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PubMed1994

Structures of three human beta alcohol dehydrogenase variants. Correlations with their functional differences.

The three-dimensional structures of three variants of human beta alcohol dehydrogenase have been determined to 2.5 A resolution. These three structures differ only in the amino acid at position 47 and the molecules occupying the alcohol binding site. Human beta 1 alcohol dehydrogenase has an Arg at position 47 and was crystallized in a complex with NAD(H) and cyclohexanol. A naturally occurring variant of beta 1 alcohol dehydrogenase, found in approximately 50% of the Asian population, possesses a His at position 47 (beta 2 or beta 47H) and was crystallized in a complex with NAD+ and the inhibitor 4-iodopyrazole. A site-directed mutant of beta 1 alcohol dehydrogenase in which a Gly is substituted for Arg47 (beta 47G) was crystallized in a complex with NAD+. By comparing both the common and unique features of these structures, it is clear that position 47 contributes significantly to the strength of protein-coenzyme interactions. The substitution of Arg47 by His produces an enzyme with a 100-fold lower affinity for coenzyme, but creates no large changes in the enzyme structure. The substitution of Arg47 by Gly produces an enzyme with coenzyme binding characteristics more similar to the wild-type enzyme than to the enzyme with His at position 47, but the structure of the Gly47 variant exhibits differences in and around the coenzyme binding site. These changes involve a rigid-body rotation of the catalytic domain towards the coenzyme domain by approximately 0.8 degrees and local rearrangements of amino acid side-chains, such as a 1.0 A movement of Lys228, relative to the beta 1 enzyme. These structural alterations may compensate for the loss of coenzyme interactions contributed by Arg47 and can explain the high affinity of the Gly47 variant for coenzyme.

Alcohol Dehydrogenase↗

PubMed1994

Uptake, metabolism and elimination of cyclohexanone in humans.

The metabolism and toxicokinetics of cyclohexanone (CH-one), an important solvent and chemical intermediate, have been studied in volunteers during and after 8-h exposures to CH-one vapour at a concentration of 101, 207 and 406 mg.m-3. The pulmonary ventilation in these experiments was typically 11 l.min-1 and retention in the respiratory tract was 58%. After exposure to CH-one, 207 mg.m-3, the metabolic yields of cyclohexanol (CH-ol), 1,2- and 1,4-cyclohexanediol (CH-diol) as determined in urine by a gas chromatographic method involving hydrolysis of glucuronide conjugate were 1.0% +/- 0.3%, 39% +/- 5% and 18% +/- 2% (n = 8), respectively. Peak excretion of CH-ol was achieved at the end of the exposure period, after which it decayed rapidly. Elimination of 1,2- and 1,4-CH-diol reached maximum values a few hours following exposure, with subsequent elimination half-times of 16 +/- 2 and 18 +/- 4 h, respectively. Repeated exposure to CH-one vapour (around 200 mg.m-3) for five consecutive days (8 h/day) resulted in cumulative excretion of CH-diols. The permeation rate of CH-one liquid through the skin was 0.037-0.069 mg.cm-2.h-1 (n = 3), indicating that the contribution of percutaneous absorption to total CH-one occupational intake is of minor importance. CH-diols are recommended as biomarkers of exposure to CH-one.

Administration, Cutaneous↗

PubMed1995

Discriminative stimulus effects of anandamide in rats.

Anandamide (arachidonylethanolamide), a putative endogenous ligand for the cannabinoid receptor, produces a tetrad of behavioral effects in mice characteristic of psychoactive cannabinoids including catalepsy, antinociception, hypothermia, and hypomobility. The present study examined the discriminative stimulus effects of anandamide in rats trained to discriminate delta 9-tetrahydrocannabinol or the potent cannabinoid receptor ligand CP 55,940 [(-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)-phenyl]-trans-4-(3- hydroxypropyl)cyclohexanol)] from vehicle. Intraperitoneal injections of anandamide substituted for delta 9-tetrahydrocannabinol and for CP 55,940; however, unlike substitution dose-effect curves with the training drugs, anandamide substitution occurred at a single dose (30 or 45 mg/kg) and was accompanied by severe decreases in response rates. The results of the present study suggest that, although systemic anandamide administration may have cannabimimetic effects similar to those of delta 9-tetrahydrocannabinol and CP 55,940, some differences in the behavioral effects of anandamide and other psychoactive cannabinoids also are apparent.

Animals↗

PubMed1989

Evaluation of the subacute nephrotoxicity of cyclohexane and other industrial solvents in the female Sprague-Dawley rat.

The subacute nephrotoxicity of more than 20 industrial solvents has been compared in female Sprague-Dawley rats. The animals were given 5 i.p. injections of the solvents per week for 2 weeks at doses ranging from 1/20 to 1/5 of the i.p. or oral LD50 and the urinary excretion of N-acetyl-beta-D-glucosaminidase, beta 2-microglobulin and albumin was determined. Under these experimental conditions, two solvents, cyclohexane and styrene, were found to cause some tubular injury as evidenced by a statistically significant increase of beta 2-microglobulinuria. At the same dose, styrene was more tubulotoxic than cyclohexane but the opposite was observed when the solvents were administered proportionally to their LD50. The increased beta 2-microglobulinuria caused by cyclohexane was both time- and dose-dependent. It was not accompanied by changes in the glomerular filtration rate and the renal plasma flow, but at the highest dose (1.5 g/kg) the renal concentrating ability was depressed. These renal tubular effects can most likely be ascribed to cyclohexanol, the main metabolite of cyclohexane. As cyclohexane is a widely used industrial solvent with a relatively high threshold limit value (TWA-TLV: 300 ppm) it might represent an underestimated risk for the renal function of exposed populations.

Albuminuria↗

PubMed1994

Conformational analysis of the prototype nonclassical cannabinoid CP-47,497, using 2D NMR and computer molecular modeling.

In an effort to determine the stereochemical requirements for pharmacological activity among the series of nonclassical cannabinoids synthesized at Pfizer, we have studied the conformational properties of the parent bicyclic analog CP-47,497. For this study, we have used a combination of solution NMR and theoretical computational approaches. The energetically favored conformation has the phenolic ring almost perpendicular to the cyclohexanol ring which exists in a chair conformation. The OH bond of the phenol is preferentially coplanar with the aromatic ring and points toward the C2 ring proton, while the dimethylheptyl side chain adopts a conformation almost perpendicular to the aromatic ring. The conformational features of this nonclassical cannabinoid analog closely resemble those of its classical counterparts. The only apparent difference is the small dihedral angle (psi 1 = 62 degrees) between the planes of the two rings of CP-47,497 compared to that of the tricyclic tetrahydro- or hexahydrocannabinol analogs (psi 1 = 137 degrees). However, CP-47,497 can be perfectly superimposed over the respective tricyclic analog by rotation around the Ph-cyclohexyl bond (C6-C7 bond) and assume a conformation which is energetically higher than the preferred one by 3.0 kcal/mol. It can be argued that such a conformation may be acquired by the nonclassical analog during its interaction with the active site.

Cannabinoids↗

PubMed1984

A cannabinoid derived prototypical analgesic.

The synthesis and analgesic testing of 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]cyclohexanol (1) are described. Prior (SAR) studies led us to conclude that the pyran ring of 9-nor-9 beta-hydroxyhexahydrocannabinol (HHC) was not necessary for the expression of biological activity in this series of cannabinoids. Analysis of models and the use of molecular mechanics calculations suggested that a simpler compound, such as 1, would possess the biological activity of HHC. Compound 1 was prepared in nine steps from [3-(benzyloxy)phenyl]acetonitrile (2). Biological testing in five models of pain shows that compound 1 and morphine are equally potent as analgesics and demonstrates that the pyran ring of HHC is not necessary for biological activity. Further simplification of 1 was pursued by the synthesis of 4-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-2-pentanol (17), but this derivative exhibits significantly reduced analgesic activity.

Analgesics↗

PubMed1993

Metabolic interaction of ethanol and cyclohexanone in rabbits.

The interaction of ethanol (EtOH) and cyclohexanone (CHN) metabolism was studied to demonstrate the influence of alcohol beverage in cyclohexanone poisoning. Rabbits were administered CHN and EtOH separately or together, and the plasma concentration of CHN and cyclohexanol (CHL), a metabolite of CHN, and blood concentrations of EtOH were measured at various times. When CHN alone was administered orally, the time to maximum plasma concentration (Tmax) of CHN was as short as 15 min, but that of CHL was 120 min. The short Tmax of CHN was considered to be due to the first-pass effect. The plasma concentration of CHL was much greater than that of CHN. On the other hand, when the same amount of molar CHL was administered in rabbits for sake of comparison, only small amounts of CHN were detected in plasma. The interconversion between CHN and CHL at the time of equilibration tended to shift predominantly toward the formation of CHL, whose plasma concentration ratio was about 1:6 to 1:8. The coadministration of EtOH decreased the plasma concentration of CHN and increased that of CHL more than the administration of CHN alone. The blood concentration of EtOH was also decreased with the coadministration of CHN. The coadministration of EtOH with CHN demonstrated an acceleration in the metabolism of both CHN and EtOH, which may be due to an increase in the concentrations of the alcohol dehydrogenase-NADH and -NAD complexes.

Administration, Oral↗

PubMed1975

Kinetic equivalence of the active sites of alcohol dehydrogenase from horse liver.

The reduction, catalysed by liver alcohol dehydrogenase, of benzaldehyde in the presence and absence of pyrazole, and the oxidation of benzyl alcohol and cyclohexanol in the presence of isobutyramide, has been measured by the stopped-flow technique. In performing these experiments particular care was taken to purify the enzyme, coenzymes, substrates and inhibitors, and to minimise as much as possible the effects of a blank substrate reaction. The calculation of the amount of substrate converted to product during the various phases of the transient process was based on the absorption coefficients for the enzyme-coenzyme and enzyme-coenzyme-inhibitor complexes determined in the absence of substrate. The results show that the two active sites of liver alcohol dehydrogenase are kinetically equivalent and that the enzyme does not exhibit half-of-the-sites reactivity.

Alcohol Oxidoreductases↗

PubMed1981

Effect of nicomol on high density lipoprotein (HDL) subfractions, HDL2e and HDL3e, separated by electrophoresis.

High density lipoprotein (HDL) fractions were separated by dextran sulfate-Mg++ from sera of 5 healthy males before and after oral administration of a daily 1200 mg dose of Nicomol (2,2,6,6-tetrakis (nicotinoyloxymethyl) cyclohexanol; Cholexamin, Kyorin Pharmaceutical Co. Ltd.) for 2 weeks. The HDL fractions were further subdivided into HDL2e and HDL3e by Utermann's electrophoretic method on polyacrylamide gel containing lauric acid. These subfractions roughly corresponded to HDL2 and HDL3, respectively, which were separated by ultracentrifugation. Nicomol treatment increased the HDL2e/HDL3e ratio as is observed for the HDL2/HDL3 ratio, in addition to the increase in total HDL cholesterol concentration. The electrophoretic determination of HDL2e/HDL3e ratio in combination with HDL cholesterol level seemed to be clinically important in assessment of the alteration of HDL2 and HDL3 under physiological and pathological conditions.

Adult↗

PubMed1992

A comparison of the discriminative stimulus properties of delta 9-tetrahydrocannabinol and CP 55,940 in rats and rhesus monkeys.

CP 55,940 [(-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3- hydroxypropyl)cyclohexanol] is a potent bicyclic analog of delta 9-tetrahydrocannabinol (THC) which has been used as a probe for a cannabinoid recognition site in neural tissue. In the present study, CP 55,490 was evaluated for delta 9-THC-like effects in rats and rhesus monkeys trained to discriminate delta 9-THC from vehicle. Rats trained to discriminate delta 9-THC (3.0 mg/kg i.p.) from vehicle were tested with various doses of delta 9-THC and CP 55,940 at both 30 and 90 min postinjection. Catalepsy was measured immediately after these operant tests using an adaptation of the mouse ring-test. In rats, CP 55,940 substituted for delta 9-THC at both 30 and 90 min postinjection at a dose of 0.1 mg/kg that had minimal effects on rates of responding. Doses of delta 9-THC (greater than 3.0 mg/kg) and CP 55,940 (greater than 0.1 mg/kg) that reduced response rates by greater than 50% also produced substantial increases in catalepsy. CP 55,940 and delta 9-THC had a similar time course for discriminative stimulus effects, but CP 55,940 was about 30 times more potent. In monkeys, the training dose of delta 9-THC ranged from 0.04 to 0.16 mg/kg i.m., adjusted individually to minimize response-rate disruption. After training, monkeys were tested with various doses of delta 9-THC and CP 55,940 at 30 min postinjection.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗

PubMed1978

The effect of cyclohexane derivatives on selection of bacterial groups forming activated sludge microflora.

The effect of cyclohexanol, cyclohekxanon and cyclohexylamine on the selection of bacteria in a model population composed of bacteria isolated from activated sludge was examined. The initial population consisted of both gram-positive and gram-negative bacteria. The latter, which accounted for 90-97% of the population, belonged mainly to three Pseudomonas groups and the Enterobacteriaceae, Vibrio-Aeromonas, Achromobacter-Alcaligenes and Flavobacterium groups. Seven day growth in medium containing cyclohexane derivatives caused pronounced qualitative changes in the population. The compounds favored the development of bacteria of the genus Pseudomonas and inhibited the growth of all other gram-negative bacteria. The direction of selection was independent of the type of cyclohexane derivative.

Alcaligenes↗

PubMed1993

Inversion of the substrate specificity of yeast alcohol dehydrogenase.

The relationship between the size of the substrate binding pocket and the catalytic reactivities with varied alcohols was studied with the Saccharomyces cerevisiae alcohol dehydrogenase I (ScADH) and compared with the liver enzymes from horse (EqADH, EE isoenzyme) and monkey (MmADH alpha, alpha-isoenzyme). The yeast enzyme is most active with ethanol, and its activity decreases as the size of the alcohol is increased, whereas the activities of the liver enzymes increase with larger alcohols. The substrate pocket in ScADH was enlarged by single substitutions of Thr-48 to Ser (T48S), Trp-57 to Met (W57M), and Trp-93 to Ala (W93A), and a double change, T48S:W93A, and a triple, T48S:W57M:W93A. The T48S enzyme has the same pattern of activity (V/K) as wild-type ScADH for linear primary alcohols. The W57M enzymes have lowered reactivity with primary and secondary alcohols. The W93A and T48S:W93A enzymes resemble MmADH alpha in having an inverted specificity pattern for primary alcohols, being 3- and 10-fold more active on hexanol and 350- and 540-fold less active on ethanol, and are as reactive as the liver enzymes with long chain primary alcohols. The three Ala-93 enzymes also acquired weak activity on branched chain alcohols and cyclohexanol.

Aldehyde Dehydrogenase↗

PubMed1976

Evaluation of 2-benzylidenecyclohexanones and 2,6-bis(benzylidene)cyclohexanones for antitumor and cytotoxic activity and as inhibitors of mitochondrial function in yeast: metabolism studies of (E)-2-benzylidenecyclohexanone.

Some 2-benzylidenecyclohexanones, 2,6-bis(benzylidene)cyclohexanones, and related compounds were evaluated for antitumor and cytotoxic activities; (E)-2-benzylidenecyclohexanone (Ia) was shown to have significant cytotoxic properties and a potent inhibitory effect on yeast mitochondria. After intraperitoneal injection of Ia, unchanged drug and a metabolite, tentatively identified as 2-(p-hydroxybenzyl)cyclohexanol, were found in the urine. No metabolites were found in the feces. Oral administration of Ia afforded three unidentified metabolites in the urine and three unidentified metabolites in the feces.

Animals↗

PubMed1988

[3H]vesamicol binding in brain: autoradiographic distribution, pharmacology, and effects of cholinergic lesions.

An autoradiographic analysis of high-affinity binding sites for the vesicular acetylcholine transport blocker [3H]vesamicol (2-(4-phenylpiperidino) cyclohexanol; AH 5183) was conducted in rat brain. [3H]Vesamicol binding was displaced 52-99% by DPPN [( 2,3,4,8]-decahydro-3-(4-phenyl-1-piperidinyl)-2-napthalenol) (IC50 = 14 nM) and by ketanserin (500 nM), haloperidol (43 nM), and vesamicol analogs, but not by drugs selective for adenosine, adrenergic, amino acid, calcium channel, monoaminergic, opioid, PCP, sigma, or several other receptor classes. [3H]Vesamicol binding was most concentrated in the interpeduncular nucleus and fifth and seventh cranial nerve nuclei. Moderate binding was found in the lateral caudate-putamen, medial nucleus accumbens, olfactory tubercle, vertical and horizontal diagonal bands of Broca, and basolateral amygdala. The distribution of [3H]vesamicol binding was similar to distributions of acetylcholine (r = 0.88), acetylcholine esterase (r = 0.97), choline acetyltransferase (ChAT) (r = 0.97), and [3H]hemicholinium-3 binding sites (r = 0.95-0.99). Lower correlations were obtained between [3H]vesamicol and muscarinic receptor densities (r = 0.50-0.70). Few exceptions to the match between binding and cholinergic neuronal markers were found, e.g., the molecular layer of the cerebellum and the thalamus. Lesions of cholinergic neuronal projections to the neocortex or hippocampus reduced [3H]vesamicol binding in each of these regions, but to a lesser extent than reductions in ChAT. [3H]Vesamicol binding sites appear to be anatomically associated with brain cholinergic neurons, a locus that is consistent with the control by this site of vesicular acetylcholine uptake.

Acetylcholine↗

PubMed1994

Keratinocyte-derived proinflammatory key mediators and cell viability as in vitro parameters of irritancy: a possible alternative to the Draize skin irritation test.

This study is aimed at the development of a cell culture assay which may supplement or replace the animal Draize skin irritancy test. Using human keratinocytes, the measurement of proinflammatory eicosanoid and interleukin-1 alpha release and of the impairment of cell viability have provided a suitable in vitro/in vivo correlation for at least three surfactants. The in vitro study has been extended using structurally unrelated, pharmacologically relevant compounds including ethanol, glycerol, cyclohexanol, acetone, benzoic acid, phenol, acrylamide, triethanolamine, Tween 80, sodium dodecyl sulfate, benzalkonium chloride, NiSO4, SnCl2, and ZnCl2. Time- and dose-response studies were used to establish half-maximal stimulatory (SC50) and inhibitory (IC50) as well as 10-fold stimulatory (ED10) concentrations for arachidonic acid release, cytotoxicity, and IL-1 alpha release, respectively. Based upon these values a similar ranking has been obtained for the mildly acting acetone, ethanol, glycerol, and Tween 80 and for the severely acting A23187, benzalkonium chloride, and sodium dodecyl sulfate. With respect to all other test compounds, substantial variation occurred indicating that all three test parameters provide a more complete characterization of the test compound's potency than a single endpoint. These data are ready to be validated by a controlled clinical study aimed at a qualitative and quantitative evaluation of the symptoms of skin inflammation in volunteers.

Animal Testing Alternatives↗

PubMed1981

Measurement of the urinary metabolites of N-hexane, cyclohexane and their isomers by gas chromatography.

A gas chromatographic method for analyzing the urinary metabolites of n-hexane (2-hexanol, 2,5-hexanedione, 2,5-dimethylfuran and gamma-valerolactone), of 2-methylpentane (2-methyl-2-pentanol), of 3-methylpentane (3-methyl-2-pentanol), and of cyclohexane (cyclohexanol) was developed. Processing of urine and the gas chromatographic conditions are described. The recovery rate of all hexane metabolites, except 2,5-dimethylfuran, ranged between 92 and 100%. The variation coefficient of metabolites determination was between 1.5 and 5%, apart from 2.5-dimethylfuran determination for which the variation coefficient was 15%. The detection limits ranged between 0.2 and 0.7 mg/l and between 0.05 and 0.1 mg/l when a packed or capillary column was used. Results obtained from a packed and capillary column are discussed.

Biotransformation↗

PubMed1988

Evidence to suggest that the spontaneous release of acetylcholine from rat hippocampal tissue is carrier-mediated.

The effect of L- and D-stereoisomers of 2-(4-phenylpiperidino) cyclohexanol (AH 5183) on the spontaneous release of acetylcholine (ACh) from rat hippocampal tissue was studied. L-AH 5183 was approximately 100 times more potent than was D-AH 5183 in reducing spontaneous ACh release. Spontaneous ACh release was also temperature dependent. These results may suggest that the spontaneous release of ACh from brain tissue is carrier-mediated.

Acetylcholine↗

PubMed1993

Ethanol metabolism in isolated hepatocytes. Effects of methylene blue, cyanamide and penicillamine on the redox state of the bound coenzyme and on the substrate exchange at alcohol dehydrogenase.

Ethanol metabolism in hepatocytes increases the NADH/NAD+ ratio. The mechanism was investigated by measurements of the redox state of the coenzyme bound to alcohol dehydrogenase and of ethanol-acetaldehyde exchange and concomitant hydrogen transfer between ethanol molecules. Isolated hepatocytes from fed rats were incubated with cyclohexanone and cyclohexanol or with [1,1-2H2]-and [2,2,2-2H3]ethanol, followed by gas chromatographic determination of the redox state and isotope analysis of the ethanol by gas chromatography-mass spectrometry, respectively. Cyanamide and methylene blue decreased the redox shift caused by ethanol and increased the rates of acetaldehyde reduction during the exchange. Both drugs increased the extent of hydrogen transfer between ethanol molecules during oxidoreduction. Penicillamine had no significant effect on the ethanol-induced change in redox state of the bound coenzyme although it decreased the rate of acetaldehyde reduction. The results indicate that methylene blue inhibits aldehyde dehydrogenase and that accumulation of acetaldehyde decreases the redox effects of ethanol. The redox effect appears to result primarily from rapid elimination of acetaldehyde and equilibration with the NAD system on the alcohol dehydrogenase, but is not enhanced by further decreases in acetaldehyde concentration. Thus, penicillamine could probably be used to decrease the concentration of acetaldehyde without increasing the redox effects.

Acetaldehyde↗