYP2S1 exhibits many features of interest for human health and thus warrants further investigation.

Animals↗
PubMed1993

Methods development toward the measurement of polyaromatic hydrocarbon-DNA adducts by mass spectrometry.

The measurement of DNA adducts in human samples is at an early stage. The accuracy of some of the current measurements is not defined, the structures are unknown for a significant number of the adducts that have been detected, and there is little information about how many adducts remain to be discovered. This is due largely to the trace amounts of human DNA adducts in any sample. A consequence of this is that the true potential of DNA adducts as indicators of exposure and risk in human toxicology is far from realized. Mass spectrometry, a powerful technique for organic analysis, is the key to exploiting fully the usefulness of human DNA adducts as biomarkers of human exposure and risk. Mass spectrometry can make accurate measurements, discover unknown compounds, and determine the structures of these unknown compounds. However, the trace (very small) amounts of human DNA adducts have limited mass spectrometry's usefulness in analyzing such samples. This project focused on increasing the sensitivity of mass spectrometry for measuring human DNA adducts. Advances in sensitivity have been achieved for two modes of mass spectrometry applied to standards related to DNA adducts: gas chromatography with electron-capture negative ion mass spectrometry, and fast-atom-bombardment mass spectrometry. These advances involve both sample preparation and instrument conditions.

2-Acetylaminofluorene↗
PubMed1993

Estimation of octanol-water partition coefficients and correlation with dermal absorption for several polyhalogenated aromatic hydrocarbons.

n-Octanol-Water partition coefficients (K(ow)) were experimentally estimated for: 2,3,7,8-tetrachloro-and 2,3,7,8-tetrabromodibenzo-p-dioxin; 2,3,7,8-tetrachloro-, 2,3,7,8-tetrabromo-, and 1,2,7,8-tetrabromodibenzofuran; 1,2,3,7,8-pentachloro-, 1,2,3,7,8-pentabromo-, 2,3,4,7,8-pentachloro-, and 2,3,4,7,8-pentabromodibenzofuran; 1,2,4,6,8,9-hexachlorodibenzofuran (HxCDF), and 3,4,3',4'-tetrachlorobiphenyl (3,4,3',4'-TCB). The method involved correlation of literature K(ow) with reverse-phase high-performance liquid chromatography (RP-HPLC) retention time for a series of 23 calibration standards and estimation of K(ow) for test compounds from measured RP-HPLC retention. Retention times for all standards and test chemicals were measured in duplicate on the same octadecasilane (C18) reverse-phase column with an isocratic 85:15 methanol:water mobile phase; solutes were detected by uv absorbance (254 nm). Literature log K(ow) values used for the calibration standards had been measured exclusively by the generator column method. Log K(ow) estimates for the test compounds in the present study ranged from 5.45 for 3,4,3',4'-TCB to 6.81 for HxCDF. K(ow) estimates were then plotted against laboratory data for the in vivo 3-day dermal absorption of single equimolar doses (200 pmol and 20 nmol, or approximately 1 nmol/kg and approximately 0.1 mumol/kg) of selected test compounds in male F344 rats. Strong inverse correlations were found between octanol-water partition coefficient estimates and single-dose dermal absorption for most of the compounds studied. In addition, RP-HPLC retention time itself appeared to be as equally suited as K(ow) to such correlations with dermal absorption. The structure-activity relationships suggested in this study were sought in order to explain observed differences in the dermal absorption of polyhalogenated dibenzo-p-dioxin, dibenzofuran, and biphenyl congeners differing in number, position, and/or type (Cl or Br) of halogen substituents. Moreover, these results should be of predictive value in the risk assessment of dermal exposure to polychlorinated dibenzo-p-dioxins, dibenzofurans, biphenyls, and their brominated analogues.

Animals↗
PubMed1992

Inhibition of aminopeptidase activity by aromatic and other cyclic compounds.

The effect of 2-naphthylamine, p-nitroaniline, o-phenanthroline, sodium deoxycholate and hydrocortisone succinate on the activity of human urine aminopeptidase, rat kidney methionyl and arginyl aminopeptidase, soybean and Enterolobium contortisiliquum seed aminopeptidase was studied using aminoacyl-2-naphthylamide and L-Leu-p-nitroanilide as substrates. Ki values ranged from 10 microM to 2.7 mM. On the basis of Ki and Km values, and catalytic efficiency for each enzyme, it is clear that the aminopeptidases from human urine and from soybean seed should be assayed with both substrates, whereas L-Leu-p-nitroaniline is a more appropriate substrate for the rat kidney aminopeptidases. Sodium deoxycholate is a better inhibitor than hydrocortisone succinate. Non-competitive inhibition was observed in all cases except for E. contortisiliquum seed aminopeptidase.

Aminopeptidases↗
PubMed1991

[The specificity of the genotoxic action of carcinogenic aromatic compounds on Drosophila mus mutants].

Hypersensitivity to the toxic effect of benzo(a)pyrene (B(a)P) was determined in homozygous larvae of two D. melanogaster mus strains (mus 208B2 and mus210). The two others (mus205B1 and mus208B1) were found to be less sensitive and the parent strain was resistant. The lack of correlation between the sensitivity in larvae and the activity of aryl hydrocarbon hydroxylase in S15 fractions from adult flies whole body homogenates of the same strains was demonstrated. The hypertoxic effect of B(a)P and 2-acethylaminofluorene in strain mus210 seems to be rather specific because noncarcinogenic pyrene, benzo(e)pyrene and fluorene did not affect the survival of this most sensitive strain. Perspectives of the strain mus210 use for the environmental genotoxic pollutants screening were discussed.

Animals↗
PubMed1995

Improving the affinity and selectivity of a nonpeptide series of cholecystokinin-B/gastrin receptor antagonists based on the dibenzobicyclo[2.2.2]octane skeleton.

We have recently described a novel series of nonpeptidic cholecystokinin-B (CCKB)/gastrin receptor antagonists based on a dibenzobicyclo[2.2.2]octane skeleton. We wish now to report on compounds arising out of our earlier work which have substantially greater affinity as antagonists for the CCKB/gastrin receptor system and which maintain, or improve on, the already high selectivity with respect to CCKA receptors. Thus, cis-7-[[[(1S)-[[3,5-dicarboxy-phenyl)amino]carbonyl]-2- phenylethyl]amino]carbonyl]-8-[[(1-adamantylmethyl)amino]- carbonyl]-2,3:5,6-dibenzobicyclo[2.2.2]octane expressed a pKi of 8.80 in mouse cortical membranes at CCKB/gastrin receptors. The selectivity for these receptors over CCKA receptors was in the order of 1000-fold.

Animals↗
PubMed1985

Effects of using liver fractions from different mammals, including man, on results of mutagenicity assays in Salmonella typhimurium.

Twenty chemicals, including 16 aromatic amines, were studied in the Salmonella/mammalian-microsome mutagenicity test using the bacterial strains TA100 and TA98 to compare the activation potential of liver preparations from several mammalian species. The hepatic post-mitochondrial supernatants (S-9 fractions) of rat, mouse, hamster, dog, monkey and man were used for metabolic activation. Striking quantitative and even qualitative differences were apparent in the capacity of the different preparations to activate the compounds to mutagens. All compounds that gave positive results in the Ames test when activated with a liver preparation from Aroclor-pretreated rats were also identified as mutagens when tested in the presence of S-9 from one or more other species. Four substituted anilines, however, were converted to mutagenic metabolites only in the presence of a post-mitochondrial fraction of hamster liver. Three human carcinogens, 2-aminoanthracene, benzidine and cyclophosphamide were detected as mutagens under various experimental conditions, including metabolic activation by human or monkey liver S-9. There were no qualitative differences in the mutagenic responses obtained in assays with human and monkey liver S-9.

Amines↗
PubMed1991

Biogeochemical processes governing exposure and uptake of organic pollutant compounds in aquatic organisms.

This paper reviews current knowledge of biogeochemical cycles of pollutant organic chemicals in aquatic ecosystems with a focus on coastal ecosystems. There is a bias toward discussing chemical and geochemical aspects of biogeochemical cycles and an emphasis on hydrophobic organic compounds such as polynuclear aromatic hydrocarbons, polychlorinated biphenyls, and chlorinated organic compounds used as pesticides. The complexity of mixtures of pollutant organic compounds, their various modes of entering ecosystems, and their physical chemical forms are discussed. Important factors that influence bioavailability and disposition (e.g., organism-water partitioning, uptake via food, food web transfer) are reviewed. These factors include solubilities of chemicals; partitioning of chemicals between solid surfaces, colloids, and soluble phases; variables rates of sorption, desorption; and physiological status of organism. It appears that more emphasis on considering food as a source of uptake and bioaccumulation is important in benthic and epibenthic ecosystems when sediment-associated pollutants are a significant source of input to an aquatic ecosystem. Progress with mathematical models for exposure and uptake of contaminant chemicals is discussed briefly.

Animals↗
PubMed1994

Activation of CYP3A4: evidence for the simultaneous binding of two substrates in a cytochrome P450 active site.

A unique characteristic of the CYP3A subfamily of cytochrome P450 enzymes is their ability to be activated by certain compounds. It is reported that CYP3A4-catalyzed phenanthrene metabolism is activated by 7,8-benzoflavone and that 7,8-benzoflavone serves as a substrate for CYP3A4. Kinetic analyses of these two substrates show that 7,8-benzoflavone increases the Vmax of phenanthrene metabolism without changing the Km and that phenanthrene decreases the Vmax of 7,8-benzoflavone metabolism without increasing the Km. These results suggest that both substrates (or substrate and activator) are simultaneously present in the active site. Both compounds must have access to the active oxygen, since neither phenanthrene nor 7,8-benzoflavone can competitively inhibit the other substrate. These data provide the first evidence that two different molecules can be simultaneously bound to the same P450 active site. Additionally, structure-activity relationship studies were performed with derivatives of 7,8-benzoflavone structure. The effects of 13 different compounds on the regioselectivity of phenanthrene, chrysene, and benzo[a]pyrene metabolism were determined. Of the 13 compounds studied, 6 were activators, 2 were partial activators, and 5 were inhibitors. Analyses of the data suggest that (1) naphthalene substituted with a ketone in the 2-position can activate 3A4 and (2) the presence of an activator results in a narrower effective substrate binding site. Since the CYP3A enzymes are very important in drug metabolism, the possibility of activation, and autoactivation, must be considered when in vitro-in vivo correlations are made and when possible drug interactions are considered.

Animals↗
PubMed2005

Electron and energy transfer modulation with photochromic switches.

This tutorial review illustrates how work on the reversible interconversion between the colorless and colored forms of photochromic compounds can be exploited to modulate electron and energy transfer processes. Indeed, a photochrome can be designed to accept electrons or energy from a complementary donor in one of its two states only. Alternatively, the photoinduced transformations associated with a photochromic switch can be engineered to control the relative orientation and distance of donor-acceptor pairs. If either the donor or the acceptor is fluorescent, the photoregulated transfer of energy or electrons results in the modulation of the emission intensity. Thus, these fascinating molecular and supramolecular systems can advance the basic understanding of electron and energy transfer processes, while leading to viable operating principles to control light with light.

Benzene Derivatives↗
PubMed2005

Modulation of UDP-glucuronosyltransferase 1A1 in primary human hepatocytes by prototypical inducers.

The primary objective of this study was to evaluate the modulation of UGT1A1 expression in human hepatocytes using prototypical CYP450 inducers. A bank of 16 human livers was utilized to obtain an estimate of the range of UGT1A1 protein expression and catalytic activity. Concentration-dependent changes in UGT1A1 response were evaluated in hepatocyte cultures after treatment with 3-methylchloranthrene, beta-napthoflavone, rifampicin, or phenobarbital. Pharmacodynamic analyses of UGT1A1 expression were conducted and compared to those of CYP450 after treatment with inducers in 2-3 different hepatocyte preparations. Additionally, expression of UGT1A1 mRNA and protein was evaluated in human hepatocytes treated with 14 different compounds known to activate differentially the human pregnane-X-receptor or constitutive androstane receptor. Pharmacodynamic modeling revealed EC50 values statistically significant between UGT1A1 and CYP2B6 after treatment with PB, but not statistically distinguishable between UGT1A1 and CYP's 1A2 or 3A4 after treatment with 3-methylchloranthrene or rifampicin, respectively. UGT1A1 was most responsive to the pregnane-X-receptor-agonists rifampicin, ritonavir, and clotrimazole at the mRNA level and, to a lesser extent, the constitutive androstane receptor-activators, phenobarbital and phenytoin. Pharmacodynamic analyses support a mechanism of coordinate regulation between UGT1A1 and a number of CYP450 enzymes by multiple nuclear receptors.

Cells, Cultured↗
PubMed2003

Stress on stress response of wild mussels, Mytilus edulis and Mytilus trossulus, as an indicator of ecosystem health.

Mussels' health as indicated by the survival time of 50% of sampled animals (LT(50)) when maintained in air at 15 degrees C was examined at three sites in Halifax Harbour with expected differing levels of contamination. Condition and gonad indices, lipid content and the body burden of polycyclic aromatic compounds (PACs) were compared with this stress response in 60 groups of mussels covering two species. At each sampling time, the bioaccumulation of PACs, lipid content and condition indices were higher within Mytilus edulis and Mytilus trossulus displaying shorter survival than at the other sites. M. edulis was generally more tolerant than M. trossulus (for n=11, LT(50) of 9.3 and 7.9 days), with indications of shorter and later gonad development in M. trossulus. Minimum and maximum tolerance was apparent in June and October (LT(50) spanning 3-14 days), respectively. Our results indicate that the stress on stress response provides a simple and sensitive indicator of environmental health, which could be integrated with mussel watch studies.

Animals↗
PubMed1999

Effect of plant matrix and fluid ethanol concentration on supercritical fluid extraction efficiency of schisandrin derivatives.

An investigation of the effect of plant matrix on the supercritical fluid extraction efficiency of five schisandrin derivatives is reported, exhibiting a great difference with respect to extraction efficiency depending on the matrix. Pure supercritical CO2 at 60 degrees C and 34.0 MPa cannot fully recover schisandrin derivatives from the leaves as much as from the other matrices. Only 36.9% of these compounds are extracted from leaves of Schisandra chinensis by supercritical CO2 in comparison with organic solvent extraction. However, more than 80% of schisandrin derivatives are obtained from both stem and fruit parts. Ethanol addition also shows a different effect depending on plant matrix; that is, CO2 modified with 10% ethanol could enhance the yield of schisandrin derivatives from leaves by four times when compared with that of pure CO2, but it has little effect on both stems and fruits.

Carbon Dioxide↗