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PubMed2000

Specific binding of ethanol to cholesterol in organic solvents.

Although ethanol has been reported to affect cholesterol homeostasis in biological membranes, the molecular mechanism of action is unknown. Here, nuclear magnetic resonance (NMR) spectroscopic techniques have been used to investigate possible direct interactions between ethanol and cholesterol in various low dielectric solvents (acetone, methanol, isopropanol, DMF, DMSO, chloroform, and CCl(4)). Measurement of (13)C chemical shifts, spin-lattice and multiplet relaxation times, as well as self-diffusion coefficients, indicates that ethanol interacts weakly, yet specifically, with the HC-OH moiety and the two flanking methylenes in the cyclohexanol ring of cholesterol. This interaction is most strong in the least polar-solvent carbon tetrachloride where the ethanol-cholesterol equilibrium dissociation constant is estimated to be 2 x 10(-3) M. (13)C-NMR spin-lattice relaxation studies allow insight into the geometry of this complex, which is best modeled with the methyl group of ethanol sandwiched between the two methylenes in the cyclohexanol ring and the hydroxyl group of ethanol hydrogen bonded to the hydroxyl group of cholesterol.

2-Propanol↗
PubMed1980

Primary and secondary deuterium isotope effects on equilibrium constants for enzyme-catalyzed reactions.

Primary deuterium equilibrium isotope effects for the reaction of five secondary alcohols with nicotinamide adenine dinucleotide (DPN) to give reduced deuterionicotinamide adenine dinucleotide (DPND) (cyclohexanol-1-d, 1.18; 2-propanol-2-d, 1.175; threo-DL-isocitrate-2-d, 1.168; L-malate-2-d, 1.173; L-lactate-2-d, 1.19) are all approximately 1.18, while for a primary alcohol, ethanol, the value is 1.07, for an amino acid, L-glutamate-2-d, it is 1.14, and for a hemiacetal, glucose-1-d, it is 1.28. In each case deuterium becomes enriched in the alcohol, amino acid, or hemiacetal with respect to DPNH (TPNH). beta-Secondary equilibrium isotope effects for reduction of ketones by DPNH (cyclohexanone-2,2,6,6-d4, 0.82; acetone-d6, 0.78; pyruvate-d3, 0.83; alpha-ketoglutarate-3,3-d2 reduced to glutamate, 0.898; oxaloacetate-3,3-d2, 0.877; oxaloacetate-3R-d, 0.945) give an average value of 0.946/D, with deuterium becoming enriched in the alcohol or amino acid with respect to the ketone. For reduction of acetaldehyde-1-d by DPNH, the observed value of 0.953 includes the equilibrium effect on the hydration equilibrium in addition to that on the reduction, and the calculated values for reduction of the free aldehyde and the hydrate are 0.78 and 1.07. For reduction of benzaldehyde-1-d, which is not hydrated, the observed value was 0.79. The secondary equilibrium isotope effect for conversion of DPN-4-d to DPNH is 0.89, with deuterium becoming enriched in DPNH, and, for conversion of fumarate-2,3-d2 to malate, the value is 0.69, with deuterium becoming enriched in L-malate. The equilibrium isotope effect for reaction of cyclohexanol-1-d with DPN is temperature independent over the range 15-35 degrees C.

Alcohol Oxidoreductases↗
PubMed2001

"Intermolecular" trapping of a nonheme Fe(IV)=O intermediate.

The reactions of Fe(III)(TPA) (TPA = tris(2-pyridylmethyl)amine) complexes with 2-methyl-1-phenyl-2-propyl-hydroperoxide (MPPH) delivered by syringe pump under anaerobic conditions afford nearly quantitative conversion of MPPH to products derived from the benzyl radical. These results unequivocally show that MPPH breaks down by O-O bond homolysis, leading to the formation of the benzyl radical and a high valent Fe(IV)=O species. Without added substrates, the benzyl radical reacts with the high valent species to form benzyl alcohol or benzyl halides. The Fe(IV)=O species can also effect the two-electron oxidation of added substrates such as thioanisole, cyclohexanol, and cyclooctene under appropriate conditions. The oxidation of thioanisole and cyclohexanol is likely facilitated by pre-equilibrium binding of the substrate to the metal center, allowing these substrates to intercept the high valent iron-oxo species as it forms. These results suggest the importance of close proximity to direct the high valent metal center down a desired pathway.

Chemical Phenomena↗
PubMed1990

2-Phenyl-2-(1-hydroxycycloalkyl)ethylamine derivatives: synthesis and antidepressant activity.

A series of 2-phenyl-2-(1-hydroxycycloalkyl)ethylamine derivatives was examined for the ability to inhibit both rat brain imipramine receptor binding and the synaptosomal uptake of norepinephrine (NE) and serotonin (5-HT). Neurotransmitter uptake inhibition was highest for a subset of 2-phenyl-2-(1-hydroxycyclohexyl)dimethylethylamines in which the aryl ring has a halogen or methoxy substituent at the 3- and/or 4-positions. Potential antidepressant activity in this subset was assayed in three rodent models--the antagonism of reserpine-induced hypothermia, the antagonism of histamine-induced ACTH release, and the ability to reduce noradrenergic responsiveness in the rat pineal gland. An acute effect seen in the rat pineal gland with several analogues, including 1-[1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl]cyclohexanol (23) and 1-[2-(dimethylamino)-1)-(4-methoxyphenyl)ethyl]cyclohexanol (4), was taken as a possible correlate of a rapid onset of antidepressant activity. Compound 4 (venlafaxine) is presently undergoing clinical evaluation.

Adrenocorticotropic Hormone↗
PubMed1982

Chemical synthesis and molecular pharmacology of hydroxylated 1-(1-phenylcyclohexyl-piperidine derivatives.

The following monohydroxy derivatives of 1-(1-phenylcyclohexyl)piperidine (phencyclidine, PCP) were synthesized: o-, m-, and p-phenols of PCP, 1-(1-phenylcyclohexyl)-4-piperidinol, and two stereoisomeric pairs of 3-phenyl-3-(1-piperidinyl)cyclohexanol and 4-phenyl-4-(1-piperidinyl)cyclohexanol. Inhibition of specific binding of tritiated PCP, morphine, or quinuclidinyl benzylate (QNB) in rat brain homogenates was measured for these compounds. Inhibition of PCP binding for selected compounds correlated with mouse rotarod assay activity. The most characteristic effects of hydroxylation of PCP on the cyclohexyl, piperidine, or phenyl moieties are the following: (i) it generally decreases its activity in inhibiting [3H]PCP binding by a factor of 10 to 80; (ii) it does not produce a large variation in the affinity for the morphine receptor; (iii) it produces a considerable decrease of the affinity for the muscarinic receptor. An important exception to these general observations was the metaphenolic derivative of PCP. This PCP derivative has an affinity for the [3H]PCP binding sites that is 8 times higher than that of PCP itself; its affinity for the muscarinic receptor is only twice lower than that of PCP, but its affinity for the morphine receptor is 430 times higher than that of PCP and only one order of magnitude lower than that of morphine itself.

Animals↗
PubMed2001

FTIR sensing of inhomogeneous systems using immobilized organometalcarbonyl probe groups.

Tricarbonyl(eta 5-cyclohexadienyl)iron(0) and dicarbonyl(triphenylphosphine)(eta 5-cyclo-hexadienyl)iron(0) were derivatized by attachment of an aminopropylsilyl link and covalently attached to fumed silica particles. The fumed silica was coated onto the ZnSe element of an attenuated total reflection (ATR) cell for Fourier transform infrared (FTIR) spectroscopic analysis. The immobilized organometalcarbonyl probe groups are shown to retain their capacity to function as a key element of a molecular sensor assembly and the nu(CO) bands of the two probe groups were interrogated to calibrate the responses for 0-5% levels of dodecane in cyclohexanol to within +/- 0.1%. The potential for dual sensing is described and the simultaneous monitoring of two discrete regions of a dynamically varying inhomogeneous system is reported for the determination of dodecane in cyclohexanol as solutions mix across a permeable barrier in the ATR cell.

Journal Article↗
PubMed1975

Deuterium transfer from [1,1-2-H] ethanol during metabolism of bile acids and cyclohexanone in the isolated perfused rat liver.

Deuterium transfer from [1,1-2-H]ethanol (95 atoms % excess) to reducible substrates was studied in the isolated perfused rat liver. The dueterium excess in cyclohexanol formed from cyclohexanone was somewhat lower (49 atoms%) than found under conditions in vivo, and this was also true of the deuterium excess in lithocholic acid formed from 3-oxo-5beta-cholanoic acid. These results may reflect a slower rate of ethanol oxidation in the isolated organ than in vivo. Cycloserine decreased the dueterium transfer to both substrates, whereas addition of lactate and malate resulted in an increased deuterium excess in cyclohexanol and a decreased deuterium excess in lithocholic acid. Addition of heavy water to the perfusion fluid resulted in labelling at C-3 of lithocholic acid formed from 3-oxo-5beta-cholanoic acid, and at C-3, C-4 and C-5 of 3alpha-hydroxy-5alpha-cholanoic acid formed from 3-oxo-4-cholenoic acid. The deuterium excess of hydrogens derived from NADPH (at C-3 and C-5) was approximately the same as that of hydrogen derived directly from water (at C-4). Thus, the hydrogen of NADPH is extensively exchanged with protons of water, which explains the dilution of deuterium with protium during the transfer from [1,1-2-H]ethanol via NADPH to the bile acids. The labelling at C-5 in the reduction of the 4,5-double bond indicates that different pools of NADPH are used for reduction of this double bond and the 3-oxo group, since in a previous study it was shown that deuterium is transferred from [1,1-2-H]ethanol only in the latter reaction.

Animals↗
PubMed1976

Transfer of the 1-pro-R and the 1-pro-S hydrogen atoms of ethanol in metabolic reductions in vivo.

The transfer of deuterium from [1 R-2H]ethanol and [1 S-2H]-ethanol to reduced metabolites of administered compounds was measured in female rats provided with bile fistulas. Administered cyclohexanone was reduced to cyclohexanol, and in this reduction hydrogen was transferred only from the 1-pro-R position of the ethanol. The deuterium content in the cyclohexanol was about 67% of that in the ethanol. In the reduction of the 17-oxo group in 3beta-hydroxy-5alpha-androstan-17-one, hydrogen was transferred both from the 1-pro-R position and the 1-pro-S position, resulting in degrees of labelling that were about 25% and 2%, respectively, of those in the specific positions of the ethanols. The 1-pro-R and 1-pro-S positions of ethanol contributed about 9% and 5%, respectively, of the 3beta hydrogen in lithocholic acid formed from 3-oxo-5beta-cholanoic acid. The results indicate that alcohol dehydrogenase and aldehyde dehydrogenase do not share a common pool of NAD, and that NADH formed during acetaldehyde oxidation is utilized for reductions in the cytosol to a smaller extent than the NADH formed in the alcohol dehydrogenase reaction. This result supports the concept that aldehyde oxidation is mainly an intramitochondrial process. The relatively extensive utilization of the 1-pro-S hydrogen of ethanol in the reduction of 3-oxo-5beta-cholanoic acid, that is probably NADPH-dependent, indicates that cytosolic NADPH may be produced from malate or isocitrate formed intramitochondrially.

Alcohol Oxidoreductases↗
PubMed1992

A single-residue exchange gives human recombinant beta beta alcohol dehydrogenase gamma gamma isozyme properties.

Amino acid residue 48 in human alcohol dehydrogenase constitutes one of 21 residue differences between the common, adult-type isozyme subunits beta and gamma. It is at the inner part of the substrate pocket and has been ascribed a role in hydrogen-bond formation with both the substrate and coenzyme. In order to allow direct evaluation of its importance, Thr48 of a recombinant non-acetylated beta subunit was mutated to Ser (as in the gamma subunit) or Ala (as in no native form, and not allowing side-chain hydrogen bonds), and the proteins were expressed in Escherichia coli. The two non-acetylated recombinant proteins, the beta 48T form and the mutant beta 48S, gave enzymatically active enzymes with indistinguishable specific activities towards ethanol, whereas the mutant beta 48A showed no enzymatic activity. The most striking differences between dimers with the beta subunit and the beta 48S subunit (both non-acetylated) were observed with cyclohexanol, hydroxysteroids, methanol and ethanol. With cyclohexanol, the Km was lowered from 11 mM to 280 microM, and the kcat/Km ratio, although still less than that for the gamma gamma isozyme, was increased 80-fold. Similarly, beta 48S could use 3 beta-hydroxy-5 beta-androstan-17-one as substrate, like gamma gamma, although again with a catalytic efficiency much less than that for the gamma gamma isozyme. Furthermore, testosterone inhibited beta 48S to 50% at a concentration of 100 microM, whereas the beta beta form was not inhibited. All these results show that residue 48 is responsible for a large part of the differences between the two isozymes beta beta and gamma gamma of human class-I alcohol dehydrogenase. The form with the inactive beta 48A subunit was possible to purify by AMP-Sepharose chromatography, suggesting the presence of a functional NAD-binding site. The enzymatic measurements, demonstrating a transition from one isozyme activity to that characteristic of another, confirmed that a side-chain hydroxyl in residue 48 is required for activity, and interpretation by computer modelling showed marked differences at the active site.

Alcohol Dehydrogenase↗
PubMed1982

Studies on the effects of orally administered dicyclohexyl phthalate in the rat.

The oral administration of 500-2500 mg/kg/day dicyclohexyl phthalate (DCHP) to young male Sprague-Dawley rats for 7 days resulted in liver enlargement and induction of some parameters of hepatic xenobiotic metabolism. Additional studies indicated that the hepatic enzyme induction resembled that of sodium phenobarbitone rather than that of polycyclic hydrocarbons. Morphological examination of the livers of DCHP treated rats revealed centrilobular cell hypertrophy and ultrastructural examination demonstrated marked proliferation of the smooth endoplasmic reticulum. Mitochondrial structure and numbers of peroxisomes (microbodies) were not affected. DCHP treatment did not affect kidney and testes weights but some histological evidence of testicular damage was obtained with 2500 mg/kg/day of DCHP. The metabolites of DCHP, namely monocyclohexyl phthalate (MCHP) and cyclohexanol, also induced certain parameters of hepatic xenobiotic metabolism. MCHP, but not cyclohexanol also produced marked testicular atrophy. It is concluded that DCHP is a weak drug-type inducer of hepatic xenobiotic metabolism in the rat and the hepatic effects of this phthalate diester are different from those of di-(2-ethylhexyl) phthalate.

Animals↗
PubMed1995

Generation of polyclonal catalytic antibodies against cocaine using transition state analogs of cocaine conjugated to diphtheria toxoid.

Six novel transition state analogs (TSAs) of cocaine (10-14 and 17) and one non-cocaine, p-aminophenylphosphonyl ester of cyclohexanol (19), were synthesized and characterized by 1H- and 13C-NMR and FAB-MS. (1R)-ecgonine methyl ester or cyclohexanol were subjected to phenylphosphonylation in the presence of dicyclohexyl carbodiimde (DCC) and 4-N,N-dimethyl aminopyridine (4-DMAP). TSA-IV (10), however, was synthesized from norcocaine which was protected with dibromoethane to yield 4 before acid hydrolysis, esterification and phenylphosphonylation were carried out. TSA-III (11) TSA-I (12) and (19), using various length spacer arms, were coupled with the immunogenic protein, diphtheria toxoid (DT). The TSAs coupled with DT were used to immunize mice and after appropriate boosts their sera were tested for the presence and titer of anti-TSA polyclonal antibodies using ELISA. Preliminary results show that the mice immunized with these TSAs produced high titers of polyclonal catalytic antibodies, except for (19), with the ability to hydrolyze the substrate 125I-4'-iodococaine in an in vitro assay, even in the presence of noncatalytic anti-TSA antibodies.

4-Aminopyridine↗
PubMed1990

Chemical synthesis of dual-radiolabelled cyclandelate and its metabolism in rat hepatocytes and mouse J774 cells.

1. The chemical synthesis of 3,3,5-trimethyl[1-3H]cyclohexanol, 3,3,5-trimethyl[2,3-3H]cyclohexanol and 3,3,5-trimethyl[2,3-3H]cyclohexanyl[1-14C]mandelate (cyclandelate) are described. The ratio of 3H/14C radioactivity in the ester was 27:1. 2. Cultured rat hepatocytes accumulated trimethylcyclohexanol rapidly and excreted its glucuronide into the culture medium. Rat hepatocytes also accumulated cyclandelate rapidly, hydrolysing the ester and excreting trimethylcyclohexanol into the medium. This trimethylcyclohexanol then re-entered the cells and was converted to its glucuronide prior to excretion. 3. In contrast, no hydrolysis of cyclandelate was seen on incubation with J774 cells, a transformed mouse macrophage. 4. Similar differences in hydrolytic activity were seen with microsomal fractions prepared from rat liver and J774 cells. Hepatic microsomes caused a rapid hydrolysis of cyclandelate while no hydrolysis was detectable after incubations of over an hour with J774 microsomes. 5. This difference in hydrolytic activity may have important implications for the action of cyclandelate on cholesterol metabolism in extrahepatic tissues.

Animals↗
PubMedDate not supplied

Metabolism and disposition of cyclohexanone oxime in male F-344 rats.

Cyclohexanone oxime (CHOX), an intermediate used in the synthesis of Polycaprolactam/Nylon, was found to be rapidly absorbed and cleared from the body within 24 hours after a single oral administration of 1, 10 and 30 mg/kg of [14C]-CHOX to the adult male Fischer rats. The majority of the CHOX derived radioactivity (65-90% of the dose) was excreted in the urine. Elimination in the feces accounted for 5-10% of the dose and very low levels of radioactivity (2-3%) were retained in the tissues 24 hours after exposure. After iv administration of 1 mg/kg of [14C]-CHOX, the oxime was rapidly cleared from plasma with half-lives of 1.6 (alpha phase) and 18.2 min (beta phase). However, when CHOX was applied dermally (30 mg/kg), only about 4-5% of the dose was recovered in urine, feces and the tissues. The majority of the dose volatilized from the skin surface. However, the absorbed oxime was readily distributed and excreted, and its metabolic fate was no different than observed after oral administrations. HPLC analysis of urine showed that the majority of the radioactivity excreted was in the form of three metabolites, cyclohexylglucuronide and the monoglucuronides of cis- and trans-cyclohexane-1,2-diol. In vitro studies showed that these metabolites arise primarily by hydrolysis of the oxime to cyclohexanone which is then reduced to cyclohexanol and eliminated as the glucuronide conjugate. The cyclohexanol, in turn could be metabolized to cis- and trans-cyclohexane-1,2-diols, which excreted as their monoglucuronides.

Administration, Oral↗
PubMed1978

[Metabolic transformations of the trimethyl - 3,5,5, cyclohexene-2, one-1 (isophorone) (author's transl)].

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.

Animals↗
PubMed2002

Highly stereoselective and efficient synthesis of functionalized cyclohexanes with multiple stereocenters.

Chiral 7-oxo-2-enimides 2, which were readily obtained through a silyloxy-Cope rearrangement of syn-aldol products 1, have proved to be versatile substrates for a one-step, highly efficient and stereoselective synthesis of functionalized cyclohexanes. Organocopper and organoaluminum reagents have been employed as nucleophiles that underwent a conjugate addition to the enimide structure of the Cope products. The enolates formed in situ attacked the aldehyde or iminium ion in an intramolecular aldol or Mannich reaction, respectively, to directly yield cyclohexanols 3 and 4 and cyclohexylamines 5, respectively, in moderate to good yields and with excellent stereocontrol.

Cyclohexanes↗
PubMed2001

Porous polymer monoliths: simple and efficient mixers prepared by direct polymerization in the channels of microfluidic chips.

Porous monolithic polymers have been prepared by photoinitiated polymerization of mixtures consisting of 2-hydroxyethyl methacrylate, ethylene dimethacrylate, UV-sensitive free radical initiator and porogenic solvent within channels of specifically designed microfluidic chips and used as micromixers. Substituting azobisisobutyronitrile with 2,2-dimethoxy-2-phenylacetophenone considerably accelerated the kinetics of the polymerization. Mixtures of cyclohexanol and 1 -dodecanol and of hexane and methanol were used, respectively, to control the porous properties and therefore the mixing efficiency of the device. The performance of the monolithic mixers has been tested by pumping aqueous solutions of two fluorescent dyes at various flow rates and monitoring the point at which the boundary of both streams completely disappears. Best results were achieved with a monolithic mixer containing very large irregular pores.

Acetophenones↗
PubMed1981

Absorption and alveolar excretion of cyclohexane in workers in a shoe factory.

The lung uptake and excretion of cyclohexane were studied in five workers and three volunteers in a shoe factory. Air samples were collected from the breathing zones with personal samplers, and simultaneous samples of inhaled and alveolar air were collected with the aid of a Rhan-Otis valve. Cyclohexane was absorbed on activated NIOSH approved charcoal tubes. The uptake was calculated from the pulmonary ventilation, the retention coefficient and environmental concentration. Alveolar excretion was monitored during a 6 h post-exposure period. The amount of exhaled cyclohexane was calculated from the decay curve. According to experimental data, the alveolar retention of cyclohexane is about 34% of the inhaled dose. This corresponds to a lung uptake of 23%. The post-exposure alveolar excretion does not exceed 10% of the total uptake. The difference between respiratory uptake and excretion indicates that the amount metabolized may be very large. Nevertheless, the urinary excretion of the main metabolites, cyclohexanol and cyclohexanone, was only about 1% of the absorbed dose.

Absorption↗
PubMed1994

Effect of menthol on cytosolic Ca2+ levels in canine airway epithelium in culture.

Intracellular Ca2+ concentration ([Ca2+]i) in canine cultured tracheal epithelium in response to cyclic alcohols was measured by a fura-2 method. Menthol rapidly increased [Ca2+]i in a concentration-dependent fashion, the maximal increase from the baseline levels and the concentration of menthol required to produce a half-maximal effect (EC50) being 148 +/- 23 nM (mean +/- SE, p < 0.001) and 0.3 mM, respectively, whereas other cyclic alcohols including menthone and cyclohexanol had no effect. The menthol-induced increase in [Ca2+]i was not affected by verapamil but partially inhibited by low Ca2+ medium in the presence of EGTA. These results indicate that menthol specifically increases cytosolic Ca2+ in airway epithelium, which may be derived from intracellular Ca2+ stores.

Animals↗