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PubMedDate not supplied

A new statistical approach to predicting aromatic hydroxylation sites. Comparison with model-based approaches.

A new approach is described that is able to predict the most probable metabolic sites on the basis of a statistical analysis of various metabolic transformations reported in the literature. The approach is applied to the prediction of aromatic hydroxylation sites for diverse sets of substrates. Training is performed using the aromatic hydroxylation reactions from the Metabolism database (Accelrys). Validation is carried out on heterogeneous sets of aromatic compounds reported in the Metabolite database (MDL). The average accuracy of prediction of experimentally observed hydroxylation sites estimated for 1552 substrates from Metabolite is 84.5%. The proposed approach is compared with two electronic models for P450 mediated aromatic hydroxylation: the oxenoid model using the atomic oxygen and the model using the methoxy radical as a model for the heme active oxygen species. For benzene derivatives, the proposed method is inferior to the oxenoid model and as accurate as the methoxy-radical model. For hetero- and polycyclic compounds, the oxenoid model is not applicable, and the statistical method is the most accurate. Broad applicability and high speed of calculations provide the basis for using the proposed statistical approach for high-throughput metabolism prediction in the early stages of drug discovery.

Journal Article↗
PubMed1983

Use of laser-excited fluorescence to measure mixed-function oxidase activity.

The microsomal mixed-function oxidase (MFO) system is involved in the metabolism of various chemical compounds. Polycyclic aromatic hydrocarbons are metabolized by the cytochrome P-448 enzyme system, which contains MFOs. Induction of this MFO activity may be useful as an indicator of the toxicity of the inducer material. We have successfully used a portable centrifugal analyzer equipped with an argonion laser light source to quantify cytochrome P-448 activity induced in mouse-liver microsomes by exposing the animal's skin to different doses of liquids derived from a coal-liquefaction process. The MFO activity was determined kinetically by measuring the rate at which the highly fluorescent compound, resorufin, produced by the oxidation of 7-ethoxyresorufin substrate, was formed. The 514.5-nm laser excitation beam was directed with a fiber-optic bundle from the laser to the cuvets of a specially designed rotor; emitted fluorescence was monitored at 90 degrees to the incident beam through a 560-nm cut-on secondary filter. Use of the laser excitation source allowed very low MFO activities to be measured: picomole quantities of resorufin could be determined. We anticipate that the increased sensitivity of the method described here will allow MFO activities to be determined in body fluids and skin.

Animals↗
PubMed1997

Deprotonation and hydride shifts in nitrenium and iminium forms of aminoimidazole-azaarene mutagens.

The mutagenicity of many 2-aminoimidazole-azaarenes (AIA) is thought to be mediated by the nitrenium form of the exocyclic amine. This hypothesis is supported by the numerous correlations found between calculated and experimentally-measured chemical properties for the nitreniums and the mutagenic potencies of the nitreniums and their parent amines. One factor favoring high mutagenic potency is the presence of a methyl substituent in the 1- or 3-imidazole position. In this paper, we investigate both the deprotonation of the imidazole ring nitrogens in non-N-methylated AIA mutagens and the plausibility of a chemical pathway involving a 1-4 hydride shift to form an iminium ion, thereby stabilizing the cationic N-methyl substituted AIA mutagens. It has been widely noted that factors that stabilize the nitrenium moiety lead to significantly higher mutagenic potency; hence, the transformation of the nitrenium to a more stable species might be expected to increase the potency, provided that it does not eliminate the electrophilic reactivity of the compound. Using ab initio quantum chemistry and polarizable continuum solvation models, we find that the imidazole ring nitrogens of the nitrenium ions are extremely acidic. This suggests that upon formation of the exocyclic nitrenium these sites will deprotonate to form a neutral imine. We have also studied the 1-4 hydride shift from an imidazole ring methyl to the exocyclic nitrenium to form an iminium. We predict that for AIA mutagens with just two fused rings the resulting iminium species are more stable in the gas phase than the corresponding nitreniums. For mutagens with larger conjugated systems, the nitrenium is stabilized by resonance and is more stable than the corresponding iminium. In the aqueous phase, however, the iminium form is predicted to be more stable than the nitreniums for all polycyclic compounds studied. Although equilibrium calculations favor the iminium form, these have been experimentally shown to be short-lived and their actual concentration will depend on the complex kinetics of AIA mutagen metabolism. The quantum chemical results also show a strong correlation between the relative iminium-nitrenium energy difference and the charge on the exocyclic nitrogen.

Aza Compounds↗
PubMed2002

Method for integrated analysis of polycyclic aromatic hydrocarbons and organochlorine compounds in fish liver.

An analytical method for integrated analysis of organochlorine compounds and polycyclic aromatic hydrocarbons (PAH) in large numbers of fish liver samples has been developed using one single clean-up step. Tissues are homogenized with anhydrous sodium sulphate and Soxhlet extracted with n-hexane-dichloromethane (4:1, v/v) for 24 h. The extracts are cleaned-up and fractionated with an alumina chromatographic column allowing the separation of the extracts in two fractions. One containing most organochlorine compounds, including hexachlorobenzene, DDTs and polychlorobiphenyls, and the other the hexachlorocyclohexane isomers and PAH. These two fractions are subsequently analysed by GC-MS. Tests of repeatability result in relative standard deviations mainly under 20%. Evaluation by the standard addition method shows good linearities and recoveries.

Animals↗
PubMed1977

The epidemiology of oral cavity, pharyngeal and esophageal cancer outside of North America and Western Europe.

Geographical variations in the incidence of oral cavity, pharyngeal, and esophageal cancer were studied, with special reference to rates in countries outside of the United States and Western Europe. Although reporting techniques differ greatly and comparisons must be made with caution, significant variations are evident. Tracing such differences often reveals possible etiologic factor for these forms of cancer. The roles are discussed of known environmental carcinogens, such as N-nitroso compounds, polycyclic aromatic hydrocarbons, and such cultural habits as smoking or chewing tobacco, excessive consumption of alcoholic beverages, as well as other possible factors in the etiology of these cancer types.

Asia↗
PubMedDate not supplied

Drugs affecting the release of rheumatoid factor in a plaque-forming cell assay.

Addition of propranolol to the agarose phase of a plaque-forming cell (PFC) assay for rheumatoid factor (RF) caused reduction in the number of plaques seen. This reduction in rheumatoid factor plaque-forming cell (RF PFC) did not depend upon an effect at the beta-adrenergic receptor, since d- and 1-propranolol reduced equally well. Furthermore, in a series of polycyclic compounds with varying beta-receptor blocking capabilities there was no agreement between plaque reduction and blocking. When propranolol was tested in the agarose in an anti-sheep erythrocyte (SRC) plaque assay (anti-SRC PFC), it had no inhibitory effect, but it was capable of inhibiting the generation of new anti-SRC PFC in an in vitro culture. Propranolol is thought to exert these effects through its membrane stabilizing (anesthetic) properties.

Adrenergic beta-Antagonists↗
PubMed1994

Correlation between meteorological conditions and mutagenicity of airborne particulate samples in a tropical monsoon climate area from Kaohsiung City, Taiwan.

Kaohsiung is a city of 1.5 million located in the southern part of Taiwan. It has a serious air pollution problem mainly attributable to much industrial and commercial activity. In order to estimate the effects of traffic, season, and meteorological conditions on the mutagenicity of Kaohsiung City's urban ambient particulate matter, 624 airborne particulate samples were collected on a weekly basis from 12 locations for an entire year. The mutagenic potential of acetone extracts of air samples was evaluated by the Salmonella/microsomal test with S. typhimurium TA98 in the presence and absence of S9 mixtures. The air samples from November 1990 showed the highest direct and indirect mutagenicity among the 12 months, whereas those from June and July 1991 had the lowest direct and indirect mutagenic activity, respectively. The mutagenicity showed a good correlation with amounts of the acetone extractable matter of airborne particulates. The meteorological conditions, monthly mean precipitation, and wind speed also showed a good correspondence with mutagenicity. Wind direction and temperature had a moderate relationship. The major mutagenic fractions of air samples that had the highest mutagenic activity in a month were purified using Sephadex LH-20 column chromatography, and the contents of PAHs, 1-NP, and DNPs were analyzed by HPLC. The characteristic concentration ratios of PAHs indicated that, for the main pollution sources of airborne particulates from Kaohsiung city, the mobile sources were more important than the stationary ones. The total amounts of 1-NP and DNPs in airborne particulates seemed to correspond to their mutagenicity. Although the total amounts of 1-NP and DNPs in the air samples correlated with their mutagenicity, the major mutagenic chemicals in the airborne particulate samples from Kaohsiung City need further investigation.

Air Pollutants↗
PubMed1982

Activity of nitro-polynuclear aromatic hydrocarbons in the sister chromatid exchange assay with and without metabolic activation.

Nitro-polynuclear aromatic hydrocarbons are found in diesel particulates. These compounds are potent mutagens in the Ames test. To determine whether nitro-polynuclear aromatic hydrocarbons are active in a mammalian cell assay, 1-nitropyrene, 1,8-dinitropyrene, 2-nitrofluorene, and 4-nitrobiphenyl were incubated with cultures of Chinese hamster ovary cells. The frequency of sister chromatid exchange (SCE) was measured in the presence and absence of rat liver S-9 mix. The addition of S-9 mix resulted in a large increase in the SCEs induced by all four compounds.

Animals↗
PubMed1984

Structural features of nitroaromatics that determine mutagenic activity in Salmonella typhimurium.

Seventeen structurally homologous nitroaromatics were tested for direct-acting mutagenic potency in nine strains of Salmonella typhimurium. The following four structural features were determined to have a strong influence on mutagenic activity: physical dimensions of the aromatic rings, isomeric position of the nitro group, conformation of the nitro group with respect to the plane of the aromatic rings, and ability to resonance-stabilize the ultimate electrophile. Progressive addition of five- and six-membered rings to a nitrobenzene nucleus demonstrated that mutagenic activity was a direct function of size. Fluoranthene was of optimal size (four rings) for mutagenicity; an additional benzene ring, giving benzo[k]fluoranthene, reduced mutagenic activity. Nitroaromatics with a nitro group oriented along the long axis of symmetry of the molecule were more potent mutagens than those with the nitro group oriented along the short axis. These results are discussed in light of the insertion-denaturation model for intercalation of certain DNA adducts. Nitroaromatics with nitro groups sterically forced out of the plane of the aromatic rings were weakly mutagenic or nonmutagenic. Nitro groups located between two peri hydrogens or in a bay-region are examples of this conformation. Finally, structural features that contribute to resonance stabilization of the reactive nitrenium ion enhance mutagenic potency. Thus, 6-nitroindene was at least tenfold more mutagenic than 5-nitroindene. These positional isomers are structurally identical with the exception of the position of an olefinic bond in the adjacent five-membered ring which can contribute to resonance stabilization of a carbonium ion formed after bioactivation of 6-nitroindene but not of 5-nitroindene. The predictive value of these structure-activity relationships should permit a first approximation in the assessment of mutagenic potency of nitroaromatics.

Molecular Conformation↗
PubMed2006

Total syntheses of polyketide-derived bioactive natural products.

Recent progress of total syntheses in our laboratory has been described along with our background and methodologies. The target bioactive polyketides are classified into three categories according to their structures: (i) lactone-fused polycyclic compounds [(+)-cochleamycin A, (+)-tubelactomicin A, and (-)-tetrodecamycin], (ii) aromatic compounds [(-)-tetracycline, (-)-BE-54238B, lymphostin, and (-)-lagunamycin], and (iii) acyclic polyketides [xanthocillin X dimethylether, (+)-trichostatin D, and (+)-actinopyrone A]. Features of the total syntheses are described. Original methodologies have been developed and applied to construct the inherent structures of the target molecules. Most syntheses cited herein are the first total syntheses, and the absolute structures of the target molecules have been determined.

Alkaloids↗
PubMed2002

The combined use of chemical and biochemical markers to assess water quality in two low-stream rivers (NE Spain).

Carps (Cyprinus carpio) and red swamp crayfish (Procambarus clarkii) were sampled from two lowstream Mediterranean rivers (Anoia and Cardener) receiving extensive urban and industrial waste water discharges. Tissue residues of selected pollutants (organochlorinated compounds, polycyclic aromatic hydrocarbons (PAHs)) were determined in conjunction with different biochemical responses (cytochrome P450, phase II enzymes) with the aim of investigating whether resident organisms were responsive to changes in water quality. Biota inhabiting those rivers were highly exposed to complex mixtures of polychlorobiphenyls and dichlorodiphenyltrichloroethanes (up to 19 ng/g w.w.) and PAHs (up to 6097 ng/g of hydroxylated PAHs in bile), the highest residues being observed in carps from Cardener. This has a reflection on 7-ethoxyresorufin O-deethylase (EROD) activity; that in carps from Cardener ranged between 350 and 550 pmol/min/mg protein, whereas in carps from Anoia ranged between was 90 and 250 pmol/min/mg protein. The highest activity recorded was downstream of the sewage treatment plants in both rivers. Phase II enzymes were less sensitive to polutant exposure than EROD; nonetheless, both glutathione S-transferase and UDP-glucuronyl transferase were higher in carps from Cardener. The results support the usefulness of the combined use of chemical and biochemical responses to assess and diagnose pollution in highly stressed ecosystems.

Animals↗
PubMed1980

Metabolism and activation of chemical carcinogens.

A great deal of effort has gone into research on the mechanisms of action of chemical carcinogens. The action of the host on the carcinogen represents one approach--to determine what metabolic products may be involved. Study of the action of the carcinogen on the host requires a thorough comparison of changes wrought in cellular constituents by the carcinogen. Meshing of these two approaches increases the potential to discover the detailed mechanisms involved. Despite the increase in knowledge, many crucial molecular events and their consequences in the process of carcinogenesis still remain a mystery.

Aflatoxins↗
PubMed1975

Carcinogenesis.

An examination has been made of the major chemicals which are known to be carcinogenic, either in animals or in humans. As a result, a generalized type of chemical property seems to be a prerequisite for the carcinogenic activity. In most cases, this is some kind of reactive electrophilic intermediate produced directly from the carcinogen or from one of its immediate metabolites. This electrophilic reagent is generally a positively charged ion of some kind. In the case of the hydrocarbons it seems to be an incipient carbonium ion; in the case of nitrogen compounds, it is a corresponding nitronium ion. There are a number of possible substrate materials (nucleophilic) in a cells, but the dominant one which has been suspected is the nucleic acid component, either the DNA or the RNA. The bases of these materials all have extra pi electrons susceptible to attach by the electrophiles of the carcinogen. Such a modification, particularly of the DNA, could lead to either major or minor changes in the genetic composition of the cell. Minor changes are usually rectifiable or are not visible, and this would include a large variety of point mutations.

2-Acetylaminofluorene↗