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PubMed1999

Carboxylic acid analogues of tamoxifen: (Z)-2-[p-(1, 2-diphenyl-1-butenyl)phenoxy]-N,N-dimethylethylamine. Estrogen receptor affinity and estrogen antagonist effects in MCF-7 cells.

The triarylethylene estrogen mimetic (E, Z)-4-[1-(p-hydroxyphenyl)-2-phenyl-1-butenyl]phenoxyacetic acid (4) represents a novel class of estrogen receptor (ER) ligands which, like tamoxifen (1), can elicit estrogen agonist and antagonist effects, in turn, in nonreproductive and reproductive tissues. Analogues of 4, incorporating structural features shown previously in triarylethylenes to improve ER affinity and estrogen antagonist properties, were prepared with the ultimate aim of identifying substances with improved estrogenicity exclusive of reproductive tissues. Thus, the side chain of 4 was elongated to give oxybutyric acid 13, which was further altered by (a) repositioning of its p-hydroxyl to the neighboring m-position (12) and (b) ethylenic bond reduction (14). Also, the p-hydroxyl group and oxyacetic acid groups of 4 were, in turn, shifted to the neighboring m-positions, affording 8 and 9. Oxybutyric acid analogue 13 had about 2 times the affinity for human ERalpha as 4, and its antiproliferative effect in MCF-7 cells was greater than that of 1. Dihydro analogue 14, which was conformationally similar to cis-13, had very low ER affinity and antiestrogenicity, and m-hydroxy analogue 12 also had reduced ER affinity and potency, but its MCF-7 cell antiproliferative efficacy was retained. Modest ER affinity and antiproliferative potency were seen with 8, in which phenolic and phenyl rings were trans to one another, but 9, in which these rings were cis, was inactive. Our findings indicate that two-carbon side-chain elongation and/or m-positioning of the hydroxyl group in 4 affords analogues with dominant estrogen antagonist effects in MCF-7 cells.

Antineoplastic Agents↗
PubMed2001

Synthesis of functional aromatic multisulfonyl chlorides and their masked precursors.

The synthesis of functional aromatic bis(sulfonyl chlorides) containing an acetophenone and two sulfonyl chloride groups, i.e., 3,5-bis[4-(chlorosulfonyl)phenyl]-1-acetophenone (16), 3,5-bis(chlorosulfonyl)-1-acetophenone (17), and 3,5-bis(4-(chlorosulfonyl)phenyloxy)-1-acetophenone (18) via a sequence of reactions, involving in the last step the quantitative oxidative chlorination of S-(aryl)- N,N'-diethylthiocarbamate, alkyl- or benzyl thiophenyl groups as masked nonreactive precursors to sulfonyl chlorides is described. A related sequence of reactions was used for the synthesis of the aromatic trisulfonyl chloride 1,1,1-tris(4-chlorosulfonylphenyl)ethane (24). 4-(Chlorosulfonyl)phenoxyacetic acid, 2,2-bis[[[4-(chlorosulfonyl)phenoxyacetyl]oxy]methyl]-1,3-propanediyl ester (27), 5,11,17,23-tetrakis(chlorosulfonyl)-25,26,27,28-tetrakis(ethoxycarbonylmethoxy)calix[4]arene (38), 5,11,17,23,29,35-hexakis(chlorosulfonyl)-37,38,39,40,41,42-hexakis(ethoxycarbonylmethoxy)calix[6]arene (39), 5,11,17,23,29,35,41,47-octakis(chlorosulfonyl)-49,50,51,52,53,54,55,56-octakis(ethoxycarbonylmethoxy)calix[8]arene (40), 5,11,17,23-tetrakis(tert-butyl)-25,26,27,28-tetrakis(chlorosulfonyl phenoxyacetoxy)calix[4]arene (44), 5,11,17,23,29,35-hexakis(tert-butyl)-37,38,39,40,41,42-hexakis(chlorosulfonylphenoxyacetoxy)calix[6]arene (45), and 5,11,17,23,29,35,41,47-octakis(tert-butyl)-49,40,51,52,53,54,55,56-octakis(chlorosulfonylphenoxyacetoxy)calix[8]arene (46) were synthesized by two different multistep reaction procedures, the last step of both methods consisting of the chlorosulfonation of compounds containing suitable activated aromatic positions. 2,4,6-Tris(chlorosulfonyl)aniline (47) was obtained by the chlorosulfonation of aniline. The conformation of two series of multisulfonyl chlorides i.e., 38, 39, 40 and 44, 45, 46, was investigated by (1)H NMR spectroscopy. The masked nonreactive precursor states of the functional aromatic multisulfonyl chlorides and the aromatic multisulfonyl chlorides reported here represent the main starting building blocks required in a new synthetic strategy elaborated for the preparation of dendritic and other complex organic molecules.

Journal Article↗
PubMed2004

In vitro reactivity of carboxylic acid-CoA thioesters with glutathione.

The chemical reactivity of acyl-CoA thioesters toward nucleophiles has been demonstrated in several recent studies. Thus, intracellularly formed acyl-CoAs of xenobiotic carboxylic acids may react covalently with endogenous proteins and potentially lead to adverse effects. The purpose of this study was to investigate whether a correlation could be found between the structure of acyl-CoA thioesters and their reactivities toward the tripeptide, glutathione (gamma-Glu-Cys-Gly). The acyl-CoA thioesters of eight carboxylic acids (ibuprofen, clofibric acid, indomethacin, fenbufen, tolmetin, salicylic acid, 2-phenoxypropionic acid, and (4-chloro-2-methyl-phenoxy)acetic acid (MCPA)) were synthesized, and each acyl-CoA (0.5 mM) was incubated with glutathione (5.0 mM) in 0.1 M potassium phosphate (pH 7.4, 37 degrees C). All of the acyl-CoAs reacted with glutathione to form the respective acyl-S-glutathione products, with MCPA-CoA having the highest rate of conjugate formation (120 +/- 10 microM/min) and ibuprofen-CoA having the lowest (1.0 +/- 0.1 microM/min). The relative reactivities of the acyl-CoAs were dependent on the substitution at the carbon atom alpha to the acyl carbon and on the presence of an oxygen atom in a position beta to the acyl carbon and were as follows: phenoxyacetic acid > o-hydroxybenzoic acid--phenoxypropionic acid > arylacetic acid derivatives > 2-methyl-2-phenoxypropionic acid--2-phenylpropionic acid. For each acyl-CoA thioester, the overall hydrolysis rate was determined as the time-dependent formation of parent compound. A linear trend was observed when comparing the reactivities of the acyl-CoAs with glutathione with the corresponding overall hydrolysis rates. Thus, the most reactive compound (MCPA-CoA) was also the compound with the highest rate of hydrolysis and the least reactive compounds (ibuprofen-CoA, clofibryl-CoA) were also the compounds least susceptible to hydrolysis.

Acyl Coenzyme A↗
PubMedDate not supplied

Use of silica gels and mesoporous molecular sieves as supports for the solid-phase Claisen rearrangement.

A series of silica gels and mesoporous molecular sieves differing in both the range of particle size and mean pore size were derivatized with the p-[R,S-alpha-[1-(9H-fluoren-9-yl)-methoxyformamido]-2,4-di methoxybenzyl]- phenoxyacetic acid linker and their loading capacities were measured. Loading capacities ranging between 0.4-0.6 mmol Fmoc/g were achieved. Several of these silica based materials were derivatized with the hydroxymethyl benzoic acid linker and used as supports for the solid phase Claisen rearrangement of a support bound phenyl allyl ether. Both the silica gel and mesoporous supports were heated at 225 degrees C for 3 h to effect the Claisen rearrangement. The results showed that, compared to the same reaction run homogeneously, the silica gel support achieved similar total product yields and ratios for two Claisen products. The mesoporous supports were found to selectively produce one of the Claisen products over the other. Analysis shows that the molecules bound to the mesoporous support are physically further separated from each other as compared to those bound to the silica gel support. A mechanism is presented which accounts for the selectivity of the mesoporous support in forming one Claisen product over the other. The Claisen product was further derivatized to the resulting phenyl ethyl either through a solid phase Mitsunobu reaction on the mesoporous support.

Chemistry, Organic↗
PubMed1984

Renal actions of piretanide and three other "loop" diuretics.

Thirty-nine clearance studies were performed in 17 healthy subjects under conditions of maximal hydration or hydropenia to compare the effects on renal solute and water handling of three sulfamoylbenzoic acid derivatives-piretanide, bumetanide, and furosemide-and the phenoxyacetic acid diuretic ethacrynic acid. Except for furosemide, which caused a 7% fall in effective renal plasma flow (ERPF), and ethacrynic acid, which reduced both the glomerular filtration rate (16%) and ERPF (23%) during maximal hydration, changes in hemodynamics were insignificant. At peak saluresis piretanide induced a mean reduction of -18.3% +/- 4.9% in fractional free-water clearance during hydration and -73.2% +/- 5.9% in fractional free-water reabsorption during hydropenia. The other sulfamoylbenzoates lowered fractional clearance and reabsorption of free water to similar extents, implying a major site of action within the medullary portion of the ascending limb. Ethacrynic acid reduced fractional free-water clearance to a greater degree than did the sulfamoylbenzoates. The mean reduction in fractional free-water reabsorption after ethacrynic acid (71.4% +/- 8.2%) was of the same order as that caused by the sulfamoylbenzoates. Similar excretory maxima for sodium, chloride, potassium, calcium, and magnesium were achieved for all four diuretics. Except for piretanide under hydropenia, sulfamoylbenzoate action did not change urinary pH. Ethacrynic acid consistently lowered urinary pH. During hydration piretanide induced phosphaturia (35.3% +/- 8.8%) and uricosuria (40.9% +/- 9.1%). Both bumetanide and piretanide increased fractional urate clearance during hydropenia (16.7% +/- 5.6% and 34.2% +/- 10.5%). There were no changes in phosphate or urate excretion after ethacrynic acid. Our data support the view that sulfamoylbenzoate diuretics exert additional effects on proximal tubular segments that are not shared by ethacrynic acid. Renal responses to piretanide most closely resemble those to bumetanide.

Absorption↗
PubMed2004

Solid-phase synthesis of serine-based glycosphingolipid analogues for preparation of glycoconjugate arrays.

Synthetic glycolipids with defined structures are important tools in the study of glycolipid biology. In this paper we describe a solid-phase synthesis of three galactosylated serine-based glycosphingolipid analogues using the novel linker 2-fluoro-4-(hydroxymethyl)-phenoxyacetic acid. Gel-phase (19)F-NMR spectroscopy was used to measure the yield and stereochemical outcome of the solid-phase glycosylations. Under NIS-TfOH promotion, alpha- and beta-selective glycosylations were performed at room temperature with thioglycoside donors carrying fluorine labelled protective groups. Finally, the glycolipids were covalently linked to microtiter plates and labelled lectins with different selectivity for alpha- and beta-galactosides could bind to the glycolipid arrays.

Combinatorial Chemistry Techniques↗
PubMed1968

Enzymes catalysing conjugations of glutathione with alpha-beta-unsaturated carbonyl compounds.

1. Heat-inactivation experiments, ammonium sulphate-fractionation studies, enzyme-inhibition studies with S-(alphabeta-diethoxycarbonylethyl)glutathione, and evidence from the distribution of activities in rat liver, in rat kidney and in the livers of other animals, indicate that reactions of glutathione with (i) trans-benzylideneacetone, (ii) cyclohex-2-en-1-one, (iii) trans-cinnamaldehyde, (iv) diethyl maleate, (v) diethyl fumarate and (vi) 2,3-dimethyl-4-(2-methylenebutyryl)phenoxyacetic acid are catalysed by different enzymes. 2. Evidence is presented that the enzymes catalysing the reactions of glutathione with substrates (i)-(iv) are different from glutathione S-alkyltransferase, S-aryltransferase and S-epoxidetransferase. 3. The name ;glutathione S-alkenetransferases' is proposed for enzymes catalysing reactions of glutathione with alphabeta-unsaturated compounds. 4. The Arrenhius plot for the enzyme-catalysed reaction of diethyl maleate with glutathione is discontinuous, with lower energy of activation at 38 degrees .

Aldehydes↗
PubMed1971

Metabolism of 4-chloro-2-methylphenoxyacetate by a soil pseudomonad. Preliminary evidence for the metabolic pathway.

1. A pseudomonad capable of utilizing the herbicide 4-chloro-2-methylphenoxyacetate as a sole carbon source was isolated from soil and cultured in liquid medium. 2. Analysis of induction patterns of 4-chloro-2-methylphenoxyacetate-grown cells suggests that 5-chloro-o-cresol and 5-chloro-3-methylcatechol are early intermediates in the oxidation of 4-chloro-2-methylphenoxyacetate. Cells were not adapted to oxidize 4-chloro-6-hydroxy-2-methylphenoxyacetate. 3. In culture, 4-chloro-2-methylphenoxyacetate rapidly disappeared and the chlorine in the molecule was quantitatively released as Cl(-) ion. 4. A lactone (gamma-carboxymethylene-alpha-methyl-Delta(alphabeta)-butenolide) was isolated from cultures and established as an intermediate. 5. The following metabolic pathway is suggested: 4-chloro-2-methylphenoxyacetate --> 5-chloro-o-cresol --> 5-chloro-3-methylcatechol --> cis-cis-gamma-chloro-alpha-methylmuconate --> gamma-carboxymethylene-alpha-methyl-Delta(alphabeta)-butenolide --> gamma-hydroxy-alpha-methylmuconate. 6. The tentative identification of 5-chloro-o-cresol, a gamma-chloro-alpha-methylmuconate and gamma-hydroxy-alpha-methylmuconate in culture extracts supports this scheme. However, the catechol was never observed to accumulate in cultures. 7. The detection of 4-chloro-6-hydroxy-2-methylphenoxyacetate, 2-methyl-phenoxyacetate, a dehalogenated cresol and oxalate in culture extracts is discussed in relation to the proposed metabolic pathway.

Catechols↗
PubMed1973

Distribution of enzymes that catalyse reactions of glutathione with alpha beta-unsaturated compounds.

1. A study of the distribution of glutathione S-alkenetransferases in the livers of vertebrate species suggests that different enzymes may catalyse reactions of GSH with (i) trans-benzylideneacetone, (ii) 2,3-dimethyl-4(2-methylenebutyryl)phenoxyacetic acid, (iii) cinnamonitrile, (iv) o-chlorobenzylidenemalononitrile, (v) methyl vinyl sulphone, and (vi) 3-(beta-nitrovinyl)indole. 2. Glutathione S-alkenetransferase activity was generally greatest in rat liver, but the enzyme in hamster liver was more active towards o-chlorobenzylidenemalononitrile, and the enzyme in rabbit, hamster, guinea-pig and mouse livers was more active towards methyl vinyl sulphone. 3. Results from studies of the distribution of activities in rat liver and rat kidney, heat inactivation of rat liver supernatants, and (NH(4))(2)SO(4) fractionation and acid-precipitation experiments, differentiated further between some of the enzymes concerned with substrates (i)-(vi). 4. The infrequent detection of mercapturic acids in vivo is discussed.

Adult↗
PubMed2001

Comparison of the solid-phase fragment condensation and phase-change approaches in the synthesis of salmon I calcitonin.

Salmon I calcitonin was synthesized using both phase-change and conventional solid-phase fragment condensation (SPFC) approaches, utilizing the Rink amide linker (Fmoc-amido-2,4-dimethoxybenzyl-4-phenoxyacetic acid) combined with 2-chlorotrityl resin and the Fmoc/tBu(Trt)-based protection scheme. Phase-change synthesis, performed by the selective detachment of the fully protected C-terminal 22-mer peptide-linker from the resin and subsequent condensation in solution with the N-terminal 1-10 fragment, gave a product of slightly less purity (85 vs. 92%) than the corresponding synthesis on the solid-phase. In both cases salmon I calcitonin was easily obtained in high purity.

Calcitonin↗
PubMed2003

Characterization and cDNA cloning of a clofibrate-inducible microsomal epoxide hydrolase in Drosophila melanogaster.

In order to understand the roles of the epoxide hydrolases (EHs) in xenobiotic biotransformation in insects, we examined the induction of EHs by exogenous compounds in Drosophila melanogaster third instar larvae. Among the chemicals tested, clofibrate, a phenoxyacetate hypolipidermics drug, increased EH activity towards cis-stilbene oxide approximately twofold in larval whole-body homogenates. The same dose of clofibrate also induced glutathione S-transferase activity. The effect of clofibrate on EH induction was dose-dependent and the highest activity occurred with a 10% clofibrate application. Three other substrates conventionally used in EH assays (trans-stilbene oxide, trans-diphenylpropene oxide and juvenile hormone III) were poorly hydrolysed by larval homogenates, with or without clofibrate administration. Because the increased EH activity was localized predominantly in the microsomal fraction, we synthesized degenerate oligonucleotide primers with sequences corresponding to conserved regions of known microsome EHs from mammals and insects in order to isolate the gene. The 1597 bp putative cDNA of D. melanogaster microsomal EH (DmEH) obtained from a larval cDNA library encoded 463 amino acids in an open reading frame. Northern blot analysis showed that the transcription of DmEH was increased in larvae within 5 h of clofibrate treatment. Recombinant DmEH expressed in baculovirus hydrolysed cis-stilbene oxide (23 nmol.min-1.mg protein-1) and was located mainly in the microsomal fraction of virus-infected Sf9 cells. There was no detectable EH activity toward juvenile hormone III. These observations suggest that DmEH is involved in xenobiotic biotransformation, but not in juvenile hormone metabolism, in D. melanogaster.

Amino Acid Sequence↗
PubMed1999

Prevalence of antinuclear antibodies in a rural population.

Exposure to environmentally and occupationally encountered toxicants can be associated with the development of certain autoimmune diseases and with the induction of antinuclear antibodies (ANA). Some chemicals used in the agricultural industry are known to affect immune function but their roles in the induction of autoimmunity in general, and ANA in particular, have not been reported previously. This study was undertaken to establish the prevalence of ANA in a rural population and to determine environmental and occupational exposures with which they are associated. This cross-sectional study represented one component of an interdisciplinary project (Prairie Ecosystem Study [PECOS], Eco-Research Program, Tri-Council Secretariat of Canada) designed to explore, in a rural population, the roles of environmental exposures as determinants of human health status. Information regarding lifetime, current, and main occupational exposures in the rural-dwelling study population was derived from a self-administered questionnaire. Sera from consenting subjects, collected during the months of February and March 1996, were assayed for ANA by indirect immunofluorescence on HEp-2 cells. The study population comprised 322 adult subjects (mean age 49.3+/-14.7 yr; range 16-87 yr). Statistical analyses adjusted for age and sex revealed that the presence of ANA among the participants was associated with a current agricultural occupation that included oilseed production, hog production, or poultry production. There was a significant association between ANA positivity and a current main farming operation of crop production. There was also an association among individual participants between lifetime exposure to the insecticide class of pesticides and the presence of ANA. In this rural study population, ANA positivity was significantly associated with lifetime exposure specifically to carbamate, organochlorine (including aldrin, chlordane, dieldrin, endrin, heptachlor, and lindane, but excluding DDT and methoxychlor), and pyrethroid insecticides and to phenoxyacetic acid herbicides, including 2,4-D. After adjustment for age, sex, and other insecticide exposures, multivariate analyses indicated that ANA positivity was associated with current oilseed production and with lifetime exposure to pyrethroid insecticides. In a rural population, ANA were associated with production of certain crops and certain animals and exposure to specific pesticides. The data indicate that some occupational exposures related to the agricultural industry are associated with the presence of ANA, a serologic expression of autoimmunity.

Adolescent↗
PubMed2005

Carbaryl, 2,4-D, and Triclopyr adsorption in thatch-soil ecosystems.

Thatch development in intensively managed turf sites may cause environmental concerns for greater sorption or leaching of applied chemicals in terrestrial ecosystems. To determine the adsorption potential of Carbaryl (1-Napthyl N-methylcarbamate), 2,4-D (2,4-dichloro-phenoxyacetic acid), and Triclopyr (3,5,6-trichloro-2-pyridinyloxyacetic acid) in turf ecosystems, composite thatch and underlying soil samples from three-and six-year-old stands of cool-season Southshore creeping bentgrass (Agrostis palustris Huds.) and warm-season Meyer zoysiagrass (Zoysia japonica Steud.) were collected. The samples were processed and analyzed for total organic carbon (COrg); extractable (CExt), humic (CHA) and fulvic acid (CFA); anthrone reactive nonhumic carbon (ARC) fractions; and CHA and CFA associated iron (Fe) contents. Pesticide adsorption capacity (Kf) and intensity (1/n), organic carbon partition coefficient (KOC) and Gibbs free energy change (deltaG) were calculated for thatch materials and the underlying soils using a modified batch/flow technique. Both bentgrass (BT) and zoysiagrass thatch (ZT) contained a greater concentration of CExt, CFA, CHA, and ARC than the respective soils (BS and ZS). The CExt, CFA, CHA, and ARC concentration was higher in BT compared with ZT. The BT contained a greater concentration of bound Fe in both CFA and CHA fractions than in BS, whereas ZT had more bound Fe in CHA fraction than in ZS. On average, the BT had a greater concentration of bound Fe in CExt, CFA, and CHA fractions than in the ZT. Among the pesticides, Carbaryl had higher Kf and 1/n values than 2,4-D and Triclopyr for both thatch and soil. Although the KOC and deltaG values of Carbaryl were higher in both BT and ZT than in the underlying soils, the KOC and deltaG values of 2,4-D were significantly higher in BS and ZS than in the overlying thatch materials. The 2,4-D and Triclopyr had higher leaching indices (LI) than Carbaryl for both BT and ZT materials than the respective soils. The Carbaryl, however, had a higher LI for soils than for thatch materials. Averaged across thatch materials and soils, COrg accounted for 96, 85, and 84% variations in Carbaryl, 2,4-D, and Triclopyr adsorption, respectively. Among the COrg fractions, lignin followed by CFA and CHA accounted for greater adsorption of pesticides, especially Carbaryl. The concentration of CHA and CFA bound Fe did not correlate with Kf and 1/n values of pesticides.

2,4-Dichlorophenoxyacetic Acid↗
PubMed2003

Removal of MCPA from aqueous solutions by acid-activated spent bleaching earth.

The removal of MCPA (4-chloro-2-methyl phenoxyacetic acid) from aqueous solutions by activated spent bleaching earth (SBE) was studied as a function of time, initial concentration, adsorbent concentration, and temperature. The Langmuir and Freundlich isotherms were fitted by the adsorption data obtained. The values of Langmuir and Freundlich constants were determined. The adsorption kinetics was described by the Lagergren equation. Mass transfer coefficient and thermodynamic parameters were also calculated. Column experiments were conducted and brekthrough capacities were found for different concentrations and different flow rates. The study demonstrates that acid-treated SBE could be used as an efficient adsorbent for the removal of MCPA-bearing wastewater effluents.

2-Methyl-4-chlorophenoxyacetic Acid↗
PubMed2003

Multiresidue determination of acidic pesticides in water by HPLC-DAD with confirmation by GC-MS using conversion to the methyl ester with trimethylsilyldiazomethane.

A multiresidue pesticide methodology is studied and results for acidics are reported here, with base/neutral to follow. This work studies a literature procedure as a possible general approach to many pesticides and potentially other analytes that are considered to be liquid chromatographic (LC) candidates, rather than gas chromatographic (GC) ones. The analysis of the sewage effluent of a major southwestern U.S. city serves as an example of the application of the methodology to a real sample. Recovery studies were also conducted to validate the proposed extraction step. A gradient elution program was followed for the high-performance LC (HPLC) leading to a general approach for acidics. Confirmation of identity was by electron ionization-GC-mass spectrometry (MS) after conversion of the acids to the methyl ester (or other appropriate methylation) by means of trimethylsilyldiazomethane. The 3,4-dichlorophenoxyacetic acid is used as an internal standard to monitor the reaction, and polychlorobiphenyl #19 is used for the quantitation internal standard. Although others have reported similar analyses of acids, conversion to the methyl ester is by means of diazomethane itself, rather than by the more convenient and safe trimethylsilyldiazomethane. Thus, the present paper supports the use of trimethylsilyldiazomethane with all of these acids (trimethylsilyldiazomethane has been used in environmental work with some phenoxyacetic acid herbicides) and further supports the usefulness of this reagent as a potential replacement for diazomethane. The HPLC approach here could also serve as the separation basis for an LC-MS solution for confirmation of identity, as well as quantitation.

Acids↗
PubMed1977

Alterations of tRNA modification in mammalian systems: the effect of ethionine.

The relationship between the modification of tRNA and its ability to act as a substrate for homologous tRNA modification enzymes in vitro was studied. The tRNA extracted from the livers of rats was active as a substrate for in vitro methylation with extracts from normal rat liver 19 h after treatment with L-ethionine (35 mg/100 g/24 h). After 4 weeks of feeding a diet containing o.25% DL-ethionine, the tRNA was a poor substrate for methylation in vitro, even though it was deficient in methylated nucleosides. Only 18% and 7% of the available sites could be methylated after 67 h and 4 weeks, respectively, of ethionine treatment. 3-(3-amino-3-carboxypropyl)uridine, a nucleoside that is also synthesized from S-adenosylmethionine, was assayed in individual tRNAs by their reactivity with the N-hydroxysuccinimide ester of phenoxyacetic acid. The reactivity of tRNAIle, tRNAAsn, and tRNAThr was decreased by treatment with ethionine at 67 h as well as at 2 and 4 weeks, although no difference could be detected at 19 h.

Amino Acids↗
PubMed1992

The role of occupational exposure and immunodeficiency in B-cell malignancies. Working Group on the Epidemiology of Hematolymphopoietic Malignancies in Italy.

Excesses of non-Hodgkin's lymphoma have been observed among farmers exposed to phenoxyacetic acid herbicides and, less persuasively, among workers exposed to insecticides. Exposure to organic solvents (particularly chlorinated hydrocarbons) has also been associated with an increased risk of NHL. TCDD (which is a contaminant of phenoxy herbicides), DDT, and chlorinated solvents have all been reported to induce impairment or suppression of cell-mediated immunity. We hypothesize that NHL is caused by common viruses, such as the Epstein-Barr virus, that induce proliferation and immortalization of B-cells, followed by T-cell impairment entailing cell-mediated immunodeficiency. The increased risk of NHL with HIV infection and heart or kidney transplantation, in which immunodeficiency also occurs, is consistent with this hypothesis.

Animals↗
PubMedDate not supplied

The modification of platelet-induced coronary vasoconstriction by a thromboxane receptor antagonist.

The role of platelet-derived vasoconstrictors in coronary vasospasm was studied using arachidonic acid-stimulated washed human platelets (WPS). Transfer of this system into an organ bath, containing bovine coronary arteries (BCA) and a mixture of blocking agents resulted in a biphasic contraction, consisting of a first phase, mediated by release of thromboxane (TX) A2 and a second phase, mediated by release of 5-hydroxytryptamine (5-HT) from the WPS (1,2). Treatment of the WPS with 4-[2-(benzenesulfonamido)-ethyl]-phenoxyacetic acid (BM 13.177) (0.03-3 mumol/L) prior to stimulation revealed a concentration-dependent inhibition of the 5-HT component of the contractile response with a minor reduction of the TXA2 component of contraction and enhanced amounts of immunoreactive TXB2 in the bath fluid. Treatment of the BCA with BM 13.177 prior to addition of stimulated WPS resulted in a significant reduction of the TXA2 component of contraction, by 56% at 30 mumol/L whereas 3 mumol/L were ineffective. The 5-HT component of contraction was enhanced. For comparison, the IC50 for BM 13.177 to inhibit PGF2 alpha-induced contractions was 6 mumol/L and that to inhibit U-46,619 was 0.5 mumol/L. BM 13.177 was at least 1 order of magnitude more potent as an inhibitor of U-46,619 than of PGF2 alpha- or TXA2-induced contractions. It is concluded that BM 13.177 is a weak inhibitor of TXA2-mediated contractions of coronary vessels, suggesting different thromboxane receptors in coronary vessels and platelets.

Animals↗