Studies on the chiral isomers of fonofos and fonofos oxon: II. In vitro metabolism     

Philip W. Lee  Reza Allahyari  T.Roy Fukuto 《Pesticide biochemistry and physiology》1978,8(2):158-169

The in vitro metabolism of the chiral isomers of fonofos and fonofos oxon in the presence of mouse liver mixed-function oxidase and serum esterase was investigated. The metabolism of ³⁵S-labeled phenyl-(S)_P-fonofos mediated by mixed-function oxidase took place stereoselectively, resulting predominantly in (R)_P-fonofos oxon. Similarly, (R)_P-fonofos was converted to (S)_P-oxon. In each case, however, a significant amount of racemization occurred. Other products were diphenyl disulfide and diphenyl disulfide oxide. In addition to stereospecificity, the oxidative metabolism of (R)_P-fonofos proceeded at a rate faster than that of (S)_P-fonofos. Stereoselective rate differences also were observed in mouse or rat serum-catalzyed degradation of the fonofos oxon enantiomers, the (S)_P isomer being degraded about twofold faster than its enantiomer. The differences in toxicities of the isomers of fonofos and fonofos oxon were consistent with the in vitro metabolism data.  相似文献   

Studies on the chiral isomers of fonofos and fonofos oxon: III. In vivo metabolism     

Philip W. Lee  Reza Allahyari  T.Roy Fukuto 《Pesticide biochemistry and physiology》1978,9(1):23-32

The metabolism of the chiral isomers of ³⁵S-labeled fonofos was examined in the house fly and white mouse. Metabolism of the chiral isomers of fonofos oxon also was investigated in the mouse. Little difference in either the rate of penetration or pattern of metabolism was observed between house flies treated with the (R)_P and (S)_P enantiomers of fonofos. At the higher dosage of 8 mg/kg the less toxic (S)_P enantiomer was degraded in mice and eliminated in significantly larger amounts than (R)_P-fonofos. However, at the sublethal dosage of 4 mg/kg little difference in degradation and total elimination was observed between the two isomers although the excretion rate appeared to be faster initially with the less toxic enantiomer. Overall, metabolism and excretion of the chiral isomers of both fonofos and fonofos oxon took place more rapidly and to a greater extent with the less toxic enantiomer.  相似文献   

Induction of glutathione S-transferase by phenobarbital and pesticides in various house fly strains and its effect on toxicity     

T. Hayaoka  W.C. Dauterman 《Pesticide biochemistry and physiology》1982,17(2):113-119

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 K_m value but altered the $\text{V}{}_{\mathrm{<mtext>max</mtext>}}$ 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   

Isomerization and Beckmann rearrangement reactions in the metabolism of methomyl in rats     

Kurt Huhtanen  H.Wyman Dorough 《Pesticide biochemistry and physiology》1976,6(6):571-583

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[¹⁴CN]methomyl [CH₃S(CH₃)CNOC(O)NHCH₃] was metabolized to respiratory ¹⁴CO₂ and $\text{CH}{}_3{}^{14}\text{CN}$ in a ratio of about 2 to 1. Studies with the anti isomer showed that it was metabolized predominately to $\text{CH}{}_3{}^{14}\text{CN}$. 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)¹⁴CNOH] is further metabolized to ¹⁴CO₂ while the anti oxime is metabolized to $\text{CH}{}_3{}^{14}\text{CN}$. Proposed immediate precursors to the carbon dioxide and acetonitrile, formed by Beckmann rearrangement of the syn and anti oximes, are CH₃S¹⁴C(O)NHCH₃ and $\text{[}\text{CH}{}_3{}^{\mathrm{14\oplus }}\text{CNSCH}{}_3\text{]x}{}^{\mathrm{?}}$, respectively.  相似文献   

Metabolism of lindane in house flies: Metabolic desaturation,dehydrogenation and dehydrochlorination,and conjugation with glutathione     

Keiji Tanaka  Norio Kurihara  Minoru Nakajima 《Pesticide biochemistry and physiology》1976,6(4):392-399

In lindane-treated house flies, a cis-dehydrogenated metabolite, $\text{(}\text{36}\text{45}\text{)-}\text{hexachlorocyclohexene}$, 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 $\text{(}\text{36}\text{45}\text{)-}\text{hexachlorocyclohexene}$, $\text{(}\text{36}\text{45}\text{)- and (}\text{346}\text{5}\text{)-pentachlorocyclohexene}$ (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 $\text{(}\text{36}\text{45}\text{)-}\text{PCCHE-d}{}_5$ did not (1.18). Enzymatic conjugation with glutathione probably occurs at the stage of PCCHE.  相似文献   

Metabolism of O,O-dimethyl S-[α-carboethoxy)benzyl]phosphorodithioate (phenthoate) in the white mouse and house flies     

Dennis Y. Takade  Thurman Allsup  Abdallah Khasawinah  T.S. Kao  T.R. Fukuto 《Pesticide biochemistry and physiology》1976,6(4):367-376

The metabolism of O,O-dimethyl S-[α-(carboethoxy)benzyl]phosphorodithioate (phenthoate), an organophosphorus insecticide of low mammalian toxicity, was investigated in white mice and in susceptible and resistant strains of house flies. Phenthoate was metabolized rapidly in the mouse to a wide variety of detoxication products and only an insignificant amount of phenthoate oxon was detected. The same detoxication products were produced in house flies but, compared to the mouse, substantial amounts of phenthoate oxon also were found. The selective toxicity of phenthoate between insect and mammal is attributable to the difference in the accumulation of the oxon.  相似文献   

Neurophysiological activity and toxicity of pyrethroids derived by addition of methylene,sulfur or oxygen to the chrysanthemate 2-methyl-1-propenyl substituent     

Luis O. Ruzo  John E. Casida  Derek W. Gammon 《Pesticide biochemistry and physiology》1984,21(1):84-91

Conversion of chrysanthemates to their cyclopropane, episulfide, and epoxide derivatives by addition of methylene, sulfur, or oxygen, respectively, to the 2-methyl-1-propenyl double bond yields products generally of reduced toxicity but enhanced neurophysiological activity and photostability. The reduced toxicity is established with cis-cyphenothrin derivatives administered intracerebrally to mice and topically to house flies and with cis-phenothrin derivatives applied topically to American cockroaches and house flies, even in the presence of piperonyl butoxide for the house flies. In contrast, cyclopropane, episulfide, and epoxide derivatives of phenothrin are more potent than the parent compound in eliciting repetitive firing following stimulation of a cercal sensory nerve of the American cockroach in vitro. The individual 1′R and 1′S isomers of epoxides derived from (1R,cis,αS)cyphenothrin, (1R,cis)phenothrin, and (1R,trans)tetramethrin differ in potency by up to 20-fold for insecticidal activity, >30-fold for intracerebral toxicity to mice, and ～100,000-fold in the cercal sensory nerve assay. In each case the epoxide isomer of higher R_f is more potent than that of lower R_f when derived from a trans-chrysanthemate and vice versa from a cis-chrysanthemate.  相似文献   

Mechanism of inhibition reaction of acetylcholinesterase by phenyl N-methylcarbamates: Separation of hydrophobic,electronic, hydrogen bonding and proximity effects of aromatic substituents     

Takaaki Nishioka  Toshio Fujita  Katsuzo Kamoshita  Minoru Nakajima 《Pesticide biochemistry and physiology》1977,7(2):107-121

The association equilibrium constant, $\text{1}\text{K}{}_{\mathrm{d}}$, and the carbamylation constant, k₂, of 53 o-, m-, and p-substituted phenyl N-methylcarbamates with bovine erythrocyte acetylcholinesterase were determined. The $\text{1}\text{K}{}_{\mathrm{d}}$ value varied 1000-fold, whereas the k₂ value did not depend upon the nature and position of substituents. The variation in $\text{log}\text{(}\text{1}\text{K}{}_{\mathrm{d}}\text{)}$ 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   

Cytochrome P-450 content and aldrin epoxidation to dieldrin in isolated rat hepatocytes     

Norio Kurihara  Nobuaki Hori  Reiji Ichinose 《Pesticide biochemistry and physiology》1984,21(1):63-73

A rat hepatocyte suspension effectively epoxidized aldrin to dieldrin with a V_max of 7.19 mol/mol P-450/min and a K_m 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 $\text{O}{}_2\text{CO}{}_2$ 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 V_max of 5.11 mol/mol P-450/min and a K_m of 1.64 μM. Significant loss of some subspecies of cytochrome P-450 during fractionation of liver homogenate was indicated.  相似文献   

Deuterium isotope effects on the formation of mercapturic acids from lindane in rats     

Norio Kurihara  Tetsuya Suzuki  Minoru Nakajima 《Pesticide biochemistry and physiology》1980,14(1):41-49

Metabolism experiments with rats showed that significant isotope effects ($\text{k}{}_{\mathrm{<mtext>H</mtext>}}\text{k}{}_{\mathrm{<mtext>D</mtext>}}\text{= 2.4}\text{to}\text{3.5}$) were associated with the in vivo formation of dichloro and trichlorophenylmercapturic acids from a 1:1 mixture of normal and hexadeuterated lindane. This is evidence that rate-determining dehydrogenation and dehydrochlorination, both of which proceed with significant isotope effects, are essential in the pathway of dichloro- and trichlorophenylmercapturic acid formation from lindane. No significant primary isotope effects were associated ($\text{k}{}_{\mathrm{<mtext>H</mtext>}}\text{k}{}_{\mathrm{<mtext>D</mtext>}}\text{= 1.31 ± 0.17}$) with the formation of monochlorophenylmercapturic acid. This suggests that the 1,2-dechlorination to tetrachlorocyclohexene followed by glutathione conjugation is the probable pathway that produces this metabolite from lindane.  相似文献   

Affinity and phosphonylation constants for the inhibition of cholinesterases by the optical isomers of O-2-butyl S-2-(dimethylammonium)ethyl ethylphosphonothioate hydrogen oxalate     

D.A. Wustner  T.R. Fukuto 《Pesticide biochemistry and physiology》1974,4(3):365-376

The synthesis of the four optical isomers of known absolute configuration of O-2-butyl S-2-(dimethylammonium)ethyl ethylphosphonothioate hydrogen oxalate is described. Values for the affinity constant (K_a), phosphonylation constant (k_p), and bimolecular inhibition rate constant (k_i) for the inhibition of bovine erythrocyte acetylcholinesterase, housefly-head acetylcholinesterase, and horse serum cholinesterase by the chiral isomers and the racemic mixture are reported. Using a relatively simple spectrophotometric technique, inhibition times as low as 0.5 sec were used. The phosphorus isomers of S_p configuration were more potent inhibitors than their R_p enantiomers by 1630-fold against the bovine enzyme, 9120-fold against the fly-head enzyme, and 40-fold against the horse serum enzyme. The differences in anticholinesterase activity were attributable to differences in the affinity constant, K_a, and the phosphonylation constant, k_p. Small but consistent inhibition rate differences were attributable to asymmetry at carbon. Against horse serum cholinesterase, the S_C isomers indicated the presence of three kinetic forms in this enzyme preparation.  相似文献   

Aryl N-methoxy-N-methylcarbamates: Potent competitive reversible inhibitors of cholinesterases     

D.A. Wustner  Cecil Smith  T.R. Fukuto 《Pesticide biochemistry and physiology》1978,9(3):281-292

A series of 27 substituted aryl N-methoxy-N-methylcarbamates were synthesized and their ability to reversibly inhibit house fly-head and bovine-erythrocyte acetylcholinesterase and horse-serum cholinesterase was determined. These compounds were all competitive, reversible inhibitors of bovine erythrocyte acetylcholinesterase but some of them showed mixed competitive inhibition against the house fly-head and horse-serum enzymes. Dissociation constants (K_i) as small as 9.9 × 10^?9M and as large as 1.4 × 10^?4M were observed. A highly satisfactory correlation between log K_i for the inhibition of fly-head acetylcholinesterase by the N-methoxy-N-methylcarbamates and ?log I₅₀ for the inhibition of the same enzyme by the corresponding methylcarbamates was noted. Analysis of the anticholinesterase data by multiple regression showed -log K_i to be related to Hansch's π constant and ring position terms. The results indicate that reversible binding of these compounds to acetylcholinesterase occurs by hydrophobic bonding.  相似文献   

Steric,electronic, and polar parameters that affect the toxic actions of O-alkyl,O-phenyl phosphonothionate insecticides     

Robert L. Metcalf  Robert A. Metcalf 《Pesticide biochemistry and physiology》1984,22(2):169-177

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 (E_s), electronic (σ), and polar ($\text{σ}{}^1$) 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   

Inhibition of Penicillium duponti carboxylesterase by the fungicides captan and folpet     

Karl Neidert  Lee Van Epps  William Welch 《Pesticide biochemistry and physiology》1985,23(2):221-227

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 ($\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}\text{> 1}\text{min}$) 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   

Metabolism of O,S-dimethyl propionyl- and hexanoylphosphoramidothioate in the house fly and white mouse     

Teh-Show Kao  T.R. Fukuto 《Pesticide biochemistry and physiology》1977,7(1):83-95

The metabolism of O,S-dimethyl propionyl- and hexanoylphosphoramidothioate was investigated in the white mouse and house flies. Compared to the hexanoylphosphoramidothioate, the propionyl analog is approximately 35-fold more toxic to house flies and is 10-fold less toxic to mice. On a percentage basis, substantially larger amounts of methamidophos were detected in house flies treated topically with the propionylphosphoramidothioate than in flies treated with the hexanoyl derivative. The reverse was evident in the case of the mouse where much larger amounts of methamidophos were formed after oral treatment with the hexanoylphosphoramidothioate. Minor amounts of other metabolic products also were detected, including an unknown from the hexanoylphosphoramidothioate. Metabolism of the S-methyl moiety to carbon dioxide appeared to be a major pathway for metabolic degradation of both compounds in both the white mouse and house fly. The difference in toxicity of the two acylphosphoramidothioates to the mouse and house fly is attributed to difference in the amounts of methamidophos formed in the animals.  相似文献   

Enantioselective degradation kinetics of metalaxyl in rabbits     

Jing Qiu 《Pesticide biochemistry and physiology》2005,83(1):1-8

Metalaxyl [methyl-N-(2′-methoxyacetyl)-N-(2,6-dimethylphenyl)-d,l- alaninate] is a potent phenylamide fungicide. The (−)-(R)-isomer accounts for most of the fungicidal activity. A possible stereo and/or enantioselective kinetics of metalaxyl in rabbits was investigated by intravenous injection. The concentrations of (−)-(R)- and (+)-(S)-metalaxyl in plasma, liver, and kidney tissue were determined by HPLC with a cellulose-Tris-(3,5-dimethylphenylcarbamate)-based chiral stationary phase and gas chromatography-mass spectroscopy. After intravenous administration of racemic metalaxyl (40 mg/kg), the (+)-(S)-enantiomer levels in plasma, liver, and kidney decreased more rapidly than the (−)-(R)-isomer. The area ratio of the (−)-(R)-/(+)-(S)-enantiomer under the concentration-time curve (AUC_0 → ∞) in plasma after drug application was 1.62. The total plasma clearance value of the (+)-(S)-enantiomer was 1.53 and higher than that of the (−)-(R)-enantiomer. The [R]/[S] ratio in plasma was >1 for standard rac-metalaxyl at each time point. The other pharmacokinetic parameters of the enantiomers were also different. The results indicate substantial stereoselectivity in the degradation of metalaxyl enantiomers in rabbits.  相似文献   

Metabolism of the 1,2,4-triazolylmethane fungicides,triadimefon, triadimenol,and diclobutrazol,by Aspergillus niger (van Tiegh.)     

A.H.B. Deas  D.R. Clifford 《Pesticide biochemistry and physiology》1982,17(2):120-133

Metabolism of the triazolylmethane fungicides triadimefon, triadimenol, and diclobutrazol by Aspergillus niger was studied using a replacement culture technique and ¹⁴C substrates. Components of metabolite mixtures were characterized by TLC, GLC, radio-GC, and GC-MS analyses of the free materials and their trifluoroacetate and trimethylsilyl ether derivatives. The three compounds underwent a common metabolic change involving oxidation of C(CH₃)₃ to C(CH₃)₂CH₂OH. In this work the isopropyl analog of triadimefon, previously reported as a metabolite, was an artifact and resulted from nonbiological oxidation of the corresponding primary alcohol. The fungus also reduced triadimefon to triadimenol, giving a mixture of 1R2S, 1S2R and 1R2R, 1S2S diastereoisomers. The less fungitoxic 1R2S, 1S2R triadimenol predominated, so that this conversion may be directly associated with the relative insensitivity of A. niger to triadimefon. Implications of oxidative and reductive metabolism of these fungicides are suggested with particular reference to the differing fungitoxicities of diastereoisomers and enantiomers.  相似文献   

Decreased nerve sensitivity and decreased cuticular penetration as mechanisms of resistance to pyrethroids in a (1R)-trans-permethrin-selected strain of the house fly     

Donald H. DeVries  George P. Georghiou 《Pesticide biochemistry and physiology》1981,15(3):234-241

A fenthion-resistant strain of the house fly (Musca domestica L.) was selected with bioresmethrin resulting in ca. 90-fold resistance to the selecting agent. This strain was subsequently selected with (1R)-trans-permethrin producing ca. 140-fold resistance to this latter insecticide. The permethrin-resistant (147-R) strain was highly cross-resistant to several other pyrethroids and demonstrated resistance to knockdown by these insecticides as well as by DDT. The sensitivity of the central nervous system to four pyrethroids was investigated. The 147-R strain was 2.6-fold less sensitive to (1R)-trans-ethanoresmethrin than the susceptible (NAIDM-S) strain, and >43-fold and >67-fold less sensitive to (1R,S)-cis, trans-tetramethrin and (1R)-trans-permethrin, respectively. It also displayed decreased penetration of (1R,S)-trans-[¹⁴C]permethrin when compared to the NAIDM-S strain. Lower nerve sensitivity and decreased cuticular penetration are potential mechanisms of resistance to pyrethroids in house flies in the United States.  相似文献   

Toxicity of spinosad to susceptible and resistant strains of house flies,Musca domestica     

Jeffrey G. Scott 《Pest management science》1998,54(2):131-133

The toxicity of spinosad, a new insecticide derived from the bacterium Saccharopolyspora spinosa, was evaluated against susceptible and resistant strains of house fly (Musca domestica L.). Spinosad was highly toxic to house flies based on 72-h LD₅₀ values and the symptoms of poisoning were consistent with a neurotoxic mechanism of action. Spinosad was relatively slow acting, with the maximum toxicity noted at 72 h. Piperonyl butoxide and S,S,S,-tribu-tylphosphorotrithioate synergized the toxicity of spinosad by 3·0- and 1·8-fold, respectively, while diethyl maleate had no significant effect. These results suggest that there is a small degree of monooxygenase-mediated spinosad detoxification in house flies, while hydrolases may be only minimally important and glutathione transferases may have no role. There were no substantial levels of cross-resistance detected, except in the LPR strain where a low 4·3-fold cross-resistance was observed. The cyclodiene-resistant OCR strain was 2·7-fold more sensitive to spinosad than the susceptible strain (CS). These results suggest that cross-resistance may not be a limiting factor for the use of spinosad against house flies. © 1998 Society of Chemical Industry  相似文献   

CNS insensitivity to pyrethroids in the resistant kdr strain of house flies     

Thomas A. Miller  Janice M. Kennedy  Chrystal Collins 《Pesticide biochemistry and physiology》1979,12(3):224-230

Solutions of tetramethrin, RU 11679, or cismethrin caused uncoupled convulsions in 30–40 min in exposed thoracic ganglia from S_NAIDM house flies at concentrations down to 10^?10M: whereas these same compounds at 10^?6M concentrations failed to produce poisoning symptoms when perfused onto the exposed ganglia of the kdr strain of house fly. The pyrethroid analogs examined had a negative temperature coefficient of action on the exposed thoracic ganglia from S_NAIDM flies. DDT and GH-74 possessed positive temperature coefficients of action on the exposed thoracic ganglion of susceptible house flies. It is concluded that the central nervous system of the kdr strain of house fly is resistant to pyrethroid action; furthermore, the resistance appears to be widespread throughout the house fly nervous system, involving sensory, motor, and central neural elements.  相似文献