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PubMed1980

Biotransformation of xenobiotics in Drosophila melanogaster and its relevance for mutagenicity testing.

Biotransformation of lipophilic xenobiotics may lead to formation of reactive intermediates which can give rise to irreversible toxic events such as carcinogenesis, mutagenesis, teratogenesis, and tissue necrosis. In recent years considerable attention has been paid to the problem of testing for these effects. Short-term mutagenicity tests have been shown to have value for predicting the occurrence of delayed toxic effects in mammals following administration of indirectly acting harmful xenobiotics. In any test system the capacity to bioactivate the compound under test is a necessary prerequisite, and in most short-term test assays this is provided for by adding a metabolic activation system generally consisting of the 9,000 g supernatant fraction of a rat liver homogenate supplied with cofactors. The fruitfly Drosophila melanogaster constitutes an organism well-suited for mutagenicity testing, and it was shown that a number of precarcinogens evoke mutagenic effects in this species. Thus Drosophila is apparently able to metabolize xenobiotics to reactive intermediates, which in turn induce mutagenicity. However, knowledge about the presence and characteristics of the xenobiotic-metabolizing enzymes involved is lacking. Since knowledge of these enzymes contributes to the evaluation and interpretation of observed mutagenic events, this paper described studies concerning some important xenobiotic-metabolizing enzymes of Drosophila. Files were homogenized and subcellular fractions were investigated with respect to enzymatic activities. It was possible to demonstrate cytochrome P-450 and some related mixed-function oxidase activities. Cytochrome b5, epoxide hydrolase, and glutathione S-transferase are also present, while preliminary experiments suggest the presence of UDP-glucosyltransferase and phosphotransferase activities. The enzymes which have been found are discussed with respect to their similarities with rat liver enzymes and their relevance for mutagenicity testing with Drosophila melanogaster.

Animals↗

PubMedDate not supplied

A bioactive (1-->3)-, (1--4)-beta-D-glucan from Collybia dryophila and other mushrooms.

Polysaccharides from higher Basidiomycete mushrooms, mainly beta-D-glucans, are considered to be potent bioactive fungal compounds. In this study a beta-glucan (1.237 x 10(6) Da) consisting of (1-->3) and (1-->4) glucosidic linkages, named Collybia dryophila polysaccharide (CDP), was extracted from the wild mushroom C. dryophila. CDP was shown to strongly inhibit nitric oxide production in activated macrophages suggesting that this polysaccharide displays a potential anti-inflammatory activity. In addition it was shown that polysaccharides similar to CDP (CDP-like) are present in Lentinus edodes and different wild mushrooms collected in northeastern North America.

Agaricales↗

PubMed1998

Mechanisms of the preventive properties of some garlic components in the carbon tetrachloride-promoted oxidative stress. Diallyl sulfide; diallyl disulfide; allyl mercaptan and allyl methyl sulfide.

Previous studies evidenced that garlic extracts and/or garlic components were able to prevent against chemically induced tumors or acute toxic effects of chemicals (e.g. CCl4 induced liver injury). The chemopreventive potential of garlic has been attributed to the presence in it of several bioactive organosulfur compounds. Those components might act as antioxidants able to scavenge free radicals. In the present work we describe initial studies on the antioxidative-stress properties of some garlic components such as: diallyl disulfide (DDS), diallyl sulfide (DAS), allyl mercaptan (AMT) and allyl methyl sulfide (AMS). We found that DAS, DDS and AMT but not AMS were able to trap trichloromethyl and trichloromethylperoxyl free radicals. Further, DDS but not DAS or AMT also inhibited CCl4 promoted liver microsomal lipid peroxidation. DAS, but not DDS, AMT or AMS was able to react with free radicals arised during UVC activation of hydrogen peroxide or terbutyl hydroperoxide but not with those produced during UVC activation of terbutyl peroxide. However, all garlic components tested absorbed energy from UVC and became partially destroyed in the process. AMT, but not DDS, AMS or DAS was able to destroy 4-hydroxynonenal, a key reactive aldehyde produced during lipid peroxidation. AMT and DDS were also able to prevent UVC plus CCl4 promoted oxidation of albumin in vitro, but DAS and AMS failed to do so. Results suggest that the antioxidative stress properties of garlic might result from the contributions of its sulfur component in different steps and not necessarily from the contribution of only one of them.

Allyl Compounds↗

PubMedDate not supplied

[A convenient method for laboratory synthesis of the N-([1-14C]palmitoyl)ethanolamine, labeled by a fatty acid].

Data concerning the synthesis of bioactive lipid compound N-([1-14C]-palmitoyl)ethanolamine labeled by 14C fatty acid are reported. The method is based on the ability of ethanolamine and fatty acid to the direct chemical condensation at 180 degrees C with yielding of N-acylethanolamine. The purification of the end product by the double crystallization in ethanol allows to obtain chromatographically pure substance. The presented method of the labeled N-([1-14C]-palmitoyl)ethanolamine synthesis is simple and in extensive that's why it might be used in the area of biologically active compounds investigation.

Carbon Radioisotopes↗

PubMed2000

Bioactivity and analysis of chiral compounds.

The stereochemistry of drug and xenobiotic metabolism and toxicokinetics have recently become an issue for the pharmaceutical industry and the regulatory authorities. Chirality is an intrinsic property of macromolecular structures in the cells such as enzymes, receptors, and nucleic acids which becomes evident when they interact with a chiral drug or xenobiotic molecule, showing a high degree of stereoselectivity. There are now a range of examples of isomeric compounds whose biological activity may well reside predominantly in one enantiomer. The differences in the biological activities between enantiomers have resulted in an increased interest in determination of enantiomeric composition of drugs, xenobiotics, and/or their metabolites. The difficulty in determining enantiomeric excess arises from the fact that enantiomers have identical physicochemical properties in a non-chiral environment. The major analytical breakthrough has come with the emergency of commercially available chiral stationary phases for capillary gas chromatography, high-performance liquid chromatography, and capillary electrophoresis.

Chromatography↗

PubMed2003

Paraxanthine/caffeine ratio: as an index for CYP1A2 activity in polycyclic aromatic hydrocarbons exposed subjects.

UNLABELLED: Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous in the environment and originate from incomplete combustion process of organic materials. These compounds are bioactivated to reactive metabolites which bind covalently to DNA and subsequently initiate carcinogenesis. PAHs have been well established as an enzyme inducer of cytochrome P450 (CYP) such as CYP1A1 and CYP1A2. Caffeine is primarily metabolized by CYP1A2 to paraxanthine, so it has been used as a specific probe for assessing CYP1A2 activity. The purpose of this study was to compare CYP1A2 activity in female subjects that were automobile exhaust exposed and non-automobile exhaust exposed using serum paraxanthine/caffeine ratio as an index. Each subject took a 180 mg single oral dose of caffeine solution. Blood samples were collected before and 5 hours after caffeine intake. Serum samples were separated by centrifugation and stored at -20 degrees C until analysis by high performance liquid chromatography (HPLC). Carbon monoxide (CO) level in blood was also detected using spectrophotometer. The results showed that serum paraxanthine/caffeine ratio in exposed subjects was significantly higher than non-exposed subjects (mean +/- SE of 0.45 +/- 0.05 and 0.33 +/- 0.03, respectively; p < 0.05). CO level in exposed subjects was also significantly higher than non-exposed subjects (mean +/- SE of 4.03 +/- 0.21 and 3.01 +/- 0.18, respectively; p < 0.05). CONCLUSION: Paraxanthine/caffeine ratio, as an index for CYP1A2 activity, can be used to determine PAHs exposure. Automobile exhaust exposed subjects demonstrated significantly higher CYP1A2 activity than that of the non-exposed subjects. Exposed subjects have a possibly higher risk of chemical carcinogenesis.

Adult↗

PubMed1992

Recent trends in research on differentiation of hematopoietic cells and lymphokines (hemopoietins).

A recent trend in hematological research fields has been to isolate and characterize hematopoietic stem cells/progenitors and their growth factors (hemopoietins) to gain a much better understanding of the nature of the stem cell and the mechanisms regulating its development. It is generally accepted that all the various types of blood cells develop from a single progenitor called a hematopoietic stem cell. Quantitative studies of the function of hemopoietic stem cells began two decades ago with the development of a spleen colony assay, and then, clonal cell culture techniques for committed progenitors were developed with several models for hematopoietic differentiation being proposed. Within the last few years, some hormones have been discovered that are known as hematopoietic growth hormones or hemopoietins, each of which is of protein nature and causes specific classes of blood cells to be made and primed. These hormones also enhance the function of the mature cells, the genes of which have recently been cloned. On the other hand, long-term bone marrow culture has recently permitted detailed investigations of the relationship between hematopoietic cells and the microenvironment in which they are found, e.g. stromal cells, in vitro, relating to the regulation of cell proliferation and differentiation. Further, in hematological fields, other bioactive factors including differentiation-inducing compounds, e. g. bioactive glycosphingolipids, and leukocyte-endothelial cell recognition molecules (adhesion receptors) have been discovered, the molecular mechanism(s) of which have yet to be elucidated. This communication focuses on recent advances in research on soluble hemopoietins and other bioactive factors relating to differentiation-induction and to cell-to-cell recognition.

Cell Differentiation↗

PubMed2003

[Dietary phytoestrogen and its potential benefits in adult human health].

Human diet contains a series of bioactive vegetal compounds that can improve human health. Among these, there has been a special interest for phytoestrogens. This article reviews the evidence about the potential benefits of phytoestrogens for human health. Forty eight manuscripts were selected for their study design and relevance to human health. The cell growth inhibitory effects of phytoestrogens and their implication in breast cancer are reviewed. Also the effects of these compounds on serum lipid levels and the effectiveness of a phytoestrogen derivate, ipriflavone, on the prevention of osteoporosis are analyzed. Although these compounds have a great potential for improving health, there is still not enough evidence to recommend the routine use of phytoestrogens.

Breast Neoplasms↗

PubMed2004

[Salicylanilides: still a potential antibacterially active group].

The review presents a survey of potential biologically active salicylanilides, focusing particularly on their antibacterial activity. Emergence of bacterial resistance to a large number of antibacterial agents represents a major world-wide problem. On that account, perpetual attention is paid to the preparation of new bioactive antibacterial compounds. Salicylanilides belong to the group of compounds that have shown activity against gram-positive pathogens including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium, the strains representing the most significant problem in clinical practice. In 1998, a new mechanism of their action was proposed. Salicylanilides are inhibitors of two-component regulatory systems in bacteria. Electron-accepting substituents on the salicylic and hydrophobic groups on the anilide ring are most essential for the activity, but other electronic and structural parameters may also play an important role. Our aim, based on SAR analysis, is to develop new active drugs esterified by amino acid and later peptides. Furthermore, analogues carrying the hydroxybenzamide moiety may uncouple oxidative phosphorylation.

Anti-Bacterial Agents↗

PubMed2005

Inhibition of tumor growth and angiogenesis by water extract of Gac fruit (Momordica cochinchinensis Spreng).

The antitumor activity of the crude water extract from Gac fruit (Momordica cochinchinensis) was investigated in vivo and in vitro. A water extract prepared from 0.75 and 0.25 mg dry weight of Gac fruit per gram body weight was given daily to Balb/c mice (n=15/group). The water extract inhibited the growth of the colon 26-20 adenocarcinoma cell line, transplanted in Balb/c mice, reducing wet tumor weight by 23.6%. Histological and immunohistochemical results indicated that Gac water extract reduced the density of blood vessels around the carcinoma. The water extract also produced a marked suppression of cell proliferation in colon 26-20 and HepG2 cells. Cell cycle analysis demonstrated a significant accumulation of cells in the S phase by water extract. Immunoblotting showed that cyclin A, Cdk2, p27waf1/Kip1 were down-regulated, whereas the protein level of p21waf1/Cip1 was not decreased. Treatment of colon 26-20 cells with Gac extract induced necrosis rather than apoptosis. The antitumor component was confirmed as a protein with molecular weight of 35 kDa, retained in the water-soluble high molecular weight fraction. Thus, the bioactive antitumor compound in Gac extract is a protein, which is distinct from lycopene, another compound in Gac fruit with potential antitumor activity.

Adenocarcinoma↗

PubMed2005

Nutraceuticals as anti-angiogenic agents: hopes and reality.

Angiogenesis, the formation of new blood vessels from preexisting vascular network is a driving force of organ development in ontogeny, is necessary for ovulation and hair growth, and is prerequisite for proper wound healing. It is also a critical mechanism of numerous diseases, the most important of which are cancer and atherosclerosis. Therefore, modulation of angiogenesis is considered as therapeutic strategies of great importance for human health. Numerous bioactive plant compounds, often referred to as nutraceuticals are recently tested for the potential clinical applications. Among the most frequently studied are resveratrol, a polyphenol present in red-wine and grape-seed, epigallocatechin-3-gallate (EGCG) from green tea and curcumin from Curcuma longa. It is also possible that components of other plants, including the constituents of local food diet may find application for modulation of angiogenesis, provided that their effectiveness will be confirmed in controlled, scientifically validated trials.

Angiogenesis Inhibitors↗

PubMed2005

Effects of plant extracts on angiogenic activities of endothelial cells and keratinocytes.

Numerous bioactive chemical compounds of plant origin may influence the angiogenic activity of various cell types and may thus affect the formation of blood vessels. Here we present the angiogenic effects of extracts of edible plants collected in Crete, Southern Italy and Southern Spain. Extracts have been applied to cultured human microvascular endothelial cells (HMEC-1), human umbilical vein endothelial cells (HUVEC) and human keratinocytes (HaCaT). About half out of 96 extracts exerted an inhibitory effect on HMEC-1 proliferation. Additionally, we have noted the inhibitory effects of extracts on HUVEC differentiation on a Matrigel layer. None of the extracts showed a stimulatory activity. The extract of Thymus piperella exerted moderate inhibitory effect on cobalt-chloride induced VEGF synthesis, however, CoCl(2)-induced activation of hypoxia responsive element of VEGF promoter was significantly attenuated only by extract of Origanum heracleoticum. Our study indicates that extracts of local food plants, of potential value as nutraceuticals, contain chemical compounds which may inhibit angiogenesis. Demonstration of their real influence on human health requires, however, extensive animal studies and controlled clinical investigations.

Angiogenesis Inhibitors↗

PubMed1991

Preparation of potentially bioactive aza and thiaza polycyclic compounds containing a bridgehead nitrogen atom synthesis and antimicrobial activity of some pyrrolo[1,2,3-de]-1,4-benzothiazines.

The synthesis of the 2,3-dihydro-pyrrolo[1,2,3-de]-1,4-benzothiazine 1a and 11b, 12-dihydro-isoquino[1,2-c]-1,4-benzothiazine 8 has been accomplished by using a Bischler type cyclization of the N-(2,2-diethoxyethyl)-3,4-dihydro-2H-1,4-benzothiazines 3a and 3d, respectively. The new compounds 1a and 8 together with the known pyrrolobenzothiazines 1b,c and some their derivatives and intermediates of preparation were tested in vitro for their antimicrobial activity. Compound 1b was the most active against the Gram-positive Bacillus subtilis. Compound 7b showed interesting antifungal activity when tested against Saccharomyces cerevisiae.

Anti-Bacterial Agents↗

PubMed1989

Porcine focal symmetrical poliomyelomalacia: test for an interaction between dietary selenium and niacin.

Experiments were conducted to test the hypothesis that dietary supplementation with nicotinamide would retard or eliminate the signs of selenium induced porcine focal symmetrical poliomyelomalacia (PFSP). Mixed-sex feeder pigs, approximately five weeks old, were divided into four groups and daily received, by oral capsule, the following treatments: no supplementation (control); 2.86 mg sodium selenite per kg body wt (selenium only); 44 mg nicotinamide per kg body wt (niacin only); or both the niacin and selenium (niacin + selenium). Over the ten day treatment body weights and behavior scores were recorded, as well as collection of fluid (blood, serum, urine) samples. Upon death, tissue samples (kidney, liver, brain, spinal cord and muscle) were obtained. All of these samples were analyzed for total selenium and bioactive niacin compounds. After gross pathological analysis, 11 samples from specific brain and spinal cord regions were taken for fixation and processing for histological analysis by light microscopy. The selenium only group showed behavior signs related to PFSP after two days of treatment with the average time of death at 6.5 days. Tissue levels of selenium were elevated and histological analyses established the expected lesions of PFSP. No disorders were noted in the control and niacin only groups. The niacin + selenium groups had slightly retarded changes in behavior scores (first differences from controls on day 4) but their mean day of death (7.5 days of treatment) did not differ from that of the selenium only groups. Histological analyses of these tissues revealed similar lesions to the selenium only group, but they may have been of lesser magnitude. The data were consistent with, but only partially supportive of, the above hypothesis.

Animals↗

PubMed1995

Nicotinamide adenine dinucleotide (phosphate): quinone oxidoreductase (DT-diaphorase) as a target for bioreductive antitumor quinones: quinone cytotoxicity and selectivity in human lung and breast cancer cell lines.

Bioreductive antitumor quinones require reductive metabolism to produce their cytotoxic effects. A series of these compounds was screened for relative rates of reduction by the two-electron reductase, NAD(P)H:quinone oxidoreductase (DTD). The antitumor quinones streptonigrin (SN), 2,5-diaziridinyl-3-phenyl-1,4-benzoquinone (PDZQ), 2,5-diaziridinyl-3,6-dimethyl-1,4-benzoquinine (MeDZQ), and [3-hydroxymethyl-5-aziridinyl-1-methyl-2-(1H-indole-4,7-dione)-propen ol] (EO9) were all excellent substrates for recombinant rat and human DTD. All four compounds were reduced by DTD at least 100 times faster than the clinically important bioreductive alkylating agent, mitomycin C (MC). Reduction of the antitumor quinones was generally 4-5 times more efficient by rat DTD than by human DTD. The exception was EO9, which, surprisingly, was reduced 23 times faster by rat DTD than by human DTD. The rate of reduction of each individual quinone was similar under either aerobic or anaerobic conditions, suggesting that DTD may be an important activating enzyme in the hypoxic fraction of solid tumors. The cytotoxicity of MeDZQ and MC was examined in a panel of human breast and lung cancer cell lines. The data showed good correlations between DTD activity and toxicity for both MeDZQ (r = 0.57, p = 0.054) and MC (r = 0.69, p = 0.020), confirming biochemical data that both compounds are bioactivated by DTD. In addition, IC50 values were in general lower for MeDZQ than for MC in cell lines containing elevated DTD, a finding that was consistent with metabolic data that indicated that MeDZQ was a better substrate for DTD than MC. SR, defined as the ratio of the IC50 value for the H596 NSCLC cell line (undetectable DTD activity) to the IC50 value for the H460 NSCLC cell line (high DTD activity), were determined for all five antitumor quinones. SN was the most selective (SR = 86) followed by EO9 (SR = 62), MeDZQ (SR = 17), and MC (SR = 11). Surprisingly, PDZQ, an excellent substrate for DTD, was toxic to both cell lines (SR = 1.8). These data suggest that antitumor quionones that are substrates for DTD may be selectively toxic to tumors with high DTD activity and may be useful in the treatment of those tumors.

Animals↗

PubMed1997

Konishiol, a new sesquiterpene, and bioactive components from Cunninghamia konishii.

Three sesquiterpenes, konishiol (1), cadalenol (2), 3-cedranol (3), one diterpene, manool (4), and one lignan, (+)-tsugacetal (5), have been isolated, for the first time, from the whole plant of Cunninghamia konishii by using bioactivity-directed fractionation. Compound 1 is new to the literature, and its chemical structure was determined by various spectroscopic analyses including EIMS, HREIMS, NOE, NOESY, and by preparing its di-acetyl derivative (1a). Compounds 2-5 showed moderate to weak bioactivities in brine shrimp (BST) and mosquito larvae (YFM) bioassays as well as cytotoxicities against three human solid tumor cell lines.

Antineoplastic Agents, Phytogenic↗

PubMed2004

Diethyl 1-(4-fluorophenyl)-3-(2-furyl)-5-oxopyrrolidine-2,2-dicarboxylate and diethyl 1-(3,4-dichlorophenyl)-3-(2-furyl)-5-oxopyrrolidine-2,2-dicarboxylate.

The title compounds, C20H20FNO6 and C20H19Cl2NO6, respectively, may exhibit bioactivity. In these compounds, the pyrrolidine ring adopts a conformation intermediate between envelope and half-chair. Only one of the two ethoxycarbonyl side chains is nearly planar. Centrosymmetric pairs are formed, and the crystal structure is stabilized by weak C-H.O hydrogen bonds and van der Waals interactions.

Journal Article↗

PubMed2001

Recombinagenic activity of four compounds in the standard and high bioactivation crosses of Drosophila melanogaster in the wing spot test.

The wing somatic mutation and recombination test (SMART) using Drosophila melanogaster was employed to determine the recombinagenic and mutagenic activity of four chemicals in an in vivo eukaryotic system. Two different crosses involving the wing cell markers mwh and flr(3) were used: the standard cross and a high bioactivation cross. The high bioactivation cross is characterized by a high constitutive level of cytochromes P450 which leads to an increased sensitivity to a number of promutagens and procarcinogens. Three-day-old larvae derived from both crosses were treated chronically with the oxidizing agent potassium chromate and with the three procarcinogens cyclophosphamide, p-dimethylaminoazobenzene and 9,10-dimethylanthracene. From both crosses two types of progeny were obtained: marker-heterozygous and balancer-heterozygous. The wings of both genotypes were analysed for the occurrence of single and twin spots expressing the mwh and/or flr(3) mutant phenotypes. In the marker-heterozygous genotype the spots can be due either to mitotic recombination or to mutation. In contrast, in the balancer-heterozygous genotype only mutational events lead to spot formation, all recombination events being eliminated. The oxidizing agent potassium chromate was equally and highly genotoxic in both crosses. Surprisingly, the promutagen cyclophosphamide also showed equal genotoxicity in both crosses, whereas p-dimethylaminoazobenzene was negative in the standard cross, but clearly genotoxic in the high bioactivation cross. 9,10-Dimethylanthracene showed a rather weak genotoxicity in the high bioactivation cross. Analyses of the dose-response relationships for mwh clones recorded in the two wing genotypes demonstrated that all four compounds are recombinagenic. The fraction of all genotoxic events which are due to mitotic recombination ranged from 83% (9,10-dimethylanthracene) to 99% (p-dimethylaminoazobenzene). These results demonstrate that the wing spot test in Drosophila is most suited to the detection of recombinagenic activity of genotoxic chemicals.

Animals↗