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PubMed1984

[Studies on the distribution and transport kinetics in membrane and distribution models].

The concentration-time dependence of two weak acids (salicylic acid, benzoic acid), one weak base (benzocaine) and one neutral agent (acetanilid) has been studied in membrane or distribution models by polyacrylat-D 340-membranes or cyclohexane phases. The transport rate constants of outflow from the donator compartment or influx into the acceptor compartment as well as the distribution coefficients membrane/water or cyclohexane/water had been calculated from the concentration-time courses. In contrast to the polyacrylate membrane, the outflow from the donator compartment and the influx into the acceptor compartment proportionate to the corresponding distribution coefficient with the use of the cyclohexane phase. The influx into the acceptor compartment is in the polyacrylate membrane delayed by interactions between the membrane and the permeant. The membrane/water distribution coefficients figured out from the permeation test correspond with values formerly derived from equilibrium tests.

Acetanilides↗
PubMed1981

The metabolic basis for inhibitory effects in chemical carcinogenesis by arylamines.

The inhibition of the carcinogenicity of N-2-fluorenylacetamide (2-FAA) by acetanilide (AA), p-hydroxyacetanilide (p-OH-AA), butylated hydroxytoluene (BHT), and chloramphenicol is reviewed. The mechanisms of action by which inhibition may occur are as follows: 1) inhibition of the binding of the activated metabolite of FAA to cellular macromolecules (DNA, RNA, and proteins), 2) changes in the amount of the N-hydroxylated metabolite, believed to be the first step of activation of FAA, formed and excreted in the urine, 3) induction of the enzyme glucuronyl transferase which increases the formation of glucosiduronic acid that results in a rapid excretion of the carcinogens, 4) depletion of sulfate by p-OH-AA, the major metabolite of AA. The sulfate ion is required for the second activation step, i.e., the formation of the sulfate ester of N-OH-FAA. The data show several of the inhibitors may operate by one or more of the above mechanisms of inhibition.

2-Acetylaminofluorene↗
PubMedDate not supplied

Inhibition of human red blood cell N-acetyltransferase.

Acetanilide and derivatives of benzoic acid, benzamide, salicylic acid, and salicylamide were tested as inhibitors of p-aminobenzoic acid N-acetyltransferase partially purified from peripheral blood of three rapid and two slow dapsone acetylator human volunteers. The 50% inhibition point of these compounds does not provide a kinetic basis for differentiating the rapid and slow dapsone acetylator phenotypes.

4-Aminobenzoic Acid↗
PubMed1976

Specifity and sensitivity of the inhibition of drug metabolism following inhalation of carbon disulphide-air mixtures.

A single 8-h exposure of adult female Wistar rats to 20 ppm carbon disulphide (CS2), the threshold limit value (TLV) in several countries, was sufficient to cause inhibition of the following drug-metabolizing reactions: formation of trichloroethanol and trichloroacetic acid from trichloroethylene (aliphatic C-hydroxylation), formation of 4-hydroxyantipyrine from antipyrine (quasi-aromatic C-hydroxylation), formation of acetaminophenol from acetanilid (aromatic C-hydroxylation) and phenacetin (oxidative odealkylation), respectively, and formation of 4-aminoantipyrine from aminopyrine (oxidative N-demethylation). The behaviour of these effects was dependent on the dose of CS2 administered in that the inhibitory process was enhanced when increasing the concentration to (50), 100, 200, and 400 ppm. The respective changes could be demonstrated by a short-duration (6-h) reduction in the urinary excretion of the metabolites. In the case of trichloroethylene the limitation in metabolite formation persisted for as long as 36 h due to the varying rate of formation of trichloroethanol and trichloroacetic acid. This deficiency in excretion was compensated in part during the subsequent elimination phase (up to 24 and 36 h, respectively), an observation which suggests the rapid reversibility of the alteration. As shown by the respective prolongation of the hexobarbital sleeping time in the rat, the side-chain oxidation of hexobarbital to ketohexobarbital was increasingly inhibited by rising concentrations of CS2 in the range of 20 to 400 ppm/8 h. On the basis of the present results it is concluded that CS2 also inhibits various oxygenases of the microsomal enzyme system. In adult female NMRI mice a significant inhibition of the microsomal procaine-hydrolyzing esterase of the liver was observed only after 400 ppm/8 h; however, this limitation did not affect the LD50 of procaine-HCl, particularly as the corresponding serum esterase activity also remained uninfluenced. The aromatic N-acetylation of sulphisomidine and the quasi-aromatic N-acetylation of 4-aminoantipyrine in rats failed to be significantly reduced by CS2 even after 400 ppm/8 h, nor did the same dose of CS2 affect the glucuronidation of 4-hydroxyantipyrine in the same animal species. It is concluded from the above results that the specificity and sensitivity of the inhibition of drug metabolism observed in small laboratory animals is probably similar to that prevailing in man. This assumption has already been substantiated for the oxidative N-demethylation of aminopyrine.

Acetanilides↗
PubMed1996

Cancer incidence among alachlor manufacturing workers.

A historical cohort study was conducted to evaluate cancer incidence among chemical workers with occupational and environmental exposure to alachlor, the active ingredient in a family of pre-emergent acetanilide herbicides. The study followed 943 workers with at least 1 year of cumulative employment at the Monsanto plant in Muscatine, Iowa, from startup of the alachlor manufacturing process in March 1968 through December 1990. Approximately 96% of all workers were successfully traced to determine their last known residence and cancer status. Eighteen workers were diagnosed with cancer during the follow-up period, based on pathology information from the statewide cancer registry maintained by the State Health Registry of Iowa. The standardized incidence ratio for all cancers was 1.5 (95% CI 0.9-2.4) for all workers exposed to alachlor, which was due primarily to elevated rates for colorectal cancer and chronic myeloid leukemia. Workers with 5 or more years in estimated high alachlor exposure jobs had elevated rates of colorectal cancer (3 cases, SIR = 5.2, 95% CI 1.1-15.1). Interpretation of the study results is limited by the small size of the study population, minimal length of follow-up, and current information concerning alachlor metabolism in primates and humans. Nonetheless, the findings suggest the need for continued evaluation of this and other alachlor-exposed cohorts.

Acetamides↗
PubMed1999

Metabolism of polychlorinated dibenzo-p-dioxins by rat liver microsomes.

The in vitro metabolism of several chlorinated dibenzo-p-dioxin congeners (PCDDs) was studied using rat liver microsomes as a source of CYP 1 enzymes. The reactions were kinetically first order in both enzyme and substrate and showed a general trend toward decreasing reactivity with increasing chlorination. Michaelis-Menten kinetics were followed for 1-chlorodibenzo-p-dioxin (1-CDD); the reactivity of the enzyme preparation toward 1-CDD exactly paralleled its activity toward 7-ethoxyresorufin. The unreactive congeners 1,2,3,7,8-pentachlorodibenzo-p-dioxin (PeCDD) and 2,2'-dichlorobiphenyl (2,2'-DCB) acted as competitive inhibitors toward 1-CDD, with inhibition constants in the micromolar range, similar to the value of the Michaelis constant of 1-CDD. The inhibitory potency of furafylline, a mechanism-based inhibitor that is selective for CYP 1A2, declined in the order acetanilide (standard) > 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) > 1-CDD. We conclude that 1-CDD and 1,2,3,4-TCDD are oxidized almost exclusively by CYP 1A1, whereas 2,3,7,8-TCDD and 1,2,4,7,8-PeCDD are oxidized mainly by CYP 1A2. 1,2,3,7,8-PeCDD was oxidized too slowly for us to reach any conclusion about the P450 isozyme responsible.

Animals↗
PubMed2004

Quantitative determination of p-aminosalicylic acid and its degradation product m-aminophenol in pellets by ion-pair high-performance liquid chromatography applying the monolithic Chromolith Speedrod RP-18e column.

An ion-pair high performance liquid chromatographic method was developed for the simultaneous determination of p-aminosalicylic acid (PAS) and its degradation product m-aminophenol (MAP) in a newly developed multiparticular drug delivery system. Owing to the concentration differences of PAS and MAP, acetanilide and sulfanilic acid were used as internal standards, respectively. The separation was performed on a Chromolith SpeedROD RP-18e column, a new packing material consisting of monolithic rods of highly porous silica. The mobile phase composition was of 20 mm phosphate buffer, 20 mm tetrabutylammonium hydrogen sulphate and 16% (v/v) methanol adjusted to pH 6.8, at a flow-rate of 1.0 mL/min, resulting in a run-time of about 6 min. Detection was by UV at 233 nm. The method was validated and proved to be useful for stability testing of the new dosage form. Separation efficiency was compared between the new packing material Chromolith SpeedROD RP-18e and the conventional reversed-phase cartridge LiChroCART 125-4 (5 microm). A robustness test was carried out on both columns and different separation parameters (retention, resolution, run time, temperature) were determined.

Aminophenols↗
PubMed2004

High-performance liquid chromatographic method for simultaneous determination of sophoridine and matrine in rat plasma.

A high-performance liquid chromatographic (HPLC) method is described for the simultaneous determination of sophoridine and matrine in rat plasma. Sophoridine and matrine in the resulting supernatant of the plasma deproteinized with acetonitrile containing an internal standard (acetanilide) were directly determined by reversed-phase HPLC and ultraviolet detection. The result of limits of quantitation for matrine and sophoridine were 200 and 350 ng/mL in plasma, respectively, and recovery of both analytes was greater than 98%. The assay was linear from 250 to 4000 ng/mL for matrine and from 500 to 8000 ng/mL for sophoridine. Variation over the range of the standard curve was less than 15%. The method was used to determine the concentration-time profiles of matrine and sophoridine in the plasma following oral administration of Kexieling tablets, which is one of the preparations of Kudouzi at a dose equivalent to 30 and 60 mg/kg of matrine and sophoridine, respectively.

Alkaloids↗
PubMed1986

The murine aromatic hydrocarbon responsiveness locus: a comparison of receptor levels and several inducible enzyme activities among recombinant inbred lines.

The aromatic hydrocarbon responsiveness (Ah) locus has been correlated with genetic differences in the risk of drug toxicity, teratogenesis, chemical carcinogenesis, and mutagenesis. Hepatic cytosolic Ah receptor levels, 2-amino-5-chlorobenzoxazole (zoxazolamine) paralysis time following beta-naphthoflavone treatment and aryl hydrocarbon hydroxylase (AHH3, acetanilide 4-hydroxylase (Ac4H), and NAD(P)H:menadione oxidoreductase (NMOR)4, induction by 3-methylcholanthrene were studied in (a) the progenitors C57BL/6J (Ahb/Ahb) and DBA/2J (Ahd/Ahd) and 25 BXD recombinant inbred lines, (b) the progenitors C57BL/6N and C3H/HeN and 14 B6NXC3N recombinant inbred lines, and (c) the progenitors C57BL/6J and C3H/HeJ and 12 BXH recombinant inbred lines. The Ahb phenotype exhibits greater than 5 femtomole receptor/mg of cytosolic protein, less than or equal to 15 minutes zoxazolamine paralysis time, and twofold to 15-fold induction of these three hepatic enzyme activities; the Ahd phenotype exhibits less than or equal to 2 fmol receptor/mg protein, greater than 15 minutes zoxazolamine paralysis time, and less than 30% induction of these three activities. Among the BXD lines but especially among the B6NXC3N and BXH lines, high frequencies of recombination were found; the phenotype of each of the five parameters did not segregate with the phenotype of each of the other parameters in four or more recombinant lines. This report shows for the first time that AHH induction by 3-methylcholanthrene can occur in the Ahd phenotype mouse. These data underline the complexity of this genetic system when genes from C57BL/6 and DBA/2 are combined and particularly when genes from C57BL/6 and C3H/He inbred mouse strains are combined.

Animals↗
PubMed1989

Induction of cytochrome P-450 isozymes by mirex and chlordecone.

The effect of the insecticides, mirex and chordecone (Kepone), on the cytochrome P-450 monooxygenase system in C57BL/6N mouse liver microsomes was studied. Mice were treated intraperitoneally with low (6 mg/kg) and high (30 mg/kg) doses of mirex and chlordecone in corn oil for 2 days. For comparison, mice were also treated with either phenobarbital (PB) or 3-methylcholanthrene (3-MC). All treatments significantly increased the hepatic microsomal P-450 content over that of controls. Benzphetamine N-demethylase, ethoxyresorufin O-deethylase, benzo[a]pyrene hydroxylase, and acetanilide hydroxylase activities were also determined. Mirex and chlordecone resembled phenobarbital with respect to the induction of monooxygenase activities. Immunoquantitation with antibodies to purified P-450 IIB1 (Pb-induced P-450) and P-450 IA1 (3-MC-induced P-450) indicated that mirex and chlordecone induced P-450 IIB1 in a dose-dependent manner. The high dose of mirex also induced a small amount of a protein cross reacting with the antibody to IA1. The induction of this isozyme did not, however, contribute significantly to the monooxygenase activities measured.

Animals↗
PubMed2003

Electron ionization-induced fragmentation of N-(alkoxymethyl)anilides.

Electron ionization-induced fragmentation patterns of the series of N-(alkoxymethyl)acetanilides and related formanilides and benzanilides have been studied. The main fragmentation reaction observed for all compounds studied is the loss of an alkyl radical from the N-alkoxymethyl group leading to the appropriate protonated N-acylformanilide derivatives. This reaction is accompanied by unusually high kinetic energy release. Other important fragmentations common for majority of the compounds studied are (i) loss of an aldehyde molecule derived from an alkoxyl group yielding an appropriate N-acyl-N-methylaniline, (ii) elimination of a C(n)H(2n)O(2) fragment derived from N-alkoxymethyl group and carbonyl group oxygen atom and (iii) formation of N-methyleneaniline radical cation.

Journal Article↗
PubMed1982

Effect of some formulation adjuncts on the stability of benzoyl peroxide.

The stability of benzoyl peroxide in polyethylene glycol ointment base and some liquid vehicles (acetone, ethanol, propylene glycol, and their mixtures) was studied. Some solutions also contained an additional ingredient (acetanilide, benzoic acid, chlorhydroxyquinoline, and hydroxyquinoline) as a possible stabilizer. Benzoyl peroxide decomposed very fast (first-order K value 0.028 day-1 at 24 degrees) in polyethylene glycol ointment base. At 50 degrees, the potency of benzoyl peroxide in polyethylene glycol ointment base decreased to less than 1% in 5 days. Decomposition in solutions is complex. Considering acetone as a standard vehicle, ethanol improved the stability of benzoyl peroxide and propylene glycol had an adverse effect on the stability. Of the stabilizers studied, only chlorhydroxyquinoline improved the stability.

Benzoyl Peroxide↗
PubMed1991

Mutagenic and analgesic activities of aniline derivatives.

Phenacetin (1), acetaminophen (2), acetanilide (3), 4-aminophenol (4), and aniline (5) were tested in S.J.L. Swiss mice for their mutagenic and analgesic activities. The S-analogues of 1 and 2, 4-mercaptoacetanilide (6) and 4-ethylthioacetanilide (7), respectively, were synthesized and tested in the same way to define if both activities could be separated by molecular modification. All the compounds tested exhibited analgesic activity with ED50 values ranging from 12.6 to 158.5 mg/kg. The compounds could be arranged in a decreasing order of analgesic activity as follows: 3 greater than 4 congruent to 5 congruent to 6 greater than 1 congruent to 7 greater than 2. All the compounds, except 6, were positive mutagens in the micronucleus test (statistically significant). The order of relative mutagenic potencies was 1 congruent to 7 greater than 4 greater than 2 congruent to 3 congruent to 5. A narrow dose-response curve relationship was found for 5 and its metabolite 4, the relative mutagenic potencies of which suggest ring hydroxylation as the major pathway of biotoxification. No parallelism was found between analgesic and mutagenic activities, so they could be separated by pharmacomodulation: 6 was more effective as an analgesic in the acetic acid test than 2, and no mutagenic activity was found at the doses assayed.

Acetates↗
PubMed1994

Simultaneous determination of primidone and its active metabolites in rat plasma by high-performance liquid chromatography using a solid-phase extraction technique.

Primidone (PRM) and its active metabolites, phenylethylmalonamide (PEMA) and phenobarbital (PB), in rat plasma were simultaneously determined using a solid-phase extraction technique followed by high-performance liquid chromatography (HPLC). Twenty microliters of plasma was applied to a Bond-Elut C-18 cartridge column with 0.1 microgram of acetanilide (internal standard, IS). After the column was washed, PRM, PEMA, PB, and IS were eluted with methanol and injected into the HPLC system. Calibrations for these substances were linear in the range of 0-20 micrograms/mL. The coefficients of variation were 1.5-7.9% and 3.4-9.1% in the within-day and between-day assays, respectively. The recovery rates were 96.8-101.8%. The pharmacokinetics of these substances were examined after oral administration of PRM (50 mg/kg) to rats. The Tmax values for PRM, PEMA, and PB were 1.4, 5.7, and 6.6 h, respectively, and the Cmax values were 18.2, 8.1, and 9.6 micrograms/mL, respectively. This method is useful for pharmacokinetic studies of PRM and its active metabolites.

Administration, Oral↗
PubMed1989

Mutagen activation by cDNA-expressed P(1)450, P(3)450, and P450a.

cDNAs for rodent P(1)450, P(3)450, and P450a were expressed in the modified vaccinia virus-T7 RNA polymerase system. Each P450 exhibited its appropriate molecular weight and characteristic enzyme activity. Aryl hydrocarbon hydroxylase activity was catalyzed by P(1)450, acetanilide hydroxylase by P(3)450, and testosterone 7 alpha-hydroxylase by P450a. Ethoxycoumarin deethylase was exhibited by both P(1)450 and P(3)450. Each expressed P450 was also analyzed for its ability to activate 19 carcinogens of diverse classes to their mutagenic forms. Most notable was the activation of several polycyclic aromatic hydrocarbons by P1 and the activation of acetylaminofluorene, 4-aminobiphenyl, and several heterocyclic amine food pyrolysate products by P(3)450. P450a, in contrast, showed slight mutagen activation only toward N-hydroxy-2-acetyl aminofluorene. The vaccinia virus-T7 RNA polymerase system described here can express cDNAs for diverse forms of P450, each of which can then be characterized for substrate and product specificity and for mutagen activation.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1994

Elevated expression of the Cyp1a2 gene in the presence of nicotinamide by adult mouse hepatocytes in primary culture.

Effects of nicotinamide on expression of Cyp1a1 and Cyp1a2 genes were investigated in adult C57BL/6NCrj mouse hepatocytes in primary culture. The cells were cultivated for up to 8 days as monolayers or spheroids (multicellular aggregates), respectively, on collagen-coated or noncoated dishes. CYP1A1 mRNA was prominently induced after exposure to 3-methylcholanthrene (MCA) throughout the observation period with either type of culture. In monolayer-cultured cells, substantial induction of CYP1A2 mRNA by MCA was observed only at day 1 of cultivation, followed by a decrease to very low levels thereafter. In contrast, prominent elevation of both mRNA species in spheroid culture was observed throughout the 8-day experimental period. In the presence of nicotinamide, the decrease in expression of CYP1A2 mRNA in monolayer-cultured hepatocytes was restored concentration-dependently and at 10 mM nicotinamide the induced amounts were equivalent to those observed in spheroid cells. Nicotinamide also elevated CYP1A2 mRNA expression in spheroid culture, but in both cases induction of CYP1A1 mRNA decreased. Constitutive expression of CYP1A2 mRNA in monolayer culture rapidly decreased with increasing culture period, but addition of nicotinamide likewise inhibited the decrease. Nicotinamide also restored considerable expression of CYP1A2 mRNA when not present from the start of cultivation, but added 24 h before. Activities of aryl hydrocarbon hydroxylase (AHH) and acetanilide-4-hydroxylase (AAH) were elevated with either type of culture after treatment with MCA and the presence of nicotinamide further increased the AAH, resulting in an increment in the activity ratio of AAH vs AHH. Intracellular contents of NAD were considerably elevated by addition of nicotinamide. However, isonicotinamide, which is not converted to NAD in the cell, also elevated CYP1A2 mRNA expression prominently. Furthermore, NAD contents in spheroid culture were not higher than those in monolayer culture. These observations indicate that the presence of nicotinamide in the medium restores constitutive and inducible expression of Cyp1a2 gene, independent of NAD, and thus the compound is useful for studying the underlying mechanism of regulation of this gene in adult mouse hepatocytes in monolayer culture.

Animals↗
PubMed1994

Cloning and sequencing of rat liver carboxylesterase ES-3 (egasyn).

The cDNA of the rat carboxylesterase ES-3 encodes a polypeptide with 561 amino acid residues including a cleavable signal peptide at the N-terminus. The processed polypeptide shows over 90% sequence identity to mouse egasyn (ES-22); its calculated pI (5.5) matches the value determined for purified liver ES-3. The product expressed in COS cells migrates in native gels in the region of ES-3 and is similarly active on acetanilide. It is retained in the cells, as predicted from its C-terminus HTEL, and bears a single endo-H sensitive oligosaccharide chain. The nonglycosylated form expressed in the presence of tunicamycin is also intracellular, but substantially less active.

Amino Acid Sequence↗
PubMedDate not supplied

Biodegradation: selection of suitable model.

Biodegradation of five herbicides, two acetanilides (propanil and propachlor), and three phenylureas (diuron, monuron, and fenuron) was analyzed in samples of river water during a period of 6-8 weeks. Concentrations of 0.2-5.0 mg/liter of the herbicides were used for biodegradation. Two types of river water samples with different numbers of microorganisms were collected from the Neris River: upstream and downstream of the city of Vilnius. The initial concentration of microorganisms varied from 4.7 x 10(5) to 2.7 x 10(6) cells/liter and from 1.4 x 10(8) to 5.3 x 10(8) cells/liter in water samples from the Neris River upstream and downstream of Vilnius, respectively. Chemical analysis was performed by the HPLC technique, using standards of herbicides and likely degradation products. Chemical parameters of different river water samples used in biodegradation experiments were analyzed. A second-order reaction rate model was used for the analysis of biodegradation data. Values of the first-order rate constants (Ka) revealed the following decrease in the biodegradation rate of herbicides: propanil >> diuron > or = monuron = propachlor > fenuron. This sequence was constant for all water samples analyzed. The set of decreasing value of second-order biodegradation rate constants (Kb) differed from the set of first-order constants (Ka) because the total number of bacteria in the water samples varied by up to two orders of magnitude, and this variation influenced the calculated values of Kb. Thus, different sets of Kb values were obtained for the water samples from the river upstream and downstream of the city. Schemes of a variety of biodegradation models are presented, and the suitability of the second-order reaction rate model for the description of biodegradation of xenobiotics is discussed.

Biodegradation, Environmental↗