The chemistry of organic contaminant transport in soils.
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Hazardous Substances↗
Biomedical subjects
S A Boyd
Publications and source records attributed to S A Boyd.
2-(Alkylamino)nicotinic acid and analogs. Potent angiotensin II antagonists.
A series of pyridines and other six-membered ring heterocycles connected to a biphenyltetrazole with a -CH2-NR'-link (1) were discovered to be potent angiotensin II antagonists. In the pyrimidine carboxylic acid series (W = CR, X = N, Y = CH, Z = COOH), compounds with an alkyl group (R') on the exocyclic nitrogen were much more potent than compounds with an alkyl group (R) on the heterocyclic ring. The corresponding pyridine, pyridazine, pyrazine, and 1,2,4-triazine carboxylic acids also showed potent in vitro angiotensin II antagonism. The pyridine (W, X, Y = CH, Z = COOH, R' = n-C3H7) demonstrated potent in vitro activity (pA2 = 10.10, rabbit aorta, and Ki = 0.61 nM, receptor binding in rat liver) as well as exceptional oral antihypertensive activity and bioavailability. Any nonacidic replacement for the carboxylic acid was detrimental for activity.
Angiotensin II↗
Effects of high doses of A-74273, a novel nonpeptidic and orally bioavailable renin inhibitor.
Previous studies with peptidic renin inhibitors have shown that high intravenous (i.v.) doses can induce unexpectedly large decreases in blood pressure (BP) that appear to be independent of plasma renin inhibition. A-74273 represents a new class of potent and orally bioavailable nonpeptidic renin inhibitors. We evaluated the BP effects of this renin inhibitor administered orally (p.o.) or i.v. at high doses to conscious salt-depleted dogs. Administration of A-74273 at 30 and 60 mg/kg p.o. (n = 6 per dose) produced similar maximum reductions in BP (-40 +/- 4 vs. -46 +/- 5 mm Hg) despite the occurrence of greater plasma drug concentrations at the higher dose. Duration of hypotension, however, was increased (p < 0.05) from 9 h at 30 mg/kg to 18 h at 60 mg/kg. The initial depressor response to 10 and 30 mg/kg i.v. doses of A-74273 (n = 6 per dose) was comparable, although duration and overall BP response was greater at 30 mg/kg i.v. No BP responses to A-74273 were noted in salt-replete dogs (n = 5). The hypotension produced by 30 mg/kg p.o. A-74273 was completely reversed by norepinephrine (NE 5 micrograms/kg/min; n = 5) or isotonic saline (4 ml/min/kg, n = 5) infusion. These studies demonstrate that high doses of A-74273 result in predictable BP responses that are renin-dependent and reversible. Therefore, large decreases in BP with high doses is not an attribute common to all renin inhibitors but appears to be a function of the structural characteristics specific to a particular compound.
Administration, Oral↗
Cardiovascular effects and hemodynamic mechanism of action of the novel, nonpeptidic renin inhibitor A-74273 in dogs.
A-74273 is a nonpeptidic, potent inhibitor of human and canine renin (IC50 = 3.1 and 43 nM, respectively, in plasma at pH 7.4) and has been shown to be orally active in dogs. To determine the hemodynamic mechanism underlying this renin inhibitor's hypotensive activity, the cardiac and hemodynamic effects of A-74273 were studied in sodium-depleted and sodium-replete pentobarbital-anesthetized dogs. Vehicle [5% dextrose in water (V, D5W), n = 8] or a single dose of A-74273 was administered intravenously (i.v.) as a bolus followed by a 30-min infusion (one tenth the bolus dose per minute). Baseline mean arterial pressure (MAP) was similar among all treatment groups, but baseline plasma renin activity (PRA) was increased in the sodium-depleted dogs as compared with the sodium-replete dogs. In sodium-depleted dogs (n = 7-8/dose), MAP decreased maximally as compared with baseline by 4 +/- 1, 19 +/- 3, and 23 +/- 3% during infusion of A-74273 at doses of 0.001, 0.01, and 0.1 mg/kg/min, respectively (p < 0.05 vs. baseline or V). The two highest infusion doses also produced significant reductions (p < 0.05 vs. baseline and V) in systemic vascular resistance (SVR, 21 +/- 2 and 25 +/- 2%) and left ventricular end-diastolic pressure (LVEDP, 40 +/- 8 and 47 +/- 12%). In sodium-replete dogs (n = 4/dose), an infusion dose of 0.01 mg/kg/min elicited no hemodynamic response, whereas 0.1 mg/kg/min reduced MAP by 13 +/- 2% (p < 0.05 vs. baseline) and SVR by 7 +/- 6%.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Oral↗
C-terminal modifications of nonpeptide renin inhibitors: improved oral bioavailability via modification of physicochemical properties.
We describe the development of a series of soluble, potent, and bioavailable nonpeptide renin inhibitors. These inhibitors derived from a series of novel nonpeptide renin inhibitors which were recently identified in our laboratories, by alteration of the nature of the C-terminus (P2') of the molecules. Introduction of basic substituents into modified hydroxyethylene dipeptide isosteres gave inhibitors with improved solubility as well as improved potency against human plasma renin. In addition, these modifications produced inhibitors which displayed markedly improved intraduodenal bioavailability in both the ferret and cynomolgus monkey. We also present data which demonstrate excellent efficacy in the monkey for A-74273 (65), with an intraduodenal bioavailability of 16 +/- 4% in the monkey, compared to 1.7 +/- 0.5% for the dipeptide renin inhibitor enalkiren (A-64662, 75). A-74273 is an example of a nonpeptide inhibitor which possesses a good balance of the desirable properties of potency, solubility, and lipophilicity and which is well absorbed into the intestine.
Administration, Oral↗
Slow, tight binding to human renin of some nonpeptidic renin inhibitors containing a 4-methoxymethoxypiperidinylamide at the P4 position.
A series of nonpeptidic human renin inhibitors with a 4-methoxymethoxypiperidinylamide at the P4 position of the molecule exhibited slow tight binding to the enzyme. Replacement of the methoxymethoxy moiety on the piperidine ring with H, OH, methoxyethyl, propyloxy or n-butyl eliminated the effect. The inhibition was partially reversed by prolonged dialysis at 4 degrees C, arguing against formation of a covalent bond in the tightened complex.
Binding Sites↗
Reductive debromination of the commercial polybrominated biphenyl mixture firemaster BP6 by anaerobic microorganisms from sediments.
Anaerobic microorganisms eluted from three sediments, one contaminated with polybrominated biphenyls (PBBs) and two contaminated with polychlorinated biphenyls, were compared for their ability to debrominate the commercial PBB mixture Firemaster. These microorganisms were incubated with reduced anaerobic mineral medium and noncontaminated sediment amended with Firemaster. Firemaster averages six bromines per biphenyl molecule; four of the bromines are substituted in the meta or para position. The inocula from all three sources were able to debrominate the meta and para positions. Microorganisms from the Pine River (St. Louis, Mich.) contaminated with Firemaster, the Hudson River (Hudson Falls, N.Y.) contaminated with Aroclor 1242, and Silver Lake (Pittsfield, Mass.) contaminated with Aroclor 1260 removed 32, 12, and 3% of the meta plus para bromines, respectively, after 32 weeks of incubation. This suggests that previous environmental exposure to PBBs enhances the debromination capability of the sediment microbial community through selection for different strains of microorganisms. The Pine River inoculum removed an average of 1.25 bromines per biphenyl molecule during a 32-week incubation period, resulting in a mixture potentially more accessible to aerobic degradation processes. No ortho bromine removal was observed. However, when Firemaster was incubated with Hudson River microorganisms that had been repeatedly transferred on a pyruvate medium amended with Aroclor 1242, 17% of the meta and para bromines were removed after 16 weeks of incubation and additional debromination products, including 2-bromobiphenyl and biphenyl, were detected. This suggests the possibility for ortho debromination, since all components of the Firemaster mixture have at least one ortho-substituted bromine.(ABSTRACT TRUNCATED AT 250 WORDS)
Aroclors↗
Anaerobic dechlorination of polychlorobiphenyls (Aroclor 1242) by pasteurized and ethanol-treated microorganisms from sediments.
A polychlorobiphenyl (PCB)-dechlorinating inoculum eluted from upper Hudson River sediments was treated with either heat or ethanol or both. The treated cultures retained the ability to dechlorinate PCBs (Aroclor 1242) under strictly anaerobic conditions. The dechlorination activity was maintained in serial cultures inoculated with transfers of 1% inoculum when the transferred inoculum was treated each time in the same manner. No methane production was detected in any treated culture, although dechlorination of PCBs in the untreated cultures was always accompanied by methane production. All treated cultures preferentially removed meta chlorines, yielding a dechlorination pattern characterized by accumulation of certain ortho- and para-subsituted congeners such as 2-4-chlorobiphenyl (2-4-CB), 2,4-2-CB, and 2,4-4-CB. In contrast, the untreated cultures showed more extensive dechlorination activities, which almost completely removed both meta and para chlorines from Aroclor 1242. These results suggest that microorganisms responsible for the dechlorination of PCBs in the upper Hudson River sediments can be grouped into two populations according to their responses to the heat and ethanol treatments. Microorganisms surviving the heat and ethanol treatments preferentially remove meta chlorines, while microorganisms lost from the enrichment mainly contribute to the para dechlorination activity. These results indicate that anaerobic sporeformers are at least one of the physiological groups responsible for the reductive dechlorination of PCBs. The selection of a dechlorinating population by such treatments may be an important step in isolation of PCB-dechlorinating microorganisms.
Aroclors↗
Differential bioavailability of soil-sorbed naphthalene to two bacterial species.
Prediction of the fate of hydrophobic organic contaminants in soils is complicated by the competing processes of sorption and biodegradation. To test the hypothesis that sorbed naphthalene is unavailable to degradative microorganisms, we developed a simple kinetic method to examine the rates and extents of naphthalene degradation in soil-free and soil-containing systems in a comparison of two bacterial species. The method is predicated on the first-order dependence of the initial mineralization rate on the naphthalene concentration when the latter is below the Michaelis-Menten half-saturation constant (Km) for naphthalene for the organism under study. Rates and extents of mineralization were estimated by nonlinear regression analysis of data by using both a simple first-order model and a three-parameter, coupled degradation-desorption model described for the first time here. Bioavailability assays with two bacterial species (Pseudomonas putida ATCC 17484 and a gram-negative soil isolate, designated NP-Alk) gave dramatically different results. For NP-Alk, sorption limited both the rate and extent of naphthalene mineralization, in accordance with values predicted on the basis of the equilibrium aqueous-phase naphthalene concentrations. For strain 17484, both the rates and extents of naphthalene mineralization exceeded the predicted values and resulted in enhanced rates of naphthalene desorption from the soils. We conclude that there are important organism-specific properties which make generalizations regarding the bioavailability of sorbed substrates inappropriate.
Biodegradation, Environmental↗
Establishment of polychlorinated biphenyl-degrading enrichment culture with predominantly meta dechlorination.
Enrichment of polychlorinated biphenyl (PCB)-dechlorinating microorganisms from PCB-contaminated sediments from the Upper Hudson River, N.Y., was attempted. The enrichment strategy was to use pyruvate as the electron donor and dechlorination of Aroclor 1242 as the electron acceptor. The enrichment medium also contained non-PCB-contaminated Hudson River sediments, which were required for the PCB-dechlorinating activity. An enrichment culture (that had stable PCBT-dechlorinating activity over nine serial transfers during 1 year) was established under these conditions; however, the rate of dechlorination did not increase after the second serial transfer. Dechlorination occurred primarily from the meta positions of the biphenyl molecule. Hydrogen could be substituted for pyruvate as the electron donor with equal activity, but when acetate was used as the electron donor a delay in dechlorination was observed. Sulfate and bromethane sulfonate inhibited dechlorination activity. The pyruvate-Aroclor 1242 enrichment also dechlorinated Aroclors 1248, 1254, and 1260; the extent of chlorine removed was the greatest for Aroclor 1254. For comparison, nonautoclaved non-PCB-contaminated Hudson River sediments used in the assay also dechlorinated Aroclors, but only after 12 to 16 weeks of incubation. This suggests that PCB-dechlorinating organisms were also present in these sediments but in numbers lower than those in the enrichment culture.
Aroclors↗
Effects of angiotensinase inhibitors on plasma protein binding and IC50 determinations of renin inhibitors.
To establish whether the use of proteinase inhibitors in the routine determination of in vitro plasma renin activity overestimates the potency of renin inhibitors in vivo, we examined the effects of phenylmethylsulfonyl fluoride and 8-hydroxyquinoline sulfate on the binding to plasma proteins and the respective IC50 values (50% inhibiting concentrations) of three renin inhibitors. All three renin inhibitors, A-64662, A-65317, and A-74273, bound (> 60%) to plasma proteins at both pH 6.0 and 7.4, with slightly greater binding at pH 7.4. Phenylmethylsulfonyl fluoride (1.45 mmol/L) had no significant effect on the protein binding at either pH 6.0 or 7.4; 8-hydroxyquinoline sulfate (3.4 mmol/L) caused a modest dissociation (10-30%) of the renin inhibitors from plasma proteins at both pH values; and the effects of both proteinase inhibitors together were similar to those of 8-hydroxyquinoline alone. At pH 7.4, phenylmethylsulfonyl fluoride increased the potencies of the three renin inhibitors slightly (< or = 43%), whereas IC50 values determined in the presence of 8-hydroxyquinoline decreased by 1.5- to 3.7-fold. The greatest increase in potency occurred with the most hydrophilic compound, and with both angiotensinase inhibitors the effect was no greater than that of 8-hydroxyquinoline alone. The results show that any dissociation of the hypotensive activity measured in vivo from the plasma renin activity measured in vitro is not simply an artifact in the plasma renin activity assay stemming from the use of these angiotensinase inhibitors, especially if only phenylmethylsulfonyl fluoride is used.
Amides↗
Trimethylphenylammonium-smectite as an effective adsorbent of water soluble aromatic hydrocarbons.
Homoionic trimethylphenylammonium (TMPA)- and tetramethylammonium (TMA)-clays were prepared by ion-exchange reactions using two smectite clays that differed in their cation exchange capacities and surface charge densities. These clays are referred to as a low-charge (SAC) and high-charge (SWa)-smectite. The organo-clays were evaluated as adsorbents of water soluble aromatic hydrocarbons including benzene, toluene, ethylbenzene, p-xylene, butylbenzene, and naphthalene. All of the aromatic hydrocarbons tested were effectively removed from water by the low-charge TMPA-smectite. The low-charge TMA-smectite was an effective adsorbent for benzene but was ineffective in the removal of the alkylbenzenes and naphthalene from water. The effect of surface charge on the adsorption properties of TMPA-smectite was pronounced. The uptake of benzene and toluene by the high-charge TMPA-smectite was greatly reduced as compared to the low-charge TMPA-smectite. These results suggest the utility of TMPA-smectite as a liner material for petroleum storage containers and waste disposal reservoirs. The use of TMPA-smectite in conjunction with Na-smectite would provide a barrier with the ability to impede the flow of water and to effectively adsorb dissolved organic contaminants.
Adsorption↗
Dechlorination of chloroform by methanosarcina strains.
Dehalogenation of carbon tetrachloride, chloroform, and bromoform in pure cultures of Methanosarcina sp. strain DCM and Methanosarcina mazei S6 was demonstrated. The initial dechlorination product of chloroform was methylene chloride (dichloromethane), which accumulated transiently to about 70% of the added chloroform; trace amounts of chloromethane were also detected. The amount of chloroform dechlorinated per mole of methane produced was approximately 10 times greater than the ratio observed previously for tetrachloroethene dechlorination by these strains. The production of CO(2) from [C]chloroform and the absence of CH(4) imply that processes in addition to reductive dechlorination operate.
Journal Article↗
Dependence of tetrachloroethylene dechlorination on methanogenic substrate consumption by Methanosarcina sp. strain DCM.
Tetrachloroethylene (perchloroethylene, PCE) is a suspected carcinogen and a common groundwater contaminant. Although PCE is highly resistant to aerobic biodegradation, it is subject to reductive dechlorination reactions in a variety of anaerobic habitats. The data presented here clearly establish that axenic cultures of Methanosarcina sp. strain DCM dechlorinate PCE to trichloroethylene and that this is a biological reaction. Growth on methanol, acetate, methylamine, and trimethylamine resulted in PCE dechlorination. The reductive dechlorination of PCE occurred only during methanogenesis, and no dechlorination was noted when CH4 production ceased. There was a clear dependence of the extent of PCE dechlorination on the amount of methanogenic substrate (methanol) consumed. The amount of trichloroethylene formed per millimole of CH4 formed remained essentially constant for a 20-fold range of methanol concentrations and for growth on acetate, methylamine, and trimethylamine. These results suggest that the reducing equivalents for PCE dechlorination are derived from CH4 biosynthesis and that the extent of chloroethylene dechlorination can be enhanced by stimulating methanogenesis. It is proposed that electrons transferred during methanogenesis are diverted to PCE by a reduced electron carrier involved in methane formation.
Anaerobiosis↗
Reductive dechlorination of hexachlorobenzene to tri- and dichlorobenzenes in anaerobic sewage sludge.
Hexachlorobenzene was dechlorinated to tri- and dichlorobenzenes in anaerobic sewage sludge. The complete biotransformation of 190 microM hexachlorobenzene (approximately 50 ppm) occurred within 3 weeks. The calculated rate of hexachlorobenzene dechlorination was 13.6 mumol liter-1 day-1. Hexachlorobenzene was dechlorinated via two routes, both involving the sequential removal of chlorine from the aromatic ring. The major route was hexachlorobenzene----pentachlorobenzene----1,2,3,5-tetrachlorobenzene--- -1,3,5- trichlorobenzene. Greater than 90% of the added hexachlorobenzene was recovered as 1,3,5-trichlorobenzene, and there was no evidence for further dechlorination of 1,3,5-trichlorobenzene. The minor route was hexachlorobenzene----pentachlorobenzene----1,2,4,5-tetrachlorobenzene--- -1,2,4- trichlorobenzene----dichlorobenzenes. These results extend reductive dechlorination to poorly water soluble aromatic hydrocarbons which could potentially include other important environmental pollutants like polychlorinated biphenyls.
Bacteria, Anaerobic↗
Anaerobic bacteria that dechlorinate perchloroethene.
In this study, we identified specific cultures of anaerobic bacteria that dechlorinate perchlorethene (PCE). The bacteria that significantly dechlorinated PCE were strain DCB-1, an obligate anaerobe previously shown to dechlorinate chlorobenzoate, and two strains of Methanosarcina. The rate of PCE dechlorination by DCB-1 compared favorably with reported rates of trichloroethene bio-oxidation by methanotrophs. Even higher PCE dechlorination rates were achieved when DCB-1 was grown in a methanogenic consortium.
Bacteria, Anaerobic↗
Kinetics of phenol biodegradation by an immobilized methanogenic consortium.
A phenol-degrading methanogenic enrichment was successfully immobilized in agar as shown by the stoichiometric conversion of phenol to CH(4) and CO(2). The enrichment contained members of three physiological groups necessary for the syntrophic mineralization of phenol: a phenol-oxidizing bacterium, a Methanothrix-like bacterium, and an H(2)-utilizing methanogen. The immobilization technique resulted in the cells being embedded in a long, thin agar strand (1 mm in diameter by 2 to 50 cm in length) that resembled spaghetti. Immobilization had three effects as shown by a comparative kinetic analysis of phenol degradation by free versus immobilized cells. (i) The maximum rate of degradation was reduced from 14.8 to 10.0 mug of phenol per h; (ii) the apparent K(m) for the overall reaction was reduced from 90 to 46 mug of phenol per ml, probably because of the retention of acetate, H(2) and CO(2) in the proximity of immobilized methanogens; and (iii) the cells were protected from substrate inhibition caused by high concentrations of phenol, which increased the apparent K(i) value from 900 to 1,725 mug of phenol per ml. Estimates for the kinetic parameters K(m), K(i), and V(max) were used in a modified substrate inhibition model that simulated rates of phenol degradation for given phenol concentrations. The simulated rates were in close agreement with experimentally derived rates for both stimulatory and inhibitory concentrations of phenol.
Journal Article↗
Complete reductive dechlorination and mineralization of pentachlorophenol by anaerobic microorganisms.
Anaerobically digested municipal sewage sludge which had been acclimated to monochlorophenol degradation for more than 2 years was shown to degrade pentachlorophenol (PCP). Di-, tri-, and tetrachlorophenols accumulated when PCP was added to the individual acclimated sludges. When the 2-chlorophenol- (2-CP), 3-CP-, and 4-CP-acclimated sludges were mixed in equal volumes, PCP was completely dechlorinated. The same results were obtained in sludge acclimated to the three monochlorophenol isomers simultaneously. With repeated PCP additions, 3,4,5,-trichlorophenol, 3,5-dichlorophenol, and 3-CP accumulated in less than stoichiometric amounts. All chlorinated compounds disappeared after PCP additions were stopped. All chlorinated compounds disappeared after PCP additions were stopped. Incubations with [14C]PCP resulted in 66% of the added 14C being mineralized to 14CO2 and 14CH4. Technical-grade PCP was found to be degraded initially at a rate very similar to that of reagent-grade PCP, but after repeated additions, the technical PCP was degraded more slowly. Pentabromophenol was also rapidly degraded by the mixture of acclimated sludges. These results clearly show the complete reductive dechlorination of PCP by the combined activities of three chlorophenol-degrading populations.
Bacteria, Anaerobic↗