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1.
An esterase or esterases in acetone powder preparations of mouse liver microsomes hydrolyze the cyclopropanecarboxylate ester linkage of pyrethroid insecticide chemicals derived from primary alcohols. The rate of cleavage of (+)-trans-chrysanthemates with various alcohol moieties decreases in the following order: 5-propargyl-2-furylmethyl; 5-benzyl-3-furylmethyl (bioresmethrin); 3-phenoxybenzyl; tetrahydrophthalimidomethyl esters. The hydrolysis rate of benzylfurylmethyl esters with various acid moieties decreases in the order: (+)- or (?)-trans-chrysanthemate; (+)-trans-ethanochrysanthemate; tetramethylcyclopropanecarboxylate; (+)- or (?)-cis-chrysanthemate or (+)-cis-ethanochrysanthemate. The trans-isomers of chrysanthemates and ethanochrysanthemates are hydrolyzed from 2.6- to more than 50-fold more rapidly than the corresponding cis-isomers. This enzyme system does not hydrolyze secondary alcohol esters, i.e., allethronyl (+)-trans- and (+)-cis-chrysanthemates.On intraperitoneal administration to mice, the (+)-trans-chrysanthemate and -ethanochrysanthemate of benzylfurylmethanol are of very low toxicity relative to the corresponding (+)-cis-isomers and the tetramethylcyclopropanecarboxylate. S,S,S-tributyl phosphorotrithioate (DEF) pretreatment increases the toxicity of these five compounds by 2.6- to more than 188-fold, with the exception of bioresmethrin whose toxicity is not altered. When the toxicity is increased, it is probably the result of esterase inhibition since DEF strongly inhibits the esterase activity of fresh liver microsomes while the mixed-function oxidase system remains active. The oxidase system metabolizes the chrysanthemates more rapidly than the ethanochrysanthemates of benzylfuryl-methanol. Depending upon the pyrethroid involved, the esterase or the mixed-function oxidase system, or both may be responsible for limiting the toxicity of these pyrethroids to mice.  相似文献   

2.
This review of studies on 20 pyrethroids with nine different acid moieties and ten different alcohol moieties reveals a diversity of functional groups undergoing metabolism in mammals, insects, other organisms, and microsomal esterase and oxidase systems. Seventy-nine metabolites are identified from the cis-isomer of permethrin and transpermethrin but fewer from other pyrethroids examined in less detail. The sites and rates of metabolic attack on each pyrethroid depend on the organism or system. Metabolism of pyrethoids by esterase and oxidase action usually limits their toxicity to mammals more than to insects, thereby conferring useful selective toxicity properties.  相似文献   

3.
Studies are presented on the effects of two synergists, piperonyl butoxide and S,S,S-tributyl phosphorotrithioate, on the metabolism of methoprene [isopropyl (2E,4E)-11-methoxy-3,7,11-trimethyldodeca-2,4-dienoate], an insect growth regulator, by the castes of the imported fire ant, Solenopsis invicta Buren. In adults, but not in larvae, pharate pupae, and pupae, piperonyl butoxide, a microsomal enzyme inhibitor, reduced methoprene metabolism by blocking O-demethylation. S,S,S-Tributyl phosphorotrithioate, an esterase and microsomal oxidase inhibitor, was most effective in reducing methoprene metabolism in larvae. In toxicity studies, against pharate pupae, the O-demethylated methoprene metabolite (alcohol-ester) was shown to be more toxic than methoprene. Synergists may be useful in bait formulations used for imported fire ant control to extend the effectiveness of methoprene.  相似文献   

4.
Formate esters have potential uses as insecticides in both grain fumigation and public health pest management. This research investigated the hydrolytic metabolism and neurological effects of formate ester compounds. Studies were conducted using Drosophila and houseflies as models for other dipteran pests of medical importance. Results indicated significant formic acid liberation from a broad range of formate esters, both in vivo and in vitro. Based on these initial observations, we subsequently investigated neurological effects of formic acid on the larval housefly nervous system. We found that formic acid caused significant neuroexcitation at concentrations lower than previously shown for inhibition of insect cytochrome c oxidase; however, this conclusion does not preclude that mitochondrial effects may also be occurring in non-nervous tissues. Finally, we investigated formate ester hydrolysis by A- and B-type esterases commonly considered in pesticide detoxification research; however, no significant interactions could be identified, suggesting that as yet unidentified carboxylesterases play roles in formate ester hydrolysis. These findings provide information on formate ester metabolism and modes of action, as well as rationale for further studies on formate ester neurotoxicology and mechanisms of selective toxicity.  相似文献   

5.
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   

6.
The metabolism in vivo and in vitro of [14C]parathion and [14C]paraoxon was studied in a susceptible (LS) and an organophosphorus-resistant (Q) strain of the sheep blowfly, Lucilia cuprina. Both strains detoxified the insecticides in vivo via a number of pathways, but the resistant strain produced more of the metabolites diethyl phosphate and diethyl phosphorothionate. No difference was found between strains in the rate of penetration of the compounds used. Also, in vitro studies showed no difference between strains in the sensitivity of head acetylcholinesterase to inhibition by paraoxon. Both the microsomal and the 100,000g supernatant fractions degraded paraoxon, but resistance in Q could be explained by the eightfold greater rate of diethyl phosphate production with or without added NADPH. Parathion was also degraded to diethyl phosphorothionate by an NADPH-requiring enzyme in microsomal preparations from both strains. However, Q produced significantly more diethyl phosphorothionate in vivo than LS. It was concluded that organophosphorus resistance in Q was due mainly to a microsomal phosphatase hydrolyzing phosphate but not phosphorothionate esters, probably enhanced by a microsomal oxidase detoxifying the latter.  相似文献   

7.
New types of juvenogens, which are biochemically activated juvenoid esters, have been assayed for juvenile hormone activity in three species of insects. The hormonally active component, liberated from the juvenogen substrate by carboxylesterase enzymes within the insect's body, was a secondary juvenoid alcohol related to the well-known group of juvenile hormone analogs derived from 4-substituted (7-alkoxygeranyloxy)benzenes. Juvenogen esters obtained by acylation of this juvenoid alcohol with a homologous series of C2 to C18 straight-chain monocarboxylic acids retain the juvenile hormone activity of the parental alcohol. The corresponding formyl derivative, as a first member of the series, was inactive and the activity of esters with longer acyl radicals than C18 also successively diminished. Such a weak dependence for juvenile hormone activity on the size of the molecule has not previously been encountered in juvenoid esters which do not yield biologically active hydrolysis products. These findings favor an assumption that juvenogens may represent selective, nontoxic, hormonally acting pesticides whose physicochemical properties (volatility, lipophility, stability) can be adjusted to suit practical requirements by simple alterations of the biologically unimportant acyl component. Moreover, this can be done without affecting the species-specific properties in the juvenile hormone activity of the built-in juvenoid product.  相似文献   

8.
Only about 60% of the total relative gravitational force conventionally used to sediment microsomes is needed to prepare highly active microsomes from the midgut tissues of an insect larva. A rapid preliminary centrifugation for 2 min at 39,000gmax effectively removed contaminating microorganisms, tissue debris, nuclei, and mitochondria. The supernatant was recentrifuged for 20 min to 210,000g to sediment the microsomes. There were no losses of microsomal oxidase activities or degradation of cytochrome P-450 to the inactive form (P-420) resulting from the application of the higher gravitational force. Incorporation of 1 mM EDTA in the buffer and washing the microsomes resulted in an improved yield of the cytochrome compared to that in microsomes prepared in sucrose. Yields of microsomal protein, cytochrome P-450, and NADPH-cytochrome c reductase in the rapidly isolated microsomes were as good as those in conventionally prepared microsomes. The apparent kinetic characteristics of several microsomal oxidation activities and optical difference spectra of Types 1 and 2 ligands were identical in the rapidly and conventionally prepared microsomes. The morphological appearance of the microsomes was examined by electron microscopy. Microsomal pellets prepared by either method were indistinguishable. The rapid procedure saves significant time in microsome preparation and yields microsomal oxidase activities as good or slightly better than those prepared by usual centrifuged procedures.  相似文献   

9.
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   

10.
NADPH-dependent inhibition of hepatic microsomal carboxylesterase by a derivative of monocrotophos (coded as RPR-5) was studied in rat and Japanese quail as a measure of monooxygenase-catalysed activation of RPR-5. There was NADPH-dependent inhibition of hepatic microsomal α-naphthyl acetate esterase (carboxylesterase) both in rat and quail, indicating monooxygenase-catalysed formation of an oxon that subsequently phosphorylated α-NaE. The pattern of in-vitro metabolism of 14C-labelled RPR-5 by 11000g supernatant (11-S), microsomes and 105000g supernatant (105-S) fractions of rat and quail livers suggested the involvement of microsomal monooxygenases and carboxylesterases. A radiolabelled metabolite (M2) was tentatively identified as an acid produced by carboxyl esterase attack. In rat, metabolism by microsomal and cytosolic (105-S) carboxylesterases appeared to predominate with relatively little oxidative metabolism. In quail, putative microsomal carboxylesterase hydrolysis of RPR-5 was much lower than in the rat with almost neglible hydrolysis by cytosolic fractions. Also, production of M2 by quail microsomes was substantially reduced after addition of NADPH, suggesting inhibition of a carboxyl esterase by the oxon of RPR-5. Differences in this detoxification of RPR-5 between rat and quail may be an important factor in determining selective toxicity and the results underline the importance of relating metabolism to toxicity when selecting animal models for toxicity testing.  相似文献   

11.
Metribuzin [4-amino-6-tert-butyl-3(methylthio)-1,2,4-triazin-5(4H)-one] metabolism was studied in soybean [Glycine max (L.) Merr. Tracy]. Pulse treatment studies with seedlings and excised mature leaves showed that [5-14C]metribuzin was absorbed rapidly and translocated acropetally. In seedlings, >97% of the root-absorbed 14C was present in foliar tissues after 24 hr. In excised leaves, 50–60% of the absorbed 14C remained as metribuzin 48 hr after pulse treatment, 12–20% was present as polar metabolites, and 20–30% was present as an insoluble residue. Metabolites were isolated by solvent partitioning, and were purified by adsorption, ion-exchange, thin-layer, and high-performance liquid chromatography. The major metabolite (I) was identified as a homoglutathione conjugate, 4-amino-6-tert-butyl-3-S-(γ-glutamyl-cysteinyl-β-alanine)-1,2,4-triazin-5(4H)-one. Metabolite identification was confirmed by qualitative analysis of amino acid hydrolysis products, fast atom bombardment (FAB), and chemical ionization (CI) mass spectrometry, and by comparison with a reference glutathione conjugate synthesized in vitro with a hepatic microsomal oxidase system from rat. Minor metabolites were identified as an intermediate N-glucoside conjugate (II), a malonyl N-glucoside conjugate (III), and 4-malonylamido-6-tert-butyl-1,2,4-triazin-3,5(2H,4H)-dione (N-malonyl DK, IV) by CI and FAB mass spectrometry. Alternative pathways of metribuzin metabolism are proposed.  相似文献   

12.
Metabolism of [phenyl-14C] and [(2,5) pyrrolidine-14C] cisanilide was investigated in vitro with microsomal preparations from rat liver. Microsomal activity was associated with a mixed-function oxidase system that required O2 and NADPH and was inhibited by CO. Two major ether-soluble metabolites were isolated. They were identified as primary oxidation products: 2-hydroxy-2,5-dimethyl-1-pyrrolidinecarboxanilide (A) and 4′-hydroxy-2,5-dimethyl-1-pyrrolidinecarboxanilide (B). Minor ether-soluble metabolites were also isolated. Precursor product studies and qualitative thin layer chromatography analysis of [pyrrolidine-14C] and methylated [phenyl-14C] hydrolysis products suggested that these metabolites were secondary oxidation products formed from metabolites A or B. One of these metabolites appeared to be the dihydroxy product 2,4′-dihydroxy-2,5-dimethyl-1-pyrrolidinecarboxanilide. Crude microsomal preparations (postmitochondrial supernatant fractions) also formed small quantities (<10%) of polar metabolites. Enzyme hydrolysis with β-glucuronidase (Escherichia coli) indicated that approximately 50% of these metabolites were glucuronides. Similarities and differences in cisanilide oxidation in vivo in plants and in vitro with rat liver microsomal preparations were discussed.  相似文献   

13.
Microsomal esterases of mouse and rat liver readily cleave the trans- but not the cis-isomers of resmethrin (5-benzyl-3-furylmethyl chrysanthemate). The ester linkage also appears to undergo oxidative cleavage when esterase attack is minimal, i.e., with (+)-cis- and particularly (?)-cis-resmethrin in microsome-NADPH systems and with any of the isomers when NADPH is added to microsomes pretreated with TEPP. Metabolites retaining the ester linkage are detected in significant amounts only with (+)-cis-resmethrin in which case they are formed by oxidation at either the trans(E)- or cis(Z)-methyl group of the isobutenyl moiety with or without oxidation of the benzylfurylmethyl group. Metabolites of each acid moiety include chrysanthemic acid and up to six derivatives of this acid formed by oxidation at the trans(E)- or cis(Z)-methyl group yielding the corresponding alcohol, aldehyde, or acid, with chrysanthemate isomer and enzyme source variations in the preferred site of oxidation. The major identified metabolite of the alcohol moiety is either benzylfurylmethanol or the corresponding carboxylic acid depending on the enzyme system used. In the course of microsomal oxidation, a fragment from the alcohol but not the acid moiety of (+)-trans- and (+)-cis-resmethrin is strongly bound to microsomal components. These findings confirm in vivo studies on the isomeric variations in metabolism of the resmethrin components.  相似文献   

14.
Studies were conducted to assess the contribution of the hepatic microsomal mixed function oxidase system to a 7.2-fold difference in susceptibility to the lethal effects of endrin between endrin-resistant and -susceptible pine voles, Microtus pinetorum. Evaluations of microsomal enzyme systems were conducted for basal and endrin-treated pine voles of both strains. The microsomal activity of ICR white mice was investigated to provide a species comparison. Maximal microsomal mixed function oxidase activities were determined in in vitro incubations for the model substrates ethylmorphine, aniline, and benzo(a)pyrene. Vmax values were estimated for the rate of disappearance of benzo(a)pyrene in in vitro incubations. No significant strain differences in basal microsomal enzyme activity were found for the model substrates investigated, although activity was invariably higher in the resistant strain. The concentration of cytochrome P-450 was significantly higher in the resistant vole though actually less than 20% different. The occurrence of significant strain differences in the levels of microsomal enzyme activity induced by endrin were rare. Significant endrin treatment effects on the levels of microsomal enzyme activity for the pine vole were observed but the degree and direction of change depended on the substrate used. A marked species difference in microsomal mixed function oxidase activity was noted between pine voles and white mice. This was particularly evident for endrin-treated animals. The microsomal activity of endrin-treated white mice was greatly induced relative to basal levels. The degree of induction depended on the substrate used. The small strain differences in microsomal enzyme activity for the systems investigated were judged to be insufficient to explain the strain difference in susceptibility to endrin.  相似文献   

15.
Female adult American cockroaches, Periplaneta americana L., showed definite age-dependent changes in levels of activity of the microsomal mixed-function oxidases. Cytochrome P-450 levels, EPN-detoxication, and p-nitroanisole O-demethylation activities were very low in young adult insects but increased steadily reaching a natural peak at about 100 days in fat body and at about 90 days in midgut and hindgut. The activities then declined rapidly reaching levels of young insects at about 130 to 140 days of age. NADPH-neotetrazolium-reductase activity was high in young insects, declined later in adult life, and returned to a peak at about 100 days.Injections of chlorcyclizine, a known microsomal enzyme inducer, significantly increased levels of cytochrome P-450, EPN-detoxication, p-nitroanisole O-demethylation, and NADPH-NT-reductase activities in young cockroaches. The drug injections were effective, however, only before the natural activity peak was reached. Beyond this point the injections had no inductive effect indicating that the microsomal oxidases in this insect are uninducible when normal enzyme levels are falling.NADPH-NT-reductase activity in male cockroaches, while being somewhat higher than in females, showed a similar age-dependent curve with the peak occurring at about 120 days.Age-dependent carbaryl resistance in male and female insects tended to follow levels of the microsomal oxidase activities. Fifty to 60-day-old insects, however, tended to be more resistant to the insecticide than microsomal enzyme levels would indicate.RNA levels of normal female insects showed age-dependent curves similar to those of the microsomal enzyme activities, being low in young adults and reaching a peak at about 100 days. Chlorcyclizine injections had little or no effect on total microsomal RNA levels.  相似文献   

16.
The activities of 47 substituted 1,2,3-benzothiadiazoles as inhibitors of microsomal epoxidation and/or hydroxylation in enzyme preparations from rat liver or armyworm (Spodoptera eridania) gut have been evaluated. Many were found to be effective inhibitors of microsomal oxidation, the most active being the 6-butyl and 6-propoxy derivatives with I50 values of 4.9 × 10?7 and 7.0 × 10?7M, respectively, for the epoxidation reaction. Regression analyses have established that activity of the 5-, 6-, and 5,6-substituted compounds can be satisfactorily described in equations in terms of π2, π, and σ whereas that of the 4-substituted derivatives depends on π and the steric parameter E8.  相似文献   

17.
The effect of various plant substances and host plants on the microsomal oxidases and glutathione S-transferase was investigated in the fall armyworm (Spodoptera frugiperda (J. E. Smith)) maintained on a meridic diet. The glucosinolate, sinigrin, and the hydrolytic products of glucosinolates, β-phenylethylisothiocyanate, indole 3-acetonitrile, and indole 3-carbinol, and flavone were found to be potent inducers of the glutathione S-transferase in the armyworm. An 18-fold increase in the transferase activity was observed when larvae were fed a diet containing 0.2% indole 3-acetonitrile for 2 days. These compounds, with the exception of β-phenylethylisothiocyanate which appeared to be inhibitory, also stimulated the microsomal aldrin epoxidase significantly. In all instances, no induction of the microsomal oxidase or glutathione S-transferase was observed by the plant hormones, indole 3-acetic acid and gibberellic acid; the terpenoids, stigmasterol, sitosterol, and β-carotene; the polyphenolic gossypol; and the flavonol, quercetin; some of them were found to be inhibitory. Using corn, potato, and sweet potato as inducers of various microsomal oxidases, it was found that the inducing pattern of the N-demethylase was different from the two epoxidases and O-demethylase. Corn leaves were the most active compared with other aerial parts of corn (silks, developing corn, and husk) in inducing the microsomal oxidase. The microsomal oxidase in the younger larvae appeared to be less inducible by host plants than in the older larvae.  相似文献   

18.
The DDT-resistant Fc strain of house flies, Musca domestica L., was analyzed genetically by means of crosses with a susceptible strain carrying a recessive mutant marker for each of the five autosomes. Progeny (substrains) retaining combinations of two, three, or four chromosomes of the resistant parent were selected for measurement of their microsomal aldrin expoidase activity and its correlation with chromosomal makeup and level of resistance to DDT and propoxur. There was no evidence that microsomal epoxidation of aldrin or resistance to propoxur, is associated with chromosome V in the Fc strain as has been reported. Instead, the well-known oxidase regulating factor on chromosome II was of major importance in the strain's microsomal oxidation of aldrin. There was also evidence, though not conclusive, that a factor on chromosome I has an influence on the oxidative metabolism of insecticides in this strain, possibly through an interaction with the factor on chromosome II. The reasons for the conflicting reports on the genetic control of microsomal oxidation in the Fc strain are discussed.  相似文献   

19.
The insecticidal activity of lindane analogs, in which some chlorine atoms were replaced by other groups susceptible to microsomal oxidative metabolism, was determined against mosquitos, house flies, and German cockroaches. When tested with a synergist, piperonyl butoxide, one of the methylthio analogs was as active as lindane, whereas several others were also highly active. By examining the ratio of synergized and unsynergized LD50 values (synergistic ratio value), the highly insecticidal methylthio, methoxy, and methyl analogs appear to undergo metabolic detoxication effectively in house flies. By means of in vitro metabolism experiments using microsomal fraction from house fly abdomen, the methoxy, ethoxy, and methylthio analogs were shown to be metabolized rapidly at similar rates. The synergized insecticidal activities of these compounds against various insect species relate linearly with each other, suggesting that the oxidative degradation is inhibited by the synergist to a similar extent and that the transport process to the site of action is not a limiting factor in determining the relative insecticidal activity.  相似文献   

20.
Methoxy-, ethoxy-, propoxy-, and butoxyresorufin were prepared and tested as substrates for the fluorometric assay of O-dealkylation by the mixed-function oxidase system in house flies, Musca domestica L. Methoxyresorufin proved to be the most suitable substrate because of the favorable reaction rates. This sensitive assay can be performed with a minimum of microsomal protein (<0.3 mg/ml) in 5 min or less. The apparent Km and maximum velocity were calculated as 2.88 μM and 0.27 nmol of resorufin produced/min/mg of microsomal protein, respectively. The O-dealkylation reaction required O2 and NADPH and was inhibited by CO.  相似文献   

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