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1.
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   

2.
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 (S)P(R)P 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   

3.
The short-term disposition and metabolism of topically administered [14C]chlorpyrifos was assessed in the black imported fire ant (Solenopsis richteri Forel) in the presence and absence of the mixed-function oxidase inhibitor piperonyl butoxide. Chlorpyrifos is readily absorbed into an internal organosoluble fraction which was quickly converted into a water-soluble fraction. The radioactivity was slowly excreted over a 24-hr period. Piperonyl butoxide slowed the conversion of the internal organosoluble radioactivity to the water-soluble fraction. Thin-layer chromatography indicated that piperonyl butoxide slowed the conversion of chlorpyrifos to material remaining at the origin, presumably water-soluble metabolites. The results of acid hydrolysis studies indicated that the water-soluble radioactivity was comprised mainly of conjugates. Although very little chlorpyrifos oxon was recovered in the metabolism experiments, in vitro studies on fire and head homogenates showed the compound to be an extremely potent anticholinesterase, with an I50 of 4.6 × 10?10M, while a major metabolite, 3,5,6-trichloropyridinol, was an ineffective acetylcholinesterase inhibitor.  相似文献   

4.
This study presents evidence for the dehydrogenation of lindane by a hepatic microsomal mixed-function oxidase system. Preliminary investigation established that the incubation of lindane with rat liver homogenates produces a chlorinated, nonpolar compound identified as hexachlorocyclohexene. Differential centrifugation resulted in the sedimentation of most of the dehydrogenase activity in the microsomal fraction. Optimum in vitro assay conditions were established and it was found that the dehydrogenase system required molecular oxygen and reduced pyridine nucleotide coenzyme for maximum activity. Inhibition by SKF 525-A and CO suggested that the enzyme was cytochrome P-450 dependent. Lack of inhibition by cyanide indicated that the cytochrome b5 desaturase system was probably not involved. Pretreatment of rats with DDT, which stimulates lindane metabolism, also induced significantly higher dehydrogenase activity. Both the in vivo and in vitro metabolism of hexachlorocyclohexene produced previously identified lindane metabolites. The existence of a cytochrome P-450 dependent mixed-function oxidase which catalyzes the dehydrogenation of lindane has not previously been reported and may be of importance in the metabolism of other xenobiotics.  相似文献   

5.
The metabolism of fenitrothion was investigated in highly resistant (Akita-f) and susceptible (SRS) strains of the house fly, Musca domestica L. The Akita-f strain was 3500 times more resistant to fenitrothion than the SRS strain. Fenitrothion, topically applied to the flies, was metabolized in vivo far faster in the Akita-f strain than in the SRS strain. In vitro studies revealed that fenitrothion was metabolized by a cytochrome P-450-dependent monooxygenase system and glutathione S-transferases. The former oxidase system metabolized fenitrothion in vitro into fenitrooxon and 3-methyl-4-nitrophenol as major metabolites, and into 3-hydroxymethyl-fenitrothion and 3-hydroxymethyl-fenitrooxon as minor metabolites. Glutathione S-transferases metabolized fenitrothion into desmethylfenitrothion. The cytochrome P-450-dependent monooxygenase system and glutathione S-transferases of the resistant Akita-f strain had 1.4 to 2.2 times and 9.7 times, respectively, as great activities as those of the susceptible SRS strain. These results suggest the importance of glutathione S-transferases in fenitrothion resistance in the Akita-f strain.  相似文献   

6.
The contact and oral toxicity of methomyl (S-methyl N-[(methylcarbamoyl)oxy] thioacetimidate) was similar for two different strains of European corn borer, Ostrinia nubilalis (Hübner). In each case, third- and fourth-instar larvae were equally susceptible, but fifth-instar insects were considerably more difficult to kill. In vivo and in vitro studies revealed that borers from both strains metabolized methomyl via a mixed-function oxidase system to water-soluble products which could not be cleaved by acid or hydrolytic enzymes. By far, the greatest metabolic activity was localized in fat body tissues of last-instar larvae, and although both strains metabolized methomyl at a similar rate, a large difference was found in the rate of metabolism of methomyl oxime.  相似文献   

7.
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 Rf is more potent than that of lower Rf when derived from a trans-chrysanthemate and vice versa from a cis-chrysanthemate.  相似文献   

8.
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   

9.
Adult Rana pipiens pipiens (Shreber) are highly sensitive to insecticidal α-cyano-3-phenoxybenzyl esters administered subcutaneously, i.e., LD50 0.13–0.35 mg/kg for deltamethrin and the most potent isomer of each of cis-cypermethrin, fenpropathrin, and fenvalerate and 0.65 mg/kg for (1R,αS)-trans-cypermethrin. Pyrethroids lacking the α-cyano substituent [pyrethrins, S-bioallethrin, kadethrin, and the Cis- and trans-isomers of (1R)-tetramethrin, (1RS)-resmethrin, (1R)-phenothrin, and (1R)-permethrin] vary greatly in their toxicity (LD50 0.14 to > 60 mg/kg) and the trans isomers are much less toxic than the corresponding cis isomers. The trans/cis specificity is due in large part to relative detoxification rates based on synergism studies with the resmethrin and permèthrin isomers and liver pyrethroid esterase assays with the permethrin and cypermethrin isomers. Poisoning by the noncyano compounds involves hyperactivity and tremors whereas by the cyanophenoxybenzyl esters involves tonic seizures and choreoathetosis, i.e., types I and II syndromes, respectively. Picrotoxinin, t-butylbicyclophosphate, and five other small cage compounds give a third type of syndrome with clonic seizures. Diazepam and its 2′-fluoro-4-methyl-4,5-dihydro analog (RO 5-3636) are more effective than 23 other compounds tested in protecting against deltamethrin toxicity. Diazepam is most effective in alleviating the Type II syndrome, intermediate with the type I syndrome, and is not active with picrotoxinin.  相似文献   

10.
The antifungal activity of twelve monoterpenes, camphene, (R)-camphor, (R)-carvone, 1,8-cineole, cuminaldehyde, (S)-fenchone, geraniol, (S)-limonene, (R)-linalool, (1R,2S,5R)-menthol, myrcene and thymol was evaluated against four plant pathogenic fungi Rhizoctonia solani, Fusarium oxysporum, Penecillium digitatum and Asperigallus niger by using mycelial growth inhibitory technique. (S)-limonene and thymol were examined for their inhibitory effects on pectin methyl esterase (PME), cellulase and polyphenol oxidase (PPO) of tested fungi. Thymol was the most potent antifungal compound against the four test fungi with EC50 values of 33.50, 50.35, 20.14 and 23.80 mg/L on R. solani, F. oxysporum, P. digitatum and A. niger, respectively. The antifungal activity of thymol was comparable to a reference fungicide, carbendazim. (S)-limonene and 1,8-cineole exhibited pronounced antifungal activity against the four tested fungi. The most effective antifungal compounds thymol and (S)-limonene showed strong inhibitory effect on the activity of PME and cellulase but revealed no inhibitory effect on PPO. The results showed that PME was more sensitive than cellulase to thymol and (S)-limonene. This is the first report on the inhibitory effects of monoterpenes thymol and (S)-limonene on PME, cellulase and PPO. The results indicated that monoterpenes may cause their antifungal activity by inhibiting PME and cellulase. The strong antifungal activity of thymol, (S)-limonene and 1,8-cineole reported in this study indicated that these compounds have a potential to be used as fungicides.  相似文献   

11.
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 (Ka), phosphonylation constant (kp), and bimolecular inhibition rate constant (ki) 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 Sp configuration were more potent inhibitors than their Rp 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, Ka, and the phosphonylation constant, kp. Small but consistent inhibition rate differences were attributable to asymmetry at carbon. Against horse serum cholinesterase, the SC isomers indicated the presence of three kinetic forms in this enzyme preparation.  相似文献   

12.
Cypermethrin and cyfluthrin were applied to wheat, which was stored for 52 weeks at 25 or 35°C, and either 12 or 15% moisture content. Total residues and the proportions of the four pairs of enantiomers, cis I [(αR),(1R)-cis + (αS),(1S)-cis], cis II [(αR),(1S)-cis + (αS),(1R)-cis], trans III [(αR),(1R)-trans + (αS),(1S)-trans], and trans IV [(αR),(1S)-trans + (αS),(1R)-trans] for each pyrethroid were determined at five intervals during storage. For all storage conditions, the cis I isomers were the most stable, and the trans IV isomers were the least stable. Calculated half-lives (weeks) for the pairs of enantiomers at 25°C (12% moisture) and 35°C (15% moisture) were: cypermethrin, cis I, 252, 62 and trans IV 66, 27; cyfluthrin, cis I, 114, 52 and trans IV 42, 23. The results suggested that one of the enantiomers of the cypermethrin trans IV pair was degraded faster than the other.  相似文献   

13.
Larvae from two strains of the European corn borer, Ostrinia nubilalis (Hübner), were compared for differences in their tolerance and metabolism of carbaryl (1-naphthyl N-methylcarbamate). The Geneva strain was about twice as susceptible to carbaryl, but both Valley and Geneva borers converted carbaryl to oxidative metabolites at similar rates in vivo and in vitro. Maximum carbaryl-metabolizing activity was present in last-instar larvae, particularly in the fat body and gut tissues. However, the specific activity of gut homogenates was highest in the Geneva strain and the specific activity of fat body was highest in the Valley strain. Other differences in the mixed-function oxidase systems of gut and fat body were also found. The major metabolite in vivo and in vitro was hydroxymethyl carbaryl.  相似文献   

14.
Several pesticide synergists known to be mixed-function oxidase inhibitors were found to inhibit the in vitro metabolism of diazinon by mouse liver microsomes. Piperonyl butoxide and NIA 16824 (O-isobutyl-O-propargyl phenylphosphonate) inhibit all oxidative reactions of diazinon to the same extent. In contrast, 1-(2-isopropylphenyl)imidazole selectively inhibits oxidative dearylation and thiophosphate to phosphate conversion without significant effect on ring side chain hydroxylation. This selectivity suggests that two different mechanisms of oxidative detoxification may be operating, mechanisms which may involve either two cytochrome P-450s or two different binding sites on the same cytochrome.  相似文献   

15.
Microsomal mixed-function oxidase systems from rat liver and house fly abdomen effectively metabolized isomers of 3,4,5,6-tetrachlorocyclohexene, 1,3,4,5,6-pentachlorocyclohexene, and 1,2,3,4,5,6-hexachlorocyclohexene to tetrachlorocyclohexenol isomers, 2,4,5,-trichlorophenol, and 2,3,4,6-tetrachlorophenol, respectively. The (3465)-isomer of pentachlorocyclohexene gave also an abundant amount of pentachlorocyclohexenol isomers. As the metabolites of (3645)-, (3546)-, and (3456)-hexachlorocyclohexene, some compounds such as 1,2,4-trichlorobenzene, 1,2,3,4-tetrachlorobenzene, and pentachlorobenzene were more abundantly formed, respectively, than 2,3,4,6-tetrachlorophenol. These oxidative metabolic reactions were shown to mainly proceed via “ene-like” hydroxylation accompanied by double bond migration. Inhibition by CO, piperonyl butoxide, and SKF 525-A suggested that the “ene-like” hydroxylating enzyme was cytochrome P-450 dependent. The formation of an isomer of pentachlorocyclohexenol from (3645)-hexachlorocyclohexene was also observed, and this reaction was activated by SKF 525-A.  相似文献   

16.
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   

17.
The in vitro metabolism of [14C-methoxy] or [32P]azinphosmethyl by subcellular fractions of abdomens from a resistant and a susceptible strain of houseflies was studied. The degradative activity in both strains was associated with the microsomal and soluble fractions and required NADPH and glutathione, respectively. The resistant strain possessed higher activity for both the mixed-function oxidases and the glutathione transferase than the susceptible strain, and both systems appear to be important in the resistance mechanism. The mixed-function oxidases were involved in the oxidative desulfuration as well as the dearylation of azinphosmethyl. A glutathione transferase located in the soluble fraction catalyzed the formation of desmethyl azinphosmethyl and methyl glutathione. This enzyme also demethylated azinphosmethyl oxygen analog. Although the soluble fraction exhibited both glutathione S-alkyltransferase and S-aryltransferase activity against noninsecticidal substrates, no evidence of the transfer of the benzazimide moiety from azinphosmethyl to glutathione was obtained. Sephadex G-100 chromatography of the soluble enzymes revealed a common eluting fraction responsible for both types of transferase activity.  相似文献   

18.
The low mixed-function oxidase activity of house fly microsomes has been associated with low cytochrome P-450 content and NADPH-cytochrome c reductase activity. The microsomal cytochrome P-450 content and NADPH-cytochrome c reductase activity could be decreased by the addition of catechol and increased by the addition of cyanide to the homogenates. Similar results were obtained with rat liver microsomes treated with tyrosinase and catechol. During the inactivation of rat liver microsomal enzymes by tyrosinase and catechol, crosslinking of microsomal proteins occurred. These results suggest that the instability of house fly microsomal mixed-function oxidase may be due in part to the action of contaminating tyrosinase on endogenous substrates.  相似文献   

19.
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 (AUC0 → ∞) 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   

20.
Radiolabeled methyl farnesoate is epoxidized to juvenile hormone III by an NADPH-dependent reaction occurring in corpus allatum homogenates from the cockroach Blaberus giganteus L. Most of the enzymatically produced juvenile hormone has the 10R configuration described for previously isolated natural juvenile hormones. The unnatural 2Z geometrical isomer of methyl farnesoate is epoxidized by the above system faster than the natural 2E isomer. Several series of chemicals known to be inhibitors of mixed-function oxidases were surveyed as inhibitors of methyl farnesoate epoxidation. The anti-juvenile hormone precocene II caused negligible inhibition at 1 · 10?4M, whereas the best inhibitor was o-bromophenoxymethyl-imidazole with an apparent I50 of 4 · 10?7M. None of the inhibitors tested were potent morphogenetic agents on Tenebrio molitor pupae, and they failed to cause precocious development of Oncopeltus fasciatus nymphs. The inhibition of in vitro juvenile hormone biosynthesis suggests the possibility of finding an anti-hormone which acts by blocking juvenile hormone biosynthesis.  相似文献   

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