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PubMed1995

Identity and pathogenesis of stomach tumors in Sprague-Dawley rats associated with the dietary administration of butachlor.

Macroscopic stomach tumors induced in Sprague-Dawley rats during two chronic bioassays with the acetanilide herbicide butachlor at a dietary concentration of 3000 ppm, were evaluated histologically and immunohistochemically in order to determine their identity and pathogenesis. The tumors, which occurred primarily in female rats, were a heterogeneous series, including a few consisting wholly or partly of classic solid or anaplastic epithelium, but with the majority containing diffusely distributed primitive neoplastic cells. The latter had either the general appearance of undifferentiated epithelium or presented a more "mesenchyme-like" pattern where the cells were epithelioid, blastema-like, neuroendocrine-like or sarcoma-like with fascicular disposition. Gastric glandular profiles were also present, usually located near the periphery of the tumors, but in some cases extending into the diffuse tumor tissue. Most of the tumors displayed variable immunohistochemical reactivity for cytokeratin, vimentin and neuron-specific enolase but were negative for muscle-specific actin or desmin except in the stromal tracts. Detailed examination of all available gastric tissue revealed the presence of additional microscopic neoplasms and precursor hyperplastic lesions. All of these were typical gastric neuroendocrine cell lesions (gastric carcinoids) originating in the fundic mucosa but occasionally invading submucosally, and consisting of epithelial cells in organized clusters, rosettes or primitive tubules. The enterochromaffin-like (ECL) nature of these microscopic neoplasms and precursor lesions was substantiated by strong immunohistochemical reactivity for cytokeratin, neuron-specific enolase and chromogranin A, and a negative reaction for vimentin. One microscopic tumor showed a transition from differentiated neuroendocrine type in the fundic mucosa to a dispersed "mesenchyme-like" pattern in the submucosal extension. An additional finding in the butachlor-treated male and female rats was atrophy of the fundic mucosa involving, in particular, reduction in the numbers of parietal cells. This effect was dose-related, being most severe in the high-dose (3000 ppm) females. On the basis of their morphological characteristics, coupled with the continuity evident in the microscopic lesions, it is concluded that the macroscopic stomach tumors associated with the dietary administration of butachlor are poorly differentiated gastric carcinoids, in some cases admixed with a non-neuroendocrine epithelial element. Fundic ECL and stem cells are known to be under the trophic influence of gastrin, which is apparently responsible for the induction of the tumors associated with butachlor administration. Gastric tumor development involving gastrin is recognized as a secondary, hormonal mechanism of carcinogenesis, demonstrating a dose-threshold phenomenon.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetanilides↗
PubMed2002

Clastogenicity of pentachlorophenol, 2,4-D and butachlor evaluated by Allium root tip test.

The meristematic mitotic cells of Allium cepa is an efficient cytogenetic material for chromosome aberration assay on environmental pollutants. For assessing genotoxicity of pentachlorophenol (PCP), 2,4-dichlorophenoxyacetic acid (2,4-D) and 2-chloro-2,6-diethyl-N-(butoxymethyl) acetanilide (butachlor), 50% effective concentration (EC(50)), c-mitosis, stickiness, chromosome breaks and mitotic index (MI) were used as endpoints of genotoxicity. EC(50) values for PCP and butachlor are 0.73 and 5.13 ppm, respectively. 2,4-D evidently induced morphological changes at higher concentrations. Some changes like crochet hooks, c-tumours and broken roots were unique to 2,4-D at 5-20 ppm. No such abnormalities were found in PCP and butachlor treated groups, however, root deteriorated and degenerated at higher concentrations (<3 ppm) in PCP. MI in 2,4-D showed a low average of 14.32% followed by PCP (19.53%), while in butachlor it was recorded 71.6%, which is near to the control value. All chemicals induced chromosome aberrations at statistically significant level. The highest chromosome aberration frequency (11.90%) was recorded in PCP at 3 ppm. Large number of c-mitotic anaphases indicated that butachlor acts as potent spindle inhibitor, whereas, breaks, bridges, stickiness and laggards were most frequently found in PCP showing that it is a potent clastogen.

2,4-Dichlorophenoxyacetic Acid↗
PubMed2002

Induction of micronuclei and erythrocyte alterations in the catfish Clarias batrachus by 2,4-dichlorophenoxyacetic acid and butachlor.

The micronucleus test (MNT) in fish erythrocytes has increasingly been used to detect the genotoxic effects of environmental mutagens and its frequency is considered to reflect the genotoxic damage to cells, mainly the chromosomes. Besides, morphologically altered erythrocyte is taken as an index of cytotoxicity. Both parameters were used in the present study by two herbicides, 2,4-dichlorophenoxyacetic acid (2,4-D, in 25, 50 and 75ppm concentrations) and 2-chloro-2,6-diethyl-N-(butoxymethyl) acetanilide (butachlor, in 1, 2 and 2.5ppm concentrations) for genotoxic and cytotoxic endpoints. The study was carried out by an in vivo method on peripheral erythrocytes of catfish Clarias batrachus using multiple sampling times (48, 72 and 96h). Cytogenetic preparations were made by haematoxylin-eosin staining technique. Pycnotic and granular micronuclei (MN) were consistently observed irrespective of chemical tested. A wide range of altered cells was also observed. Echinocytes accompanied by altered nuclei and vacuoles were prominent feature of 2,4-D, whereas, anisochromasia and anisocytosis of erythrocytes were characteristic of butachlor. Increase in MN as well as altered cells frequencies were significant. A positive dose-response relationship in all exposures and sampling times was observed. Herbicides used were found to be genotoxic as well as cytotoxic in this fish. The suitability of the adopted parameters for the screening of the aquatic genotoxicants is discussed.

2,4-Dichlorophenoxyacetic Acid↗
PubMedDate not supplied

Characterization of glutathione conjugates of reactive metabolites of 3'-hydroxyacetanilide, a nonhepatotoxic positional isomer of acetaminophen.

3'-Hydroxyacetanilide (AMAP) is a nonhepatotoxic regioisomer of acetaminophen (APAP) that nonetheless does form reactive metabolites which bind to hepatic proteins. Because differences in the nature of reactive metabolites formed from AMAP and APAP may explain differences in their propensity to cause hepatotoxicity, characterization of the reactive metabolites of AMAP was undertaken. The naturally occurring sulfhydryl-containing tripeptide glutathione (GSH) was used to trap the reactive metabolites. Four mono-GSH conjugates and one di-GSH conjugate of oxidative AMAP metabolites were characterized by 1H NMR and soft ionization (LSIMS or FAB) mass spectral techniques, as well as by comparison of liquid chromatographic and spectral characteristics with synthetic standards. Two isomeric mono-GSH conjugates of 2-acetamidohydroquinone (2-AcHQ) are formed as well as a bis-GSH conjugate. A mono-GSH conjugate of 3',4'-dihydroxyacetanilide (3-OH-APAP) also was formed. Thus, these GSH conjugates most likely arise by reaction of GSH with 2-acetamido-p-benzoquinone (2-APBQ) and 4-acetamido-o-benzoquinone (4-AOBQ), respectively, as oxidation products of the known AMAP metabolites 2-AcHQ and 3-OH-APAP. Finally, a GSH conjugate of 3'-methoxy-4'-hydroxy-acetanilide (3-OMe-APAP) was detected in bile of mice administered AMAP. This conjugate probably arises by oxidation of 3-OMe-APAP, another known metabolite of AMAP. The presumed oxidation product, N-acetyl-3-methoxy-p-benzoquinone imine (MAPQI), was synthesized and found to react with GSH to give the same GSH conjugate as that detected in bile and in incubations of 3-OMe-APAP with mouse liver microsomes plus GSH.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaminophen↗
PubMed1999

Glutathione-dependent cytotoxicity of the chloroacetanilide herbicides alachlor, metolachlor, and propachlor in rat and human hepatoma-derived cultured cells.

Alachlor, metolachlor, and propachlor are widely used chloroacetanilide herbicides. Their cytotoxicity in rat (Fa32) and human (Hep G2) hepatoma-derived cells was investigated, in connection with their influence on the endogenous glutathione (GSH) content, on the xenobiotic-metabolizing phase I enzymes 7-ethoxyresorufin O-deethylase (EROD) and 7-pentoxyresorufin O-depentylase (PROD), and phase II glutathione transferase (GST). The cytotoxicity was measured by the neutral red uptake inhibition assay. The following toxicity range was observed in both cell lines: propachlor > alachlor > metolachlor. When the endogenous GSH content was reduced by pretreatment of the cells with L-buthionine (S,R)-sulfoximine, the cytotoxicity of the herbicides increased strongly in both cell lines. EROD and PROD activities were dose-dependently increased to different degrees in Fa32, as was EROD in Hep G2, but no PROD activity was observed in these cells. The GSH content was not altered after 1 h treatment, and was approximately doubled after 24 h. GST activity was increased in Fa32 cells but not in Hep G2. A comparable cytotoxicity was observed for the investigated chloroacetanilides in both the rat and the human cell lines. Different interactions with xenobiotic-metabolizing phase I and II enzymes were observed, and GSH showed a protective effect against the acetanilides in both cell lines.

Acetamides↗
PubMed2000

Metabolism of N-isopropylacetanilide in rat.

1. Radioactivity from oral doses of N-isopropyl[1-14C]acetanilide was excreted in urine (53.5%), faeces (8.1%) and expired air (17.0%) of rat. 2. Enterohepatic circulation occurred during formation of approximately 34% of the metabolites. N-isopropylacetanilide was metabolized by oxidation in all moieties of the molecule with subsequent conjugation with glucuronic and sulphuric acids. 3. The sulphate ester of 4'-hydroxyacetanilide (acetaminophen) was the major metabolite (28 % of the dose).

Acetanilides↗
PubMed1979

Propachlor detoxication in the small intestine: cysteine conjugation.

14C-labeled 2-(S-cysteinyl)-N-isopropylacetanilide was recovered from the media of everted sacs of rat small intestine incubated in media that contained [14C] propachlor (2-chloro-N-isopropyl-[1(-14) C]acetanilide). The metabolite was identified on the basis of chromatographic characteristics and mass spectra of the butyl ester-trifluoro-acetamide derivative. This evidence shows that the cysteinyl conjugate was formed during incubations of the small intestine. Although the glutathione conjugate has not been isolated from the intestine, it is a likely precursor of the cysteinyl metabolite. Data from experiments conducted with 10(-5) and 10(-4) M propachlor in the media showed that the capacity to metabolize propachlor to polar metabolites was approximately the same throughout the length of the small intestine.

Acetanilides↗
PubMed1975

Characterization of an inducible amidase from Pseudomonas acidovorans AE1.

The main molecular and catalytic properties of an acetanilide-hydrolyzing enzyme from Pseudomonas acidovorans AE 1, purified to a homogeneous state, were investigated. The molecular weight was 57 500 as determined by gel filtration and 55 300 as computed from the amino acid composition. By polyacrylamide gel electrophoresis in dodecylsulfate a polypeptide chain weight of 56 700 was obtained. Based on the reaction of the highly purufied enzyme with diethyl-4-nitrophenyl phosphate an equivalent weight of approximately 59 100 was found. From these results it was concluded that the enzyme consists of a single polypeptide chain and contains one active site per molecule. The enzyme hydrolyzed esters as well as certain aromatic amides. It also catalysed the transfer of acetyl groups to phenetidine yielding phenacetin. The activities towards aliphatic esters were much smaller. The enzyme was stable at pH values ranging from 7 to 9 and its pH-optimum was about 10. It was strongly inhibited by organophosphorous compounds, like diethyl-4-nitrophenyl phosphate or diisopropylphosphorofluoridate, as well as by physostigmine sulfate and -SH-blocking reagents, like HgCl-2 or 4-chloromercuribenzoic acid. o-Nitrophenol caused a competitive inhibition and phenetidine an uncompetitive inhibition.

Acetanilides↗
PubMed1978

The mechanism of action of cytochrome P-450. Occurrence of the 'NIH shift' during hydroperoxide-dependent aromatic hydroxylations.

The mechanism of liver microsomal aromatic hydroxylation has been investigated by using cumene hydroperoxide as the hydroxylating agent and comparing this reaction with the NADPH-dependent reaction. The conversion of [4-(3)H]acetanilide to 4-hydroxyacetanilide by rat liver microsomes (or purified cytochrome P-450) in the presence of either cumene hydroperoxide or NADPH is attended by comparable 'NIH shifts'. This indicates that hydroxylation in the two systems proceeds via a common intermediate, presumably an arene oxide. The intermediacy of an arene oxide, phenanthrene-9,10-oxide, is established by incubating [3-(3)H]-phenanthrene with rat-liver microsomes and cumene hydroperoxide in the presence of either non-radioactive phenanthrene-9,10-oxide as a 'trap' or in the presence of cyclohexene oxide, an inhibitor of the enzyme epoxide hydrase. Incubation of phenanthrene with cumene hydroperoxide in an 18O-enriched medium has confirmed that the oxygen atom in phenanthrene-9,10-oxide is derived from the hydroperoxide and not from the medium.

Acetanilides↗
PubMed1985

Cometabolism of low concentrations of propachlor, alachlor, and cycloate in sewage and lake water.

Low concentrations of propachlor (2-chloro-N-isopropylacetanilide) and alachlor [2-chloro-2',6'-diethyl-N-(methoxymethyl)acetanilide] were not mineralized, cycloate (S-ethyl-N-ethylthiocyclohexanecarbamate) was slowly or not mineralized, and aniline and cyclohexylamine were readily mineralized in sewage and lake water. Propachlor, alachlor, and cycloate were extensively metabolized, but the products were organic. Little conversion of propachlor and alachlor was evident in sterilized sewage or lake water. The cometabolism of propachlor was essentially linear with time in lake water and was well fit by zero-order kinetics in short periods and by first-order kinetics in longer periods in sewage. The rate of cometabolism in sewage was directly proportional to propachlor concentration at levels from 63 pg/ml to more than 100 ng/ml. Glucose but not aniline increased the yield of products formed during propachlor cometabolism in sewage. No microorganism able to use propachlor as a sole source of carbon and energy was isolated, but bacteria isolated from sewage and lake water metabolized this chemical. During the metabolism of this herbicide by two of the bacteria, none of the carbon was assimilated. Our data indicate that cometabolism of these pesticides takes place at concentrations of synthetic compounds that commonly occur in natural waters.

Acetamides↗
PubMed1991

Propachlor degradation by a soil bacterial community.

Soil from a pesticide disposal site was used to enrich for microorganisms that degraded the acylanilide herbicide propachlor (2-chloro-N-isopropylacetanilide). After seven transfers of the enrichment, the culture contained about six strains. The highest yield of microbial biomass occurred if just two of these isolates, strains DAK3 and MAB2, were inoculated into a mineral salts medium containing propachlor. When only strain DAK3 was grown on propachlor, a metabolite (2-chloro-N-isopropylacetamide) was released into the medium. Strain MAB2 could grow on this metabolite. The results of morphological and physiological tests suggest that strains DAK3 and MAB2 most closely resemble species belonging to the genera Moraxella and Xanthobacter, respectively. Strain DAK3 can respire and grow on N-substituted acylanilides containing methyl, ethyl, or isopropyl substitutions, but is incapable of respiration or growth on acetanilide, aniline, or the acylanilide herbicides alachlor and metolachlor. Strain DAK3 appears to use the aromatic C atoms of propachlor for growth, as suggested by the growth yield on propachlor and the induction of catechol 2,3-oxygenase activity in acylanilide-grown cells.

Acetamides↗
PubMed1999

Characterization of two novel propachlor degradation pathways in two species of soil bacteria.

Propachlor (2-chloro-N-isopropylacetanilide) is an acetamide herbicide used in preemergence. In this study, we isolated and characterized a soil bacterium, Acinetobacter strain BEM2, that was able to utilize this herbicide as the sole and limiting carbon source. Identification of the intermediates of propachlor degradation by this strain and characterization of new metabolites in the degradation of propachlor by a previously reported strain of Pseudomonas (PEM1) support two different propachlor degradation pathways. Washed-cell suspensions of strain PEM1 with propachlor accumulated N-isopropylacetanilide, acetanilide, acetamide, and catechol. Pseudomonas strain PEM1 grew on propachlor with a generation time of 3.4 h and a Ks of 0.17 +/- 0.04 mM. Acinetobacter strain BEM2 grew on propachlor with a generation time of 3.1 h and a Ks of 0.3 +/- 0.07 mM. Incubations with strain BEM2 resulted in accumulation of N-isopropylacetanilide, N-isopropylaniline, isopropylamine, and catechol. Both degradative pathways were inducible, and the principal product of the carbon atoms in the propachlor ring was carbon dioxide. These results and biodegradation experiments with the identified metabolites indicate that metabolism of propachlor by Pseudomonas sp. strain PEM1 proceeds through a different pathway from metabolism by Acinetobacter sp. strain BEM2.

Acetanilides↗
PubMed1979

99mTc-IDA imaging in the differential diagnosis of acute cholecystitis and acute pancreatitis.

99mTc-IDA (99mTc-dimethyl-acetanilide-iminodiacetic acid) hepato-biliary imaging was evaluated for its efficacy in distinguishing acute cholecystitis from acute pancreatitis. In a retrospective review, gallbladders were demonstrated by 99mTc-IDA in 13 of 15 patients (87%) with acute pancreatitis. This is significantly higher than reports on the frequency of gallbladder filling with oral and intravenous cholangiography in the presence of acute cholecystitis.

Acetanilides↗
PubMed1987

In vivo screening of glutathione related detoxification products in the early state of drug development.

Glutathione (GSH) adducts and consecutive degradation products thereof are indications of reactive intermediates during drug metabolism. As demonstrated with the analgesic SX-PP 16 (4-amino-3,5-dibromacetanilide), however, interactions of a drug with GSH can be detected by labelling the GSH-stores with labelled cysteine, and consecutive administration of the unlabelled drug even at therapeutic doses. The GSH-adducts are sensitively and specifically traced by HPLC, applying column-switching and a combination of diode-array- and radioactivity detection. This approach seems to be much more sensitive than a classical GSH-depletion study. The structure of the main metabolite of SX-PP 16 (46% of urinary excretion) was elucidated as 3-bromo-4-amino-5-mercapturyl-acetanilid.

Acetanilides↗
PubMed1991

Release of liver microsomal beta-glucuronidase from hepatocytes in vitro and in vivo by organophosphates and hepatotoxic agents.

Liver microsomal beta-glucuronidase is stabilized within microsomal vesicles by complexation with the accessory protein, named egasyn. In this study, we showed that egasyn is identical to one of the carboxylesterase isozymes and organophosphorus and carbamate insecticides, acetanilide which is a specific substrate of egasyn and halothane caused a rapid dissociation of the egasyn-microsomal beta-glucuronidase complex when administered in vivo or when added in vitro to isolated hepatocytes. The dissociation was relatively specific to organophosphates, carbamates, but not pyrethroids. Dissociation of the egasyn-beta-glucuronidase complex in vivo by organophosphates was followed by massive and rapid secretion of microsomal beta-glucuronidase into plasma. From these results, we concluded that release of liver microsomal beta-glucuronidase is the most rapid and sensitive marker to organophosphorus or carbamate insecticide-induced intoxication.

Acetanilides↗
PubMed1975

The metabolism of foreign compounds in the cestode, Moniezia expansa, and the nematode, Ascaris lumbricoides var suum.

1. The ability of the cestode Moniezia expansa and the nematode Ascaris lumbricoides var suum to metabolize foreign compounds has been assessed. 2. Both species were unable to oxidase aldrin, aniline, biphenyl, butylbenzene and nitrobenzene or to demethylate aminopyrine, and 4-nitroanisole. 3. M. expansa and A. lumbricoides var suum readily induced 4-nitroanisole, nitrobenzene, 4-nitrobenzoic acid and 4-nitrophenol to the corresponding amines. Azobenzene, dimethylaminoazobenzene, and 1,2-dimethyl-4-(4-carboxyphenylazo)-5-hydroxybenzene were also reduced. 4. Hydrolysis of esters, acetanilide, acetylsalicylic acid, aryl sulphates and aryl phosphates took place readily. However, beta-glucuronides were not hydrolysed. 5. The following reactions were not detected in either species: phosphate, sulphate, beta-glucuronide or beta-glycoside conjugation of phenolic compounds; acetylation of amino compounds, or the formation of glycine conjugates with 4-aminobenzoic acid or benzoic acid. 6. Male nematodes showed a higher rate of drug metabolism than female nematodes.

Acetanilides↗
PubMed1976

Subcellular localization and some properties of the N-deacetylase of the Cestode Moniezia expansa.

1. Acetanilide, acetamidophenol, acetanisidide, acetamidobenzoic acid and acetamidobenzaldehyde were hydrolysed by enzyme preparations from Moniezia expansa. Deacetylation occurred in the distal cytoplasm of the proglottids. 2. N-Deacetylase activity was found in the 75 000g supernatant of the tapeworm homogenates. The molecular weight of the enzyme was about 95 000. 3. The optimal pH of deacetylation for all substrates was 7-4. Dithiothreitol enhanced the reaction, but glutathione and cysteine were without effect. 4. Deacetylase activity was inhibited by p-chloromercuribenzoate, N-ethylmaleimide, Zn++, Cu++ and anthelmintic organophosphates.

Acetanilides↗