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PubMed1977

The localization and some properties of the N-deacetylase of Ascaris lumbricoides var suum.

1. Hydrolysis of acetanilide by the nematode Ascaris lumbricoides var suum occurred in the cytosol of the intestinal epithelium and to a lesser degree in the cytosol of the reproductive organs. Cuticle and mesenchyme fluid showed no measurable activity. 2. The molecular weight of the enzyme responsible for hydrolysis was estimated to be about 90 000. 3. Hydrolysis of N-acetyl compounds occurred optimally at pH 7-4 at 30-35 degrees and at a substrate concentration of 10(-2) M. 4. The reaction was inhibited 50% by Cu2+, Zn2+, n-ethylmaleimide or p-chloromercuribenzoate at 10(-4) M. The anthelmintic organophosphates inhibited N-deacetylation by 50% at 10(-7) M. Dithiothreitol enhanced the reaction rate but glutathione and thioglycollic acid were without effect.

Acetanilides↗
PubMed1983

Studies on the re-establishment of the intestinal microflora in germ-free rats with special reference to the metabolism of N-isopropyl-alpha-chloroacetanilide (propachlor).

Conventional rats metabolize 2-chloro-N-isopropylacetanilide (propachlor) mainly to various 2-methylsulphonylacetanilides and to residues in the faeces that are unextractable. Mercapturic acid pathway (MAP) metabolites of propachlor are the source of the methylsulphonyl sulphur and the insoluble faecal residues. Germ-free and antibiotic-treated rats quantitatively metabolized propachlor only to MAP metabolites, which were excreted in the urine and faeces (all water-soluble). Germ-free rats given enemas of caecal contents from conventional rats were qualitatively similar to conventional rats with respect to the metabolism of propachlor within 56 days of the inoculations i.e. they excreted 2-methylsulphonyl acetanilides in the urine and insoluble residues in the faeces. They approached quantitative similarity within 180 days. Antibiotic-treated rats spontaneously recovered the ability to metabolize propachlor as conventional rats, qualitatively within 6 days and quantitatively within 21 days. While differences occurred in the faecal metabolites of propachlor, biliary secretion of metabolites by germ-free rats was not different from that of conventional or antibiotic-treated rats.

Acetanilides↗
PubMed1988

The fate of 4-cyanoacetanilide in rats and mice; mechanism of formation of a novel electrophilic metabolite.

1. The metabolic fate of 4-cyanoacetanilide (CAA), labelled with 14C and 13C in the N-acetyl group, was studied in rats (oral dose, 22.5 mg/kg) and mice (oral dose 21.7 mg/kg). 2. The metabolic profile in the urine of rats was compared with that obtained previously with 4-cyano-N,N-dimethylaniline (CDA) and confirms the intermediacy of CAA in the metabolism of CDA. 3. The precursor of a major metabolite of CDA and CAA (the mercapturic acid N-acetyl-S-[2-keto-2-(4-cyanoanilino)ethyl]cysteine, metabolite C) was identified in the urine of CAA-dosed rats as the O-sulphate conjugate of N-(4-cyanophenyl)glycolamide. 4. Pretreatment of rats with the sulphotransferase inhibitor pentachlorophenol reduced the yield of the mercapturic acid metabolite C, further indicating the intermediacy of a sulphate conjugate. 5. Metabolite C was not formed from CAA by mice; thus, this species difference, also observed with CDA, occurs at the level side-chain (acetyl) hydroxylation as well as at N-acetylation of 4-cyanoaniline as previously proposed. 6. The significance of this pathway as a bioactivation reaction of CDA, CAA and other acetanilides is discussed.

Acetanilides↗
PubMed1990

Evidence for the absence of cysteine S-conjugate N-acetyltransferase activity in the metabolism of propachlor, naphthalene, and dichlobanil in calves.

1. The glutathione conjugate of 2-chloro-N-isopropyl[1-14C]acetanilide (14C-propachlor) was perfused through a calf kidney in situ; 23% of the dose was excreted in the perfused kidney urine as the cysteine conjugate, no mercapturic acid was detected. 2. A 5-day-old calf dosed orally with 14C-propachlor excreted 70% dose in the urine as the cysteine conjugate; no mercapturic acid was detected. Rumen microflora were established in the calf (5 weeks older) and the experiment was repeated with the same results. 3. When the same calf was dosed 1 week later with 14C-naphthalene, 99% dose was excreted in the urine, mostly as the dihydrodiol-glucuronide (34%) and the dihydrohydroxy-cysteine conjugate (47%); no mercapturate was detected. 4. A 9-day-old calf dosed orally with 2,6,-dichlorobenzo[14C]nitrile (14C-dichlobanil) excreted 67% dose in the urine as cysteine conjugates (34%), and products of cysteine conjugate beta-lyase cleavage of cysteine conjugates (30%); no mercapturates were detected. 5. Cysteine S-conjugate N-acetyltransferase activity in calf kidney and liver was about 10% of that in the corresponding rat tissues.

Acetanilides↗
PubMed1994

Biotransformation of monochloroanilines in guppy, Poecilia reticulata.

1. Guppies (Poecilia reticulata) were exposed for 96 h to 4-chloroaniline (4CA), 3-chloroaniline (3CA) and 2-chloroaniline (2CA) in a static exposure system. 4-Chloroacetanilide (N4CA), 3-chloroacetanilide (N3CA), and 2-chloroacetanilide (N2CA) were identified in test water as the respective biotransformation products. 2. Dependence of biotransformation on aqueous concentration was investigated with 4CA. The measured biotransformation product in water (N4CA) increased with concentration increase of parent compound, 4CA, and with exposure time. 3. Quantitative differences in net acetylation of the three monochlorinated anilines were examined. The amount of acetanilide found in water increased in the following order: N2CA < N3CA < N4CA. Mass balance calculations indicated the highest loss of aniline occurred for 2CA. This compound, which is highest in toxicity, had the smallest amount of acetylated product formed. 4. This study proves, for the first time, that the acetylation reaction in fish is reversible. Quantitative differences in the net deacetylation of monochloroacetanilides were observed. The amount of deacetylated product found in water increased in the order 4CA < 3CA < 2CA.

Acetanilides↗
PubMedDate not supplied

Polyamines and drug oxidations.

The addition of spermine or of spermidine to rat liver assay systems produced marked changes in a number of microsomal drug oxidations. The hydroxylation of aniline and the N-demethylation of ethylmorphine were both enhanced with concentrations of 1-10 mM spermine or of spermidine. The results with putrescine on ethylmorphine metabolism were less dramatic, and no effect could be observed with putrescine in studies with other drug substrates. In contrast to the enhancing effects, inhibition was observed when spermine or spermidine was added to p-nitroanisole O-demethylation assay mixtures, and no effect was observed in assays for acetanilide hydroxylation. The inhibiting and enhancing effects of the polyamines can be observed in assays containing liver preparations from both male and female rats, and those from rats pretreated with phenobarbital or 3-methylcholanthrene. In all studies, the alterations were kinetically noncompetitive. The effects were shown to be independent of the NADPH-generating system and the cation requirements, and were not mediated through an interaction with NADPH-cytochrome c reductase. The possibility is considered that the enhancing and inhibiting effects may be related to the ability of these polycations to bind to microsomal membranes and cause alterations at different sites of substrate interaction.

Acetanilides↗
PubMedDate not supplied

Local anaesthetic activity of some new substituted acylamides II.

Six new substituted acylamides, chemically related to lignocaine were studied for local anaesthetic activity and toxicity in mice, frogs and guinea pigs. Only one of these compounds, w-pyrrolidino 2, 3, 5, 6 tetramethyl acetanilide was found to possess potency comparable to lignocaine with a slightly higher therapeutic index. Study of the S.A.R. of this group indicated that by removal of two methyl groups at position 3 and 5 in the above compound, a local anaesthetic with greater potency than lignocaine may be obtained. Further exploration of the potentialities of a compound having pyrrolidine group as a part of basic side chain is indicated.

Acetanilides↗
PubMedDate not supplied

[Interaction of local anesthetics with model ion channels].

A theoretical study of intermolecular interactions between local anesthetics of the acetanilide series and model ionic channels was performed. A dimer of gramicidine A and melittin were used as models of ionic channels. The geometry of molecules was determined by the method of molecular mechanics. Statistically significant correlation equations were derived, which relate the indices of local anesthetizing activity to the characteristics of intermolecular interactions in the anesthetic-peptide system. A comparative analysis of intermolecular interactions in anesthetic-gramicidine A and anesthetic-melittin systems was carried out.

Acetanilides↗
PubMed1975

[Action of the herbicide Ramrod on the embryogenesis of white rats].

The embryotoxic and teratogenic activity of the acetanilide Ramrod is subjected to experimental testing. Studies are conducted on 103 white unbred female rats, to which the preparation was administered throughout the full gestation period, at doses 1/5, 1/10, 1/30 and 1/40 LD50. Following in reduction of the preparation, an increase in the total embryonal lethality was noted, conditioned entirely by the considerable rise, as compared to controls, of the pre-implantation deaths of embryos. The embryotoxic action of the preparation was furthermore manifested with a decrease in body weight and in the craniocaudal fetal sizes. Upon giving 1/5 and 1/10 LD50 Ramrod, a slight teratogenic effect was recorded. Ramrod at dose 1/40 LD50 exerted no effect whatsoever on embryogenesis.

Acetanilides↗
PubMed1975

[Formation of sulfhemoglobin using various drugs].

It is well known that aniline and hydroxylamine derivatives induce methemoglobinemia in humans as well as various animal species. It was noticed that sulfhemoglobinemia was induced by subchronic administration of N-(4-chlorophenyl)-beta-(4-hydroxymethylphenoxy)ethylurethane (HPU) to rabbits (p.o.), cats (i.p.) and mice (i.p.). Sulfhemoglobin (SHb) and methemoglobin (MHb) formation by various compounds structurally related to HPU were examined by a single and three consecutive intraperitoneal administrations to mice. It was found that by a single administration, methemoglobinemia was induced by phenylhydroxylamine (PHA), nitrobenzene (NB), aniline (A), 2-chloro-A (2-Cl-A), 3-Cl-A, 4-Cl-A, acetanilide (AA), phenacetin (PA), N-(4-chlorophenyl)ethylurethane (CPU), hydroxylamine (HA) and sodium nitrite (SN), and was not observed with phenylurethane, HPU, methylhydroxylamine (MHA), methylamine and nitromethane (NM). On the other hand, with sulfhamoglobinemia which appeared much more delayed than MHb, a single administration, was found to be induced by PHA, 3-Cl-A, 4-Cl-A, PA, CPU, MHA and SN. Furthermore, with three consecutive administrations, such was induced by NB, 2-Cl-A, AA, HPU and NM even though SHb was not demonstrated with a single administration. Structure-SHb forming property relationship and mechanism for SHb formation are discussed.

Acetanilides↗
PubMedDate not supplied

Perazine as a potent inhibitor of human CYP1A2 but not CYP3A4.

The effects of perazine on the activities of CYP1A2 and CYP3A4 in a primary culture of human hepatocytes of one patient were studied in vitro. The CYPs activities were assessed by measuring the rate of acetanilide 4-hydroxylation (CYP1A2) and cyclosporine A oxidation (CYP3A4) after treatment with TCDD (a CYP1A subfamily inducer) or rifampicin (mainly a CYP3A4 inducer). The amounts of the metabolites formed in hepatocytes were assayed in the extracellular medium using the HPLC method. TCDD and rifampicin induced the formation of 4-hydroxyacetanilide and cyclosporine A metabolites (monohydroxycyclosporine A, dihydroxycyclosporine A, N-desmethylcyclosporine A), respectively. The formation of 4-hydroxyacetanilide was strongly inhibited by three different concentrations of perazine (10, 25 and 50 microM) reaching 8, 3 and 2% of the control value, respectively. In the case of CYP3A4 activity, no such an effect of perazine was observed. Perazine showed only a week inhibition of the activity of cyclosporine A oxidase (to 96-86% of the control value). The obtained results suggest a strong inhibitory effect of perazine on human CYP1A2 activity with predicted Ki value similar to those of the known for CYP1A2 inhibitors, such as furafylline and fluvoxamine.

Acetanilides↗
PubMed2004

Characterization of a strain of Sphingobacterium sp. and its degradation to herbicide mefenacet.

A bacterium (designated strain Y1) degrading acetanilide herbicide mefenacet was isolated from aerobic sludge. Based on the analyses of partial 16S rRNA gene, cellular fatty acid and BIOLOG-GN, and general physiological and biochemical characteristics, strain Y1 was identified as Sphingobacterium multivolum. Strain Y1 was able to degrade mefenacet used as sources of carbon and energy. Degradation of mefenacet was accompanied by producing the metabolites N-methylaniline and an unidentified compound with molecular weight 205, indicating a metabolic pathway of mefenacet initiated by hydrolysis of amido bond.

Acetamides↗
PubMedDate not supplied

Development of EPA method 535 for the determination of chloroacetanilide and other acetamide herbicide degradates in drinking water by solid-phase extraction and liquid chromatography/tandem mass spectrometry.

U.S. Environmental Protection Agency (EPA) Method 535 has been developed in order to provide a method for the analysis of "Alachlor ESA and other acetanilide degradation products," which are listed on EPA's 1998 Drinking Water Contaminant Candidate List. Method 535 uses solid-phase extraction with a nonporous graphitized carbon sorbent to extract the ethane sulfonic acid (ESA) and oxanilic acid degradates of propachlor, flufenacet, dimethenamid, alachlor, acetochlor, and metolachlor from finished drinking water matrixes. Separation and quantitation of the target analytes are achieved with liquid chromatography/tandem mass spectrometry. Dimethachlor ESA and butachlor ESA were chosen during the method development as the surrogate and internal standard. Drinking water samples were dechlorinated with ammonium chloride without adversely affecting the analyte recoveries. Typical mean recoveries of 92-116% in deionized water and 89-116% in ground water were observed with relative standard deviations of <5%.

Acetamides↗
PubMed1989

Addition of reducing agents to the peroxidase-o-phenylenediamine buffer reduces background of enzyme immunoassays.

The concentrations of o-phenylenediamine (OPD), H2O2, citrate and H+ in a substrate buffer for peroxidase immunoassays were optimized for minimal background. The background was reduced 2-3 fold with 5.5 mM OPD, 3 mM H2O2, 150 mM citric acid/sodium citrate, pH 4.8, and the reproducibility interassay was increased. A further 3-5 fold reduction of the background was obtained by the addition of 1.5 mM acetanilide, 0.14 mM beta-mercaptoethanol and 5 mM nitrilotriacetic acid to the substrate buffer. This low-background substrate buffer allows increased sensitivity and lowers the interassay variation coefficient. It has been used successfully in peroxidase immunoassays of human C-reactive protein, human antiestreptolysin and human rheumatoid factor.

Acetanilides↗
PubMed1989

[Activity of enzymes participating in xenobiotic metabolism and the condition of microsomal membranes of rat liver in vitamin K deficiency].

Alimentary deficiency or vitamin K (vitamin K-poor diet) as well as the vitamin deficiency resulting from sinkumar administration are accompanied by a decreased activity of microsomal demethylases, hydroxylase, NADH- and nNADPH-reductases of dichlorophenolindophenol and neotrazolium. The activity of cytosolic enzymes (only glutathione-S-transferases, aryl- and allyl esterases) is diminished in a lesser degree. Vitamin K deficiency does not significantly interfere with the effect of the xenobiotic metabolism enzyme inducer (phenobarbital) or the cytochrome P-450 inhibitor (cobalt chloride). The changes in the enzyme activity result in a decrease of acetanilide biotransformation. A possible reason for the observed changes in the activity of microsomal enzymes is the weakening of hydrophobic and polar interactions in microsomal membranes. This hypothesis was confirmed by experiments with the use of membrane perturbants as well as by solubilization of membrane-bound enzymes.

Acetanilides↗
PubMed1985

Metabolic activation and toxicity of acetaminophen and related analogs. A theoretical study.

Reaction thermodynamics have been calculated for an oxene model for cytochrome P-450 oxidations of four related arylamines: aniline, p-hydroxyaniline, acetanilide, and acetaminophen, by both radical and nonradical mechanisms, using a semiempirical molecular orbital method (modified neglect of differential overlap). The results indicate that for both p-hydroxyaniline and acetaminophen, a recently proposed peroxidase-like mechanism leading directly to p-benzoquinoneimines via radical intermediates is thermodynamically favored over N-hydroxylamine formation by H abstraction or addition rearrangement. These studies also provide a detailed characterization of three candidate species for the toxic reactive intermediate of acetaminophen: 1) p-benzoquinoneimines, 2) the radical intermediate formed by H abstraction from the nitrogen, and 3) the radical intermediate formed by H abstraction from the phenol. Calculated electron and spin densities indicate that the radical formed by H abstraction from the phenol oxygen does not remain localized on the oxygen, but is primarily a semiquinone aryl radical with significant unpaired spin density on the ring carbon atoms, particularly on C-3 and C-5. This result is consistent with the hyperfine splitting pattern observed for a transient radical species in a hydroxyl radical-mediated chemical oxidation of acetaminophen. The radical formed by H abstraction from the nitrogen also delocalizes on the ring carbons, but to a lesser extent and at the 2- and 4-positions. A closed shell mechanism of N oxidation of arylamines appears to lead directly to the hydroxylamines with less likelihood of precursor reactive intermediates. Toxic species could then be formed by loss of H2O from the hydroxylamines.

Acetaminophen↗
PubMed1987

Trypanocidal activity of a 5-substituted 2-nitroimidazole compound (Ro 15-0216) in mice.

The trypanocidal activity of a 5-substituted 2-nitroimidazole compound (Ro 15-0216, 2-(dimethylamino)-4'-[(1-methyl-2-nitroimidazole-5-yl) methoxy] acetanilid) was tested in stocks of T.b. brucei, T.b. evansi, T. vivax, and T. congolense. The trypanosome stocks showed different sensitivities, the Trypanozoon group was most sensitive followed by T. vivax and T. congolense. Administration of the compound in the drinking water was superior to single intraperitoneal injections. A T.b. brucei stock with reduced sensitivity to Mel B and insensitive to diminazene aceturate was cured by a dose 13 times greater than that necessary for the drug-sensitive T.b. brucei stock, administered in the drinking water. Quinapyramine- and quinapyramine/suramin-resistant stocks of T.b. evansi were eliminated with doses of 63 and 160 mg/kg i.p., respectively; to eliminate the drug-sensitive T.b. brucei stock, 250 mg/kg i.p. were required. The combination of Ro 15-0216 with suramin showed a synergistic effect in suramin-sensitive and in suramin-resistant stocks of T.b. evansi, although high doses of suramin were applied in the latter. Synergism of Ro 15-0216 with diminazene aceturate was demonstrated in T. congolense-infected mice.

Acetanilides↗
PubMedDate not supplied

[Effect of various supplies of vitamin B2 in the rat body on the activity of enzymes participating in the metabolism of xenobiotics].

Studies on the effect of different content of vitamin B2 (alimentary deficiency, additional administration) in the rat organism on the activity of enzymes participating in the metabolism of foreign substances and on the inducing effect of phenobarbital have shown that vitamin B2 to a considerable extent controls the activity of flavin-containing enzymes participating in the metabolism of xenobiotics (D-amino acid oxidase, xanthine and aldehyde oxidases, NADH- and NADPH-reductase activity of neotetrazolium) and a number of enzymes for which flavins do not play the role of prosthetic group (esterases aldehyde and formaldehyde dehydrogenases, demethylase and hydroxylase). Different content of vitamin B2 in animal organism also influences the action of phenobarbital, an inductor of xenobiotics metabolism, and the acetanilide biotransformation rate.

Acetanilides↗