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1.
Keiji Tanaka Norio Kurihara Minoru Nakajima 《Pesticide biochemistry and physiology》1976,6(4):392-399
In lindane-treated house flies, a cis-dehydrogenated metabolite, , was identified by gas-liquid chromatography and mass spectrometry. The in vitro metabolism study showed that in the presence of NADPH the microsomal fraction of house flies converted lindane to three hexane-soluble metabolites. This conversion was inhibited by piperonyl butoxide, SKF-525A, and carbon monoxide. These metabolites were identified as , (PCCHE) by gas-liquid chromatography. They, as well as lindane, were excellent substrates for the reaction with the postmicrosomal fraction in the presence of glutathione. While the reaction with lindane-d6 showed a significant deuterium isotope effect (6.82), that of did not (1.18). Enzymatic conjugation with glutathione probably occurs at the stage of PCCHE. 相似文献
2.
Takaaki Nishioka Toshio Fujita Katsuzo Kamoshita Minoru Nakajima 《Pesticide biochemistry and physiology》1977,7(2):107-121
The association equilibrium constant, , and the carbamylation constant, k2, of 53 o-, m-, and p-substituted phenyl N-methylcarbamates with bovine erythrocyte acetylcholinesterase were determined. The value varied 1000-fold, whereas the k2 value did not depend upon the nature and position of substituents. The variation in was analyzed using free energy related substituent parameters and regression analyses. The effect of substituents at o-, m-, and p-positions was nicely separated into hydrophobic, electronic, hydrogen bonding, and proximity (steric and field electronic for o-substituents) factors. The physicochemical significance of these factors was established by comparison with those for model organic reactivities. The mechanism of the whole reaction process was elucidated in terms of physical organic chemistry. 相似文献
3.
Methomyl {S-methyl-N-[(methylcarbamoyl)oxy]thioacetimidate}, also known as Lannate, may exist in two geometric configurations but the more stable syn isomer is the form applied as an insecticide. In the rat, syn[14CN]methomyl [CH3S(CH3)CNOC(O)NHCH3] was metabolized to respiratory 14CO2 and in a ratio of about 2 to 1. Studies with the anti isomer showed that it was metabolized predominately to . These and other data are presented supporting the contention that syn methomyl is partially isomerized to the anti isomer in the animal prior to the hydrolysis of the ester linkage. After hydrolysis, the syn oxime [CH3S(CH3)14CNOH] is further metabolized to 14CO2 while the anti oxime is metabolized to . Proposed immediate precursors to the carbon dioxide and acetonitrile, formed by Beckmann rearrangement of the syn and anti oximes, are CH3S14C(O)NHCH3 and , respectively. 相似文献
4.
The toxicity of the (R)P and (S)P chiral isomers and racemates of fonofos and fonofos oxon to insects and white mice were determined. (R)P-Fonofos and (S)P-fonofos oxon were 2- to 12-fold more toxic to house flies, mosquito larvae, and mice than were the corresponding enantiomers. The racemates were intermediate in toxicity. Stereoselectivity also was observed in the in vitro inhibition of house fly-head and bovine erythrocyte acetylcholinesterase, horse serum cholinesterase, chymotrypsin, trypsin, and a variety of esterases. In all cases the (S)P-oxon was a more potent inhibitor than the (R)P-oxon with k1 ratios of ranging from 4- to 60-fold. Further, differences in levels of house fly-head, mouse brain, and blood cholinesterase obtained from house flies and mice treated with the enantiomers and racemates of fonofos and fonofos oxon were observed. Differences in toxicity of the enantiomers and racemates to house flies and mice were more closely related to in vivo than to in vitro cholinesterase inhibition. 相似文献
5.
Captan, folpet, and perchloromethylmercaptan were effective inhibitors of Penicillium duponti p-nitrophenylpropionate esterase activity (I50 = 0.5 – 2 μM) whereas α-naphthyl acetate esterase activity was not affected by the presence of these compounds. Captan and folpet are both equally effective at pH 7.3 and 8.3. The ionic composition of the medium had strong effects on the degree of inhibition produced by all inhibitors but did not alter esterase activity. Neither succinamide nor phthalimide caused inhibition of the p-nitrophenylpropionate esterase activity: The trichloromethylmercaptan portion of these fungicides appears to be responsible for the observed inhibition. The rapidity of captan and folpet inhibition of esterase activity (complete in < 1 min) compared to the rates of spontaneous decomposition () and the insensitivity of captan and folpet inhibition to hydrogen ion concentration suggest that generation of spontaneous decomposition products is not required for inhibition. The results are consistent with a mechanism in which the entire fungicide molecule binds to the protein followed by enzyme-promoted reactions of captan and folpet which result in loss of esterase activity. 相似文献
6.
The organophosphorus insecticides, parathion and azinphos (10?5-10?4M), significantly stimulate the Ca2+-pump activity of sarcoplasmic reticulum, while malathion has a limited effect. The rates of Ca2+ translocation and ATP hydrolysis are both stimulated and, apparently, the ratio is improved. Parathion and azinphos maximally increase this ratio by 26 and 14%, respectively. The organochlorine compounds, DDT and aldrin, also stimulate the Ca2+ pump, and lindane has a reduced effect. These effects are smaller than those observed for parathion and azinphos. The order of effectiveness is similar to the toxicity of the compounds to mammals and can be described as follows: parathion > azinphos > DDT ≈ aldrin > malathion ≈ lindane. 相似文献
7.
The effect of phenobarbital and certain pesticides on glutathione S-transferase activity was investigated. The maximum amount of enzyme induction occurred 96 hr after phenobarbital treatment. Chlorinated hydrocarbons were more effective inducers than the other pesticides evaluated. Phenobarbital treatment did not alter the apparent Km value but altered the value of glutathione S-transferase to 3,4-dichloronitrobenzene. The amount of reduced glutathione was not increased by phenobarbital treatment. Pretreatment of house flies with phenobarbital provides some protection against methyl parathion, methyl paraoxon, azinphosmethyl, and methidathion toxicity. 相似文献
8.
A rat hepatocyte suspension effectively epoxidized aldrin to dieldrin with a Vmax of 7.19 mol/mol P-450/min and a Km of 9.27 μM. Viability and metabolic activity were stable for 6 hr after isolation when cells were maintained at room temperature (20°C) with the gentle introduction of onto the surface of the suspension. The cytochrome P-450 content of the suspension was 303 pmol/106 cells. Primary maintenance culture of the cells also epoxidized aldrin. During culture for 3 days, metabolic activity decreased slowly day by day. Metabolic activity of microsomal fraction from rat liver was also examined. Microsomes epoxidized aldrin with a Vmax of 5.11 mol/mol P-450/min and a Km of 1.64 μM. Significant loss of some subspecies of cytochrome P-450 during fractionation of liver homogenate was indicated. 相似文献
9.
A variety of membrane-specific parameters was examined in both intact cells and isolated plasma membranes following exposure of cultured human liver cells to the insecticide 1,1-(2,2,2-trichloroethylidene)bis(4-chloro)benzene (DDT). Uptake of DDT was at equilibrium within 6 hr. In contrast, a decrease in the number of β-adrenergic hormone receptors first became significant after 48 hr of cell exposure. Whereas the uptake was largely reversible, the loss in the number of β receptors did not recover after DDT-exposed cells were cultured in fresh medium lacking the insecticide. Experiments in vitro substantiated the time lag of the biological effect. The decrease in receptor proteins was persistent in membranes with increased phospholipid unsaturation. Temperature-activity profiles (“Arrhenius plots”) of and 5′-nucleotidase were unchanged. Endogenous tryptophan fluorescence of membrane proteins was lower in membranes from DDT-exposed cells. These selective alterations in membrane parameters suggest a specific interaction of DDT with membrane proteins; interference with cellular protein synthesis is possible. The results indicate that membrane lipid “fluidization” does not play a physiologically important role in the mechanism of DDT action in biomembranes. 相似文献
10.
The metabolic fate of six 3H-ring-substituted ethoxychlor analogs with altered aliphatic moieties and [14C]p,p′-DDT was investigated in susceptible and DDT-resistant strains of the house fly Musca domestica Linnaeus. The chloroalkane analogs, dichloroethane, chloropropane, and dichloropropane were primarily metabolized to the corresponding dehydrochlorinated products. This pathway was relatively more prominent in the resistant strain than in the susceptible strain. Biotransformation and detoxication of the isobutane, nitropropane, and neopentane derivatives was through microsomal oxidation (O-deethylation) of aryl ethoxy degradophores, and oxidation of the aliphatic moieties to produce the corresponding benzophenones, with no substantial differences between the resistant and susceptible strain. There was a strong correlation between the Taft () values for the altered aliphatic moieties of chloroalkane analogs and their rate of dehydrochlorination in both the strains. These results suggest the importance of altered aliphatic moieties in developing resistance-proof DDT derivatives. 相似文献
11.
The toxic action of a series of O-alkyl, O-substituted-phenyl alkyl- and aryl-phosphonates and phosphonothionates have been evaluated by correlating the linear free energy parameters for steric (Es), electronic (σ), and polar () effects with topical LD50 to the house fly and oral LD50 to the white mouse. In molecules free from major steric interactions with the reactive P atom, variations in these linear free energy parameters account for >90% of the variations in the LD50 values, and the degree of correlation with LD50 is at least as precise as that with the biomolecular rate constants for inhibition of the target-site enzyme acetylcholinesterase. The value of correlations of linear free energy parameters with LD50 in understanding quantitative structure-activity relationships is illustrated. 相似文献
12.
Norio Kurihara Keiji Tanaka Minoru Nakajima 《Pesticide biochemistry and physiology》1979,10(2):137-150
4-Chloro-, 2,4-dichloro-, 3,4-dichloro-, 2,3,5-trichloro-, and 2,4,5-trichlorophenylmercapturic acids were identified as main metabolites of lindane, γ-isomer of 1,2,3,4,5,6-hexachloro-cyclohexane, in rat urine. Pathways to these metabolites were shown to include as the most important intermediary metabolite. and also seem to be involved in these pathways, while plays a minor role in the pathway. Glutathione conjugation, using the rat liver soluble fraction, occurred directly on the polychlorocyclohexenes, not on their further transformed products. In in vivo biodegradation, may be dechlorinated and dehydrochlorinated at the endoplasmic reticulum before it undergoes the glutathione conjugation in cytosol, although other polychlorocyclohexenes generally react in a manner similar to that in the in vitro reaction. 相似文献
13.
A.A. Brimfield J.C. Street Jean Futrell Dale A. Chatfield 《Pesticide biochemistry and physiology》1978,9(1):84-95
The metabolism of pure cis- and trans-chlordane was studied in vitro. Microsomal preparations from the livers of male rats induced with cis- or trans-chlordane in feed for 10 days were used to metabolize the pure compound corresponding to the inducer. Subsequent extraction, column fractionation, and combined gas chromatography-mass spectroscopy resulted in the characterization of four compounds not previously reported from an in vitro system. In addition to the substrate, trans-chlordane extracts contained species with the following molecular weights and empirical formulas: 370, C10H5Cl7, heptachlor; 352, C10H6OCl6, a hydroxylated chlordene; and 422, C10H6OCl8, a hydroxylated chlordane. Dichlorochlordene, oxychlordane, and 1-chloro-2-hydroxy-dihydrochlordene were also present. With the exception of the hydroxychlordane, cis-chlordane extracts contained all of the metabolites found in the trans incubates. Additionally, a fully saturated compound, 372, C10H7Cl7, a dihydroheptachlor, was present. The 1,2-trans-dihydrodiol of heptachlor found in previous in vitro incubates of cis-chlordane was not present in this extract. This information has been incorporated into a proposed route for the biotransformation of the chlordanes that offers an explanation for the observed differences in the metabolism of cis and trans isomers. The pathway is based on the reductive dechlorination of the chlordanes through dihydroheptachlor to dihydrochlordene. Parallel pathways of hydroxylation, desaturation, and epoxide formation arise at each of these species and at chlordane itself. 相似文献
14.
Keiji Tanaka Jeffrey G. Scott Fumio Matsumura 《Pesticide biochemistry and physiology》1984,22(1):117-127
The nature of the picrotoxinin receptor was studied using the central nervous system (CNS) of the American cockroach. It first was confirmed by using an electrophysiological technique that the abdominal nerve cord of the American cockroach was sensitive to picrotoxinin. By using a binding test it was determined that the picrotoxinin receptor in CNS of this insect had a higher affinity toward picrotoxinin and heptachlor epoxide than the corresponding receptor in the rat brain. Also, the cockroach brain preparation had a higher percentage of specific binding in the total binding, making this material suitable for receptor studies. By using a sucrose density centrifugation technique, it was determined that the fraction sedimented at the interphase of 1.0 to 1.2 M sucrose at 100,000g contained the highest level of specific binding site. The receptor showed a sensitivity to all insecticidal cyclodienes tested, namely photodieldrin, oxychlordane, endrin, heptachlor epoxide, γ-chlordane, dieldrin, aldrin, heptachlor, and isodrin (expressed in the order of potency). Among four BHC isomers, the γ-isomer showed the highest potency to bind with this receptor. 相似文献
15.
Male feral pigeons were dosed with ring-labeled and the tissues and droppings analyzed for total 14C, extractable 14C, and metabolites. Only 16% of an intraperitoneal dose of 1.5–2.2 mg kg?1 was voided in the droppings over 28 days; the rate of loss reached a maximum on the 14th day and then fell quickly away. The rate of removal of 14C in droppings was low in comparison to that found in the rat and the Japanese quail. When pigeons were dosed with 32–38 mg kg?1 DDT per bird, and killed after 77 days, 5.4% of the dose was eliminated in droppings and 87% was recovered in the body. The tissues and droppings from this experiment were analyzed for DDT and its metabolites. Of the 14C remaining in tissues 88% was accounted for as the apolar compounds DDE, DDT, and DDD. Approximately half of the 14C in droppings was present as DDE, DDT, and DDD, whereas 27–35% was apparently in conjugated form, extractable from aqueous solutions by ethyl acetate after prolonged acid hydrolysis. Two polar metabolites were isolated from the acid-released material. One was p,p′-DDA; the other was extractable from aqueous solution at pH 8 and was tentatively identified as a monohydroxy derivative of p,p′-DDT. DDE accounted for 93% of the 14C present as metabolites in tissues and droppings, clearly indicating the importance of this intermediate in this study. The metabolism of DDT in the feral pigeon is discussed in relation to its metabolism by other species. 相似文献
16.
Keiji Tanaka Minoru Nakajima Norio Kurihara 《Pesticide biochemistry and physiology》1981,16(2):149-157
The factors which cause lindane resistance in the Third Yumenoshima strain, a strain of house flies highly resistant to insecticides, were studied using hexadeuterated lindane. Hexadeuterated lindane has the same physicochemical properties as lindane, but the former is much less biodegradable than the latter. The LD50 ratio of lindane to hexadeuterated lindane in this strain, deuterium isotope effect on LD50 values, was larger than that in SNAIDM, a susceptible (nonresistant) strain. The penetration rates of labeled and nonlabeled lindane through the insect cuticle were about the same for both strains. Thus, penetration rate does not cause resistance. The metabolic degradation of lindane in the resistant strain in vivo occurred much faster than in the susceptible strain. This was also the case for lindane degradation processes in vitro such as microsomal oxidation and glutathione conjugation. In both strains, significant isotope effects were observed in the degradation rates in vitro of labeled and nonlabeled lindane. Therefore, principal biodegradation and detoxication pathways should include reactions which cleave the CH bonds. When the much less biodegradable d6 counterpart of lindane was applied to both strains, the susceptible strain became much more highly intoxicated than the other within 20 to 30 min. This indicates that a combination of both greater degradability and probably lower sensitivity at the action site are the main factors underlying resistance in the Third Yumenoshima strain. 相似文献
17.
P.T. Lin A.R. Main N. Motoyama W.C. Dauterman 《Pesticide biochemistry and physiology》1983,20(2):232-237
The hydrolysis of malation by rabbit liver oligomeric and monomeric carboxylesterases (CE's) (EC 3.1.1.1) results in the formation of a mixture of α- and β-monoacids. A new chromatographic procedure was utilized to investigate the formation of α- and β-monoacids. The oligomeric carboxylesterase (oCE) produced an ratio of monoacids of 4.55, and the monomeric carboxylesterase (mCE) produced an ratio of monoacids of 2.33. The ratios of α- and β-monoacids were independent of the initial concentration of malathion and remained constant over the time course of the reaction. Kinetic studies demonstrated that the Km values were the same for the corresponding reactions which produced either α-monoacid or β-monoacid with the same enzyme. Since both carboxylesterases are electrophoretically pure, the kinetic data strongly supports the theory that the reactions which produced α- and β-monoacids are catalyzed by the same active site. Comparison of the kcat and Km values governing the hydrolysis of malathion by the two esterases, together with their relative abundance in liver, indicated that the oCE would be responsible for about 80 to 98% of the hydrolytic detoxication of malathion by rabbit liver. 相似文献
18.
Kuo-Mei Chang C.F. Wilkinson Krystyna Hetnarski 《Pesticide biochemistry and physiology》1981,15(1):32-42
Characteristics of the Type III optical difference spectra of 13 methylenedioxyphenyl compounds in NADPH-fortified armyworm midgut microsomes varied with the nature of the substituents in the aromatic ring. Compounds with electron-donating substituents yielded spectra with large peak ratios, whereas those with electron-withdrawing groups exhibited low peak ratios. Small amounts of carbon monoxide were generated during incubation of the 4,5-dihalo derivatives with midgut microsomes, and cis- and trans-methylenedioxycyclohexanes exhibited spectra with a major Soret peak at about 430 nm and a very weak absorbance maximum at about 480 nm. Formation of the Type III spectral complex occurred very rapidly and was associated with a marked decrease (up to 72%) in cytochrome P-450 levels as measured by carbon monoxide binding. Although a 24% reduction of cytochrome P-450 was observed in the absence of any measureable 458-nm spectral complex a linear relationship existed between further decreases in the cytochrome and the increase in Type III complex formation (458 nm). Inhibitory potencies of the compounds towards aldrin epoxidase and benzopyrene hydroxylase activities were not clearly correlated with either spectral complex formation or decrease in cytochrome P-450 and it is apparent that different factors are involved in the inhibition of different monooxygenase reactions. 相似文献
19.
Robert W. Rickard Gerd Walter-Echols L.Jeffry Lawrence H.Wyman Dorough 《Pesticide biochemistry and physiology》1982,18(3):325-333
Formation of the nitroso derivatives of 14C-labeled carbaryl, carbofuran, and p-chlorophenyl methylcarbamate (PCMC), and their subsequent stabilities were investigated using low levels of carbamate (0.5 μmol) and aqueous HCl concentrations encompassing those considered maximum for the gastric contents of humans (pH 1–2) and of rats (pH 3–4). Reacting the carbamates with excess sodium nitrite for 10 min at 37°C in a pH 1.0 HCl solution gave nitrosocarbamate yields of 42 to 64%, while only trace amounts were formed at pH 2 and above. The nitrosocarbamates were most stable at pH 3–5 with half-lives ranging from 114 to 470 min. Stability of all three nitroso derivatives was considerably less at pH 1.5 (, 25–34 min), but at pH 7 the stability varied: nitroso-PCMC , 6 min; nitrosocarbofuran , 70 min; nitrosocarbaryl , 139 min. Denitrosation to the parent carbamate was the predominant degradation pathway at pH 1.5, but at pH 3–7 degradation was primarily by hydrolysis of the carbamate ester linkage. Each of the nitrosocarbamates was directly mutagenic in the S. typhimurium assay system. Since the data show that nitrosation of residue levels of carbamate pesticides occurs readily at pH 1 but not at pH 2 and above, it is critical that gastric contents of any animal model used for assessing nitrosocarbamate formation have a pH approaching 1 as may occur in the human stomach. 相似文献