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Three workers developed dermatitis when synthesizing lysine from cyclohexanone; they showed positive patch tests to 2-chlorocyclohexanone and some of its derivatives. Two of them became sensitive to at least two differen compounds.
Olfactory sensitivity to acetic acid, isobutyric acid, and 2-sec-butyl-cyclohexanone was tested in 97 adult male twin pairs to determine the extent to which variation in odor perception was genetically determined. Analysis of the data revealed no evidence for heritability of olfactory sensitivity. However, factors significantly associated with odor perception included cigar, pipe, and cigarette smoking; body fatness; alcohol consumption; and diabetes mellitus.
Corynebacterium sp. strain C125, originally isolated on o-xylene, was selected for its ability to grow on tetralin (1,2,3,4-tetrahydronaphthalene) as the sole source of carbon and energy. The catabolism of tetralin in Corynebacterium sp. strain C125 was shown to proceed via initial hydroxylation of the benzene nucleus at positions C-5 and C-6, resulting in the formation of the corresponding cis-dihydro diol. Subsequently, the dihydro diol was dehydrogenated by a NAD-dependent dehydrogenase to 5,6,7,8-tetrahydro-1,2-naphthalene diol. The aromatic ring was cleaved in the extradiol position by a catechol-2,3-dioxygenase. The ring fission product was subject to a hydrolytic attack, resulting in the formation of a carboxylic acid-substituted cyclohexanone. This is the first report of the catabolism of tetralin via degradation of the aromatic moiety.
An uroporphyrin III-accumulating mutant of Escherichia coli K-12 was isolated by neomycin. The mutant, designated SASQ85, was catalase deficient and formed dwarf colonies on usual media. Comparative extraction by cyclohexanone and ethyl acetate showed the superiority of the former for the extraction of the uroporphyrin accumulated by the mutant. Cell-free extracts of SASQ85 were able to convert 5-aminolevulinic acid and porphobilinogen to uroporphyrinogen, but not to copro- or protoporphyrinogen. Under the same conditions cell-free extracts of the parent strain converted 5-aminolevulinic to uroporphyringen, coproporphyrinogen, and protoporphyrinogen. The conversion of porphobilinogen to uroporphyrinogen by cell-free extracts of the mutant was inhibited 98 and 95%, respectively, by p-chloromercuribenzoate and p-chloromercuriphenyl-sulfonate, indicating the presence of uroporphyrinogen synthetase activity in the extracts. Spontaneous transformation of porphobilinogen to uroporphyrin was not detectable under the experimental conditions used [4 h at 37 C in tris(hydroxymethyl)aminomethane-potassium phosphate buffer, pH 8.2]. The results indicate a deficient uroporphyrinogen decarboxylase activity of SASQ85 which is thus the first uroporphyrinogen decarboxylase-deficient mutant isolated in E. coli K-12. Mapping of the corresponding locus by P1-mediated transduction revealed the frequent joint transduction of hemE and thiA markers (frequency of co-transduction, 41 to 44%). The results of the genetic analysis suggest the gene order rif, hemE, thiA, metA; however, they do not totally exclude the gene order rif, thiA, hemE, metA.
The conditions under which mouse fetal liver cells in vitro are most sensitive to erythropoietin have been investigated with the object of establishing a rapid and sensitive bioassay for this hormone. Fetal liver age and incubation times are shown to be relatively unimportant. Of the commercially available media studied, Eagles Minimal Essential Medium plus 5 percent Fetal Calf Serum is superior to other media used to study erythropoiesis in mouse fetal liver cells. The number of cells per 1 ml culture is important since some evidence was obtained for cell cooperation occurring above 10-6 cells per culture. To minimize this possibility 5 x 10-5 cells are used. If (59Fe) ferric citrate is used to assess heme synthesis, no significant advantage is observed by prior binding of the isotope to mouse serum transferrin. Butan-2-one is preferred to cyclohexanone for extracting heme. Using the conditions described in this report the mouse fetal liver cell assay for erythropoietin is capable of detecting erythropoietin concentrations as low as 0.001 unit culture. Preliminary results using normal human sera show that it is sufficiently sensitive to detect erythropoietin over a range of serum concentrations. This allows a full dose-response relationship to the sera to be determined and, by a comparison with an erythropoietin standard, detailed quantitative results can be obtained. Therefore the technique seems to fulfill the need for a rapid and sensitive erythropoietin bioassay for routine clinical use.
We previously evaluated the promoting effects of 2-tert-butylcyclohexanone and its analogues on the percutaneous absorption of indomethacin (IMC), and showed that the 2-position of the cyclohexanone ring plays an important role in drug permeability through the skin. The present study investigates the in vitro penetration enhancement of IMC by five 2-n-alkylcyclohexanone derivatives. 2-n-Octylcyclohexanone was the most effective enhancer, but the other four enhancers also had significant promoting actions on skin permeability of IMC. Maximum absorption enhancement was associated with a defined range of enhancer lipophilicity. We propose that the enhancer penetrates into the stratum corneum and improves skin permeability of a drug by dissolving some of the hard lipid components or modifying the dense lipid stratum corneum.
We have demonstrated that the cyclohexanone method for the extraction of hematin can be used to measure hemoglobin synthesis induced by erythropoietin (epo) in mouse bone marrow cells cultured in medium containing methyl cellulose. The time course of hemoglobin synthesis by mouse marrow cells showed two effects due to epo: an increase in hemoglobin synthesis at day 2, which corresponded to the formation of small erythroid colonies resulting from the CFU-E (colony-forming unit, erythroid), and a very large increase in hemoglobin synthesis, which was maximal at days 7-8 and corresponded to the formation of large erythroid colonies (bursts) resulting from the BFU-E (burst-forming unit, erythroid). The epo dose-response curves for CFU-E colony counts and day-2 hemoglobin synthesis were similar, and the cell-number-response curves for these two paramaters were parallel. The epo dose-response curve for BFU-E colony counts reached a plateau at an epo concentration between 3 and 5 units/ml, whereas the dose-response curve for 6-8-day hemoglobin synthesis did not reach a plateau even at an epo dose of 10 units/ml.
In the rabbit, isophorone alpha is partly eliminated, unchanged in the expired air and in the urine and, for another part, metabolized in the organism and excreted in the urine. The metabolites which have been characterized are : dimethyl-5,5, cyclohexen-1, one-3, carboxylic-1 acid, deriving from isophorone by methyloxidation, isophorol (trimethyl-3,5,5 cyclohexen-2, ol-1) formed by the reduction of the ketonic group into a secondary alcohol and eliminated as a glucuronide, dihydroisophorone (trimethyl-3,5,5, cyclohexanone) proceeding from the hydrogenation of the cyclohexen cycle and cis and trans trimethyl-3,5,5, cyclohexanols-1. These latter compounds, found in small quantities, are very likely issued from dihydroisophorone which is transformed in the organism into isophorone alpha and cis and trans trimethyl-3,5,5, cyclohexanols-1, according to a process of dismutation.
The concentrations of toxic substances in working space air of polyvinyl chloride film production was determined, 130 workers were examined. The content of Dioctyl phthalate and cyclohexanone surpassed the standard values by 1.5-3 times. 67.7% of workers complained on disorders of digestion organs, 7.9% workers had disorders of vegetative functions; microsomal system activity was increased, enzymatic activity changed.
Seventy-two chemicals were tested for their mutagenic potential in the L5178Y tk+/- mouse lymphoma cell forward mutation assay, using procedures based upon those described by Clive and Spector (Mutat Res 44:269-278, 1975) and Clive et al. (Mutat Res 59:61-108, 1979). Cultures were exposed to the chemicals for 4 hr, then cultured for 2 days before plating in soft agar with or without trifluorothymidine (TFT), 3 micrograms/ml. The chemicals were tested at least twice. Significant responses were obtained with allyl isothiocyanate, p-benzoquinone dioxime, benzyl acetate, 2-biphenylamine HCl, bis(2-chloro-1-methylethyl)ether, cadmium chloride, chlordane, chlorobenzene, chlorobenzilate, 2-chloroethanol, chlorothalonil, cytarabine.HCl, p,p'-DDE, diazinon, 2,6-dichloro-p-phenylenediamine, N,N-diethylthiourea, diglycidylresorcinol ether, 2,4-dimethoxy aniline.HCl, disperse yellow 3, endosulfan, 1,2-epoxyhexadecane, ethyl acrylate, ethyl benzene, ethylene thiourea, F D and C yellow Number 6, furan, heptachlor, isophorone, mercuric chloride, 4,4'-methylenedianiline.2 HCl, methyl viologen, nickel sulfate.6H2O, 4,4'-oxydianiline, pentachloroethane, piperonyl butoxide, propyl gallate, quinoline, rotenone, 2,4,5,6-tetrachloro-4-nitro-anisole, 1,1,1,2-tetrachloroethane, trichlorfon, 2,4,6-trichlorophenol, 2,4,5-trimethoxybenzaldehyde, 1,1,3-trimethyl-2-thiourea, 1-vinyl-3-cyclopetene dioxide, vinyl toluene, and ziram. Apart from 2-biphenylamine.HCl, 2-chloroethanol, disperse yellow 3, ethylene thiourea, FD and C yellow number 6, phenol, and 1,1,2-tetrachloroethane, rat liver S9 mix was not a requirement for these compounds. Chemicals not identified as mutagens were acid red, 11-aminoudecanoic acid, boric acid, 5-chloro-o-toluidine, coumaphos, cyclohexanone, decabromodiphenyl oxide, di(2-ethylhexyl)adipate, ferric chloride, fluometuron, melamine, monuron, phenesterin, phthalimide, reserpine, sodium dodecyl sulfate, 4,4-sulfonyldianiline, tetrachloroethylene, and zearalenone. The assay was incapable of providing a clear indication of whether some chemicals were mutagens; these were benzyl alcohol, 1,4-dichlorobenzene, phenol, succinic acid-2,2-dimethyl hydrazide, and toluene.
A passerine bird, the European Starling Sturnus vulgaris, demonstrated a seasonal ability to respond to odor cues. Cardiac conditioned responses were most evident when birds were in breeding condition. Once birds were in nonbreeding condition, responding to odors all but ceased. For birds in breeding condition, threshold sensitivity to the odor cyclohexanone was comparable to levels reported for nonpasserine birds (0.3% vapor saturation or 3.778 x 10(14) molecules/ml). In contrast, the threshold level during the postreproductive phase of the annual cycle was 10% vapor saturation (1.256 x 10(16) molecules/ml), a level high enough to implicate the trigeminal system as the modality mediating chemosensory perception. The strong cyclic responding pattern suggests links between photoperiodically controlled endocrine production, breeding behavior, and olfactory sensitivity.
The hydrolysis kinetics of several oxazolidines derived from (-)-ephedrine and various aldehydes and ketones were studied to assess their suitability as prodrug forms for beta-amino alcohols and/or carbonyl-containing compounds. The oxazolidines were found to undergo a facile and complete hydrolysis in the pH range of 1-11 at 37 degrees. The hydrolysis rates were subject to general acid-base catalysis by buffer substances and depended strongly on pH. Most oxazolidines showed sigmoidal pH-rate profiles with maximum rates at pH greater than 7-7.5. At pH 7.40 and 37 degrees the following half-lives of hydrolysis for the various ephedrine oxazolidines were found: 5 sec (formaldehyde), 18 sec (propionaldehyde), 5 min (benzaldehyde), 5 sec (salicylaldehyde), 30 min (pivalaldehyde), 4 min (acetone), and 6 min (cyclohexanone). The reaction rates in neutral and basic solutions were shown to decrease with increasing steric effects of the substituents derived from the carbonyl component and to decrease with increasing basicity of the oxazolidines. The oxazolidines are weaker bases (pKa 5.2-6.9) than the parent beta-amino alcohol and more lipophilic at physiological pH. It is suggested that oxazolidines can be considered as potentially useful prodrug candidates for drugs containing a beta-amino alcohol moiety or carbonyl groups.
A previous report detailed the derivation and validation of an equation for calculating the Gibbs free energy of liquid-solid adsorption via high-performance liquid chromatography (HPLC). This study utilizes an improved form of that equation in conjunction with an in vitro model of solute adsorption to give an ordered listing of the antidotal activity of activated charcoal towards different drugs and other chemicals. The in vitro model consists of an activated charcoal column with a nominal particle diameter of 15 micron and a surface area of 447 x 10(4) cm2/g, together with a series of acetonitrile:water mobile phases at pH 3. A simple and efficient procedure was developed for ranking the solutes. First, each compound was run in an acetonitrile(ACN):water mobile phase chosen to give a convenient retention time and ideal chromatographic response. The capacity factor for this mobile phase was extrapolated to give a predicted capacity factor for a 35:65 (v/v) ACN:water mobile phase using an empirical equation developed from the exhaustive chromatography of four standard compounds (phenobarbital, strychnine, cyclohexanone, methyl ethyl ketone) in a variety of ACN:water mobile phases. In addition to the standards, 12 other compounds (glutethimide, chlordiazepoxide, quinine, brucine, d-propoxyphene, pentobarbital, methyprylon, methadone, meperidine, codeine, antipyrine, morphine) were evaluated. Based on these data, the Gibbs free energies of liquid-solid adsorption for these compounds were calculated and used to evaluate activated charcoal as a poison antidote for them. The results indicate that a rapid and accurate estimation of the utility of activated charcoal as an antidote for drugs and toxic substances can be obtained from a single chromatographic run of the test compound.
A specific, sensitive, accurate, and precise capillary gas chromatographic assay for determining trace levels of hydroxylamine, a well-known mutagen, in propionohydroxamic acid bulk drug and oral preparations is described. The analytical procedure involves derivatization in a nonaqueous medium with cyclohexanone and use of an internal standard. The derivative is then determined by capillary GC with a cool on-column injector and a nitrogen-selective detector. Effects of different matrices on the measurement were also determined. The lower limit of quantitation was 7 ppm, and the response was linear from 10 to 260 ppm. The procedure is simple and rapid enough for routine purposes.
The kinetics of decomposition of the following conformationally restricted N-chloro-alpha-amino acids were studied: 1-amino-1-cyclopentanecarboxylic acid (2), 1-amino-1-cyclohexanecarboxylic acid (4), 2-amino-2-norbornanecarboxylic acid (6), and 2-amino-2-benzonorbornanecarboxylic acid (8). The first-order rate constants obtained were 0.520, 5.197, 0.198, and 0.078, respectively, which correlated with the ring strain in the structurally related cyclic ketones cyclopentanone, cyclohexanone, norborane-2-one, and benzonorbornane-2-one. The data are supportive of a concerted mechanism for the decomposition reaction involving an imine-like transition state.
Vibrio cholerae neuraminidase (VCN) treatment of donor bone marrow cells results in a reduction in the number of hematopoietic colonies (CFUs) formed in the spleens of lethally irradiated mice. Treatment of marrow cells with sodium periodate under mild conditions, known to preferentially oxidize sialic acid, also reduced CFUs while subsequent potassium borohydride reduction restored CFUs to 80% of control levels. Innoculum viability as measured by in vitro incorporation of tritiated precursors into proteins, nucleic acids, and oligosaccharides was unaffected by VCN treatment. The ability of bone marrow cells in culture to respond to the hormone erythropoietin, as measured by the incorporation of 59Fe into cyclohexanone-extractable heme, was also not affected by neuraminidase, making a cytotoxic effect of the VCN preparation unlikely. Incubation of VCN-treated marrow with either beta-galactosidase or trypsin had no effect on the VCN-induced reduction in CFUs. These results are consistent with the idea that membrane sialic acid plays a direct and specific role in the implantation and development of CFUs.
The Microtox EC50 values for the following ketones are reported in the following homologous series: straight chain methyl ketones (acetone, 2-butanone, 2-pentanone, 2-hepatonone, 2-octanone, 2-decanone, and 2-tridecanone); methyl ketones substituted at one alpha carbon (3-methyl-2-butanone; 3,3-dimethyl-2-butanone); methyl substituted at two alpha carbons (2,4-dimethyl-3-pentanone; 2,2,4,4-tetramethyl-3-pentanone); phenyl groups replacing methyl in acetone (acetophenone; benzophenone); methyl groups substituted at the alpha carbons of cyclohexanone; and 2,3- 2,4-, and 2,5-hexanediones, most for the first time. While there were linear relationships between log EC50 and MW for the straight chain methyl ketones, and for methyl substitution at the alpha carbon for methyl ketones, there were no other linear relationships. As molecular weight increased, the EC50 values of soluble ketones decreased; as distance between two carbonyl groups decreased so too did EC50 values. Thus, for the ketones the geometry around the carbonyl group is an important determinant of toxicity as well as MW, water solubility, and octanol/water coefficient.
A survey was conducted in the second half of a working week on 33 women who either applied glue (with cyclohexane as an almost exclusive solvent component) or worked in the vicinity of glue application. Carbon cloth-equipped diffusive samplers were used for personal measurement of time-weighted average intensity of exposure to the solvent. The geometric mean and the highest cyclohexane concentration observed in air were 27 ppm and 274 ppm, respectively. Concentrations of cyclohexanol in urine samples and cyclohexane in whole blood and serum collected at the end of a shift showed significant correlations with the solvent exposure levels. Urinary cyclohexanone also correlated, but with a smaller correlation coefficient. The observation suggests that cyclohexanol in urine and cyclohexane in blood or serum collected at the end of a shift are useful indicators of occupational exposure to cyclohexane vapor. Quantitative estimation of balance at the end of the shift suggested that only a minute portion (< 1%) of cyclohexane absorbed is excreted in the urine as cyclohexanol, almost exclusively as a glucuronide. A survey of subjective symptoms revealed an increase in the prevalence of "dimmed vision " and "unusual smell", but hematology and serum biochemistry testing did not indicate any specific signs.