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PubMed1989

Differences in susceptibility of rat liver and brain sialidases to ethanol and gangliosides.

Based on reports that ethanol can decrease the level of sialic acid (SA) (neuraminic acid) in several tissues, we tested the hypothesis that ethanol promotes SA cleavage by enhancing the activity of sialidases (neuraminidases). We also investigated whether brain and liver sialidases have the same response to ethanol and gangliosides, especially since our prior studies have demonstrated that gangliosides could antagonize ethanol-induced behavior. Experiments were conducted on homogenates of brain and liver and of liver slices of adult rats. In liver slices, cleavage of SA did not fall in proportion to the ethanol-induced inhibition of sialidase; in fact, at 0.1 M ethanol, free SA increased, even though sialidase was inhibited. Brain sialidase activity on endogenous sialoglycoconjugates was much more resistant to ethanol than liver sialidase and was fully active even in concentrations as high as 1 M. When gangliosides were incubated with liver slices in the absence of ethanol, sialidase was markedly stimulated. The ethanol-induced inhibition of sialdase in liver slices was mimicked by sorbitol, suggesting that the inhibition may be caused by a shift in redox state as a result of increased NADH. The ethanol metabolite, acetaldehyde, does not seem to be a factor, because sialidase inhibition still occurred when slices were incubated with ethanol containing pyrazole. The results indicate that ethanol promotes the accumulation of free SA in liver without stimulating sialdase; our other work suggests that the cause is an increase in accessibility to sialoglycoconjugates rather than decreased utilization of SA. Brain and liver sialidases clearly respond differently to both ethanol and gangliosides.

Animals↗
PubMed1995

Intrastriatal injection of cannabinoid receptor agonists induced turning behavior in mice.

When injected unilaterally into the mouse striatum, cannabinoid agonists such as Win 55212-2 (1-100 ng/mouse), CP 55940 (0.1-50 ng/mouse), and anandamide (0.5-50 ng/mouse), the putative endogenous ligand of CB1 receptor, dose-dependently induced turning behavior. SR 141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-me thyl-1H- pyrazole-3-carboxamide hydrochloride], the selective antagonist of CB1 receptor, antagonized the three cannabinoid receptor agonists-induced turning with similar ED50s (0.13-0.15 mg/kg, IP). Spiroperidol (a D2 receptor blocker), (+)-SCH 23390 (a D1 receptor blocker), or prior 6-OHDA lesions of the striatum blocked Win 55212-2- and CP 55940-induced turning, thus suggesting the involvement of DA transmission in cannabinoid-induced turning. Taken together, these findings reinforce the notion of a cannabinoid receptor-mediated control of nigrostriatal function.

Analgesics↗
PubMed1991

Glucose metabolism in Giardia intestinalis.

The effect of glucose and other monosaccharides on Giardia intestinalis was investigated by growing G. intestinalis trophozoites in Diamond's TYI-S-33 medium modified by changes in the monosaccharide component, and observing changes in the trophozoite growth and product formation (alanine, ethanol and acetate). Reducing the glucose concentration from 50 mM to 10 mM had little effect on trophozoite growth and product formation. Below 10 mM glucose, ethanol production was markedly reduced, there was a lesser effect on alanine, but acetate production was unaffected. In medium in which no glucose had been added, trophozoites grew at about half the rate of controls (50 mM glucose) and continued to form the same products. Growth in medium containing 10 mM ribose or 10 mM fructose substituted for glucose produced a metabolic profile similar to that of the no glucose added condition. The activity of a number of glycolytic and related enzymes was also determined, but the enzymic profile was not affected by the monosaccharide status of the medium. Ethanol production by trophozoites was specifically depressed by the aldehyde reductase inhibitor, valproate; 3 mM valproate reduced ethanol production by 90%. The alcohol dehydrogenase inhibitor pyrazole had no effect on ethanol production or any other parameter. This differential inhibition suggests that ethanol is produced by an aldehyde reductase or related enzyme. The observations that G. intestinalis trophozoites can continue to grow, replicate and produce the same metabolites in medium containing little or no glucose suggest that G. intestinalis is not solely dependent on glucose as a metabolic fuel.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetates↗
PubMed1987

Electronic absorption and EPR spectroscopy of copper alcohol dehydrogenase: pink, violet and green forms of a type 1 copper center analog.

Blue and non-blue states of the copper center in copper-substituted alcohol dehydrogenase (EC 1.1.1.1) can be attained by coenzyme binding and/or ligand binding to the copper ion. Copper alcohol dehydrogenase has been studied by electronic absorption, CD and EPR spectroscopy in the presence and absence of coenzyme. On the basis of previous work on blue (Type 1) copper proteins with a CuSS*N2 chromophore the assignment of charge transfer transitions in copper alcohol dehydrogenase is discussed. The latter contains a CuS2N(OH2) unit in the ligand-free protein and a CuS2N2 unit in the ternary complex with NAD+ and pyrazole. It is proposed that the energy of the charge transfer transitions can be used as a structural marker in combination with EPR data. A comparison is made between the spectroscopic properties of the ternary complex of copper alcohol dehydrogenase and the copper centers in stellacyanin and cytochrome-c oxidase (CuA) in order to test the validity of recent structural models of the type CuS2N2, i.e., a cupric ion coordinated to two thiolate ligands. Finally, a close resemblance between the electronic absorption spectra of copper alcohol dehydrogenase and those of other variants of Type 1 copper centers such as the 'unusual' copper center of nitrous oxide reductase is noted as an indication of similar coordination environments.

Alcohol Dehydrogenase↗
PubMed1995

Interrelation between electrostatic and lipophilicity potentials on molecular surfaces.

Molecular electrostatics and lipophilicity are two important properties included in quantitative structure-activity relationships (QSARs) employed for rational drug design. The molecular electrostatic potential (MEP) provides information on the position, distribution, and extent of electrophilic and nucleophilic regions around a molecule. Similarly, the solvent affinity can be represented by a local phenomenological potential of semiempirical nature: the molecular lipophilicity potential (MLP). Although a simultaneous, three-dimensional display of MEP and MLP is possible, it may not provide a practical tool for comparing molecules. In this work, we deal with the simpler two-dimensional maps of the entire molecular surface projected onto an MEP-MLP plane. We analyze how these maps change with the following factors: (1) composition and molecular geometry, (2) the quality of the computation of MEP, and (3) the parameter set used for evaluating the lipophilicity potential. The approach is used to compare series of pyrazole derivatives. The methodology is useful in assessing molecular similarity, as well as in establishing the nature of differences between compounds.

Chemical Phenomena↗
PubMed1994

Effect of branching in 4-alkylpyrazoles on liver alcohol dehydrogenase inhibition: a shape analysis study.

Shape analysis methodology is applied to the study of 4-alkylpyrazoles which are known inhibitors of liver alcohol dehydrogenase. Elongation of the alkyl chain increases the inhibitory power, whereas branching of the chain diminishes the activity. These two counterpoised effects are studied simultaneously in a selected set of 4-alkylpyrazoles. A systematic conformational analysis followed by topological characterization of the van der Waals surfaces of all the local minima restricts the conformational space to potential bioactive structures. The analysis of the interrelation between the molecular electrostatic potential and van der Waals surfaces provides certain shape codes characteristic of each 4-alkylpyrazole. In both topological analyses (van der Waals surfaces and molecular electrostatic potential-van der Waals surface interrelations) graphical representations and analytical methods were used. A good correlation between the shape codes and the inhibitory activity is found for the linear derivatives. For branched pyrazoles, a tendency in their inhibitory power is predicted. Isopentylpyrazole is suggested to have the same inhibitory profile as 4-butylpyrazole, the linear derivative with one less carbon atom.

Alcohol Dehydrogenase↗
PubMed1986

The effect of an unusual workshift on chemical toxicity. I. Studies on the exposure of rats and mice to dichloromethane.

The 10- or 12-hr workday has become increasingly popular in industry. Current occupational exposure limits are designed to protect workers on the standard 8-hr/day workshift and are not intended for use for longer workshifts. Experiments were conducted to compare the effects of a 12-hr exposure schedule to those of an 8-hr schedule on the carboxyhemoglobin (COHb) formation resulting from dichloromethane (DCM) inhalation. Rats and mice were exposed to 200, 500, or 1000 ppm DCM for 8 hr/day for 5 days or 12 hr/day for 4 days. The effect of the unusual exposure schedule on COHb levels was not significant. The metabolic pathway for the formation of COHb appeared to be saturated even at the lowest concentration of DCM. To examine the possible increase in the retention of inhaled DCM in the longer exposure schedule, single exposures for 8 and 12 hr were compared. The peak blood DCM level was dependent upon the DCM exposure concentration, but the half-life was independent of the duration of exposure and the concentration of DCM. The half-life of COHb in blood was prolonged by increasing the DCM concentration, but was not affected by the exposure period. Pyrazole treatment decreased COHb level and increased blood DCM level in rats exposed to DCM. These results suggest that the exposure limit for a chemical with a short biological half-life and readily reversible toxic effect may not need to be adjusted for a longer workshift which is in agreement with some of the mathematical models based upon the pharmacokinetics of a toxicant.

Animals↗
PubMed1984

Stimulation of hepatic and renal diamine oxidase activity after acute ethanol administration.

The effect of a single administration of ethanol (2 g/kg body weight) on hepatic and renal diamine oxidase activity was studied in fasted rats. Diamine oxidase activity significantly increased in liver and kidney 6 h after ethanol intubation. Pyrazole (an inhibitor of alcohol dehydrogenase), cycloheximide or actinomycin D (inhibitors of macromolecular syntheses), as well as prior adrenalectomy, prevented the ethanol-induced stimulation of diamine oxidase in the liver, but not in the kidney. The results demonstrated that the enhancement of diamine oxidase activity in the liver was due to an enzyme induction mediated by alcohol metabolism as well as by adrenals. In contrast, the stimulation of diamine oxidase activity in the kidney did not depend on synthesis of new enzyme molecules and was not mediated by ethanol metabolism or adrenal hormones.

Amine Oxidase (Copper-Containing)↗
PubMed1995

Transglutaminase activity in rat liver after acute ethanol administration.

The acute effect of ethanol on hepatic transglutaminase (EC 2.3.2.13) activity and polyamine levels were investigated in the rat. A high dose of ethanol (5 g/kg body weight, given by gastric intubation) caused in homogenate and cytosolic fraction an inhibition of 50-70% from 3 to 24 h which thereafter was reversible. Such a decrease may be in part responsible for the observed enhancement in putrescine and spermidine contents observed at the same times. Pyrazole, an inhibitor of alcohol dehydrogenase, prevented the ethanol-induced reduction in transglutaminase activity. Disulfiram, an inhibitor of aldehyde dehydrogenase, allowed detection of an inhibitory effect on enzyme activity even at a low dose of ethanol (2 g/kg), which per se did not modify transglutaminase activity. The hepatic cytosolic fraction, incubated in the presence of various concentrations of acetaldehyde, showed a dose-dependent inhibition of transglutaminase activity. All of these results suggest that acetaldehyde, the first and toxic metabolite of ethanol, inhibits hepatic transglutaminase activity, probably by its binding to the active thiol site of the enzyme. The reduction in transglutaminase may lead to an alteration of cytoskeleton, since the enzyme is known to be involved in tubuline polymerization and microfilament assembly.

Animals↗
PubMed1989

Isolation and characterization of shrew (Suncus murinus) liver alcohol dehydrogenases.

1. Starch gel electrophoresis of adult shrew (Suncus murinus) liver extracts revealed five forms of alcohol dehydrogenase (ADH 1-5) and four of them were purified. 2. ADH-4 and ADH-5 resemble human class I ADH in terms of electrophoretic mobility, substrate specificity and sensitivity to pyrazole inhibition. 3. ADH-2 does not belong to any of the three classes of human ADHs but rather with catalytic properties similar to those of the class B ADH found in guinea pig liver. 4. ADH-1 prefers secondary alcohol over primary alcohol substrates and between the enantiomers tested, the enzyme favors the S isomers.

Alcohol Oxidoreductases↗
PubMed1990

Differences in kinetic characteristics and in sensitivity to inhibitors between human and rat liver alcohol dehydrogenase and aldehyde dehydrogenase.

1. On the basis of kinetic properties and sensitivity to pyrazole inhibition, it is shown that liver alcohol dehydrogenase present in human mainly corresponded to class I and in rat to class ADH-3 which differed in a number of parameters. 2. Two different aldehyde dehydrogenase (ALDH) isoenzymes were detected in both human and rat liver. The human isoenzymes corresponded to the ALDH-I and ALDH-II type. 3. In the rat, one isoenzyme had low Km and showed similar activity than in human liver but differed in their sensitivity to both disulfiran and nitrofazole inhibition whereas the other presented high Km and showed greater activity than the human one. 4. Caution must be therefore paid when extrapolating to human subjects the data on ethanol metabolism obtained with rats.

Acetaldehyde↗
PubMed1981

Identification of two urinary metabolites of rats treated with acrylonitrile; influence of several inhibitors on the mutagenicity of those urines.

Urines collected from rats injected with acrylonitrile (ACN) were mutagenic towards Salmonella typhimurium TA1530; this activity was reduced when the animals were pretreated by pyrazole (inhibitor of alcohol dehydrogenase) and suppressed after pretreatment either by CoCl2 and SKF 525-A (inhibitors of the mixed-function oxidases system) or by trichloroacetonitrile (radical trapping agent). On the other hand, two urinary metabolites (cyanoethanol and cyanoacetic acid) have been detected by gas chromatography. One possible scheme for the in vivo metabolism of ACN is presented which postulates the intermediate formation of a radical species and of an epoxide.

Acetates↗
PubMed1982

Gastric mucosal oxidation of ethanol is not involved in ethanol-induced mucosal damage.

The involvement of gastric mucosal metabolism of ethanol in ethanol-induced mucosal damage was studied in urethane anaesthetised rats. Pyrazole, an inhibitor of alcohol dehydrogenase (ADH), slightly aggravated the mucosal lesions produced by intragastric instillation of 30% (v/v) ethanol, but had no effect on increased mucosal permeability to ions, pepsinogen and fluid output or on gastric mucosal blood flow associated with mucosal injury. Induction of ADH by ethanol pre-treatment had no effect on the above-mentioned parameters. Intragastric instillation of acetaldehyde, the product of ethanol oxidation, did not cause lesions in the gastric mucosa. The results suggest that the gastric mucosal toxicity of ethanol may not be related to its metabolism in the gastric mucosa.

Acetaldehyde↗
PubMedDate not supplied

Ethanol-induced taste aversions: lack of involvement of acetaldehyde and the area postrema.

Two experiments were run to evaluate the role of acetaldehyde and the area postrema in the acquisition of an ethanol-induced conditioned taste aversion. An ethanol-induced taste aversion was observed in male Sprague-Dawley rats with a dose of 4 g/kg. PO, but not after doses of 1 or 2 g/kg. Pretreatment with 4-methylpyrazole (8 mg/kg, IP), which itself did not induce an aversion as compared to pyrazole (68 mg/kg, IP) that did, and/or prior application of lesions of the area postrema had no influence on the development of an ethanol-induced taste aversion. The results indicate that ethanol-induced taste aversion learning does not result from the metabolism of ethanol to acetaldehyde and does not, like other toxins, involve the mediation of the area postrema.

Acetaldehyde↗
PubMedDate not supplied

Alcohol metabolism and fetal hypoplasia in chick brain.

Chick embryos given a single dose of ethanol (1.0 g/kg) at the start of incubation (day 0) had widely differing levels of blood alcohol when sacrificed on day 7 and the blood alcohol levels were inversely correlated with whole body and brain weight. Clearance of the alcohol by the embryos was inhibited by simultaneous treatment with 4-methyl pyrazole and this treatment potentiated the brain growth inhibition due to ethanol. Treatment with indomethacin lowered blood alcohol levels on day 7 and protected against the growth inhibition. These data suggest that early chick embryos have varying amounts of alcohol dehydrogenase-like metabolic activity and that higher levels of this activity protect against alcohol-induced brain growth inhibition in this model. If similar variations in the ability to metabolize alcohol exist in human fetuses, it may represent a mechanism by which comparable maternal doses of alcohol produce widely varying fetal effects.

Alcohol Dehydrogenase↗
PubMedDate not supplied

Effect of 3-amino-1,2,4-triazole on narcosis time and lethality of ethanol in UChA rats.

The capacity of rat brain homogenates to oxidize ethanol by catalase peroxidative system, previously reported, was reevaluated in experiments using lower ethanol concentration, showing that the effect of this system can be observed even with a concentration of 50 mM, equivalent to non lethal blood level. The involvement of catalase was confirmed by its blocking by aminotriazole (AT) or methanol but not by pyrazole or butanol. Evidence for a functional role of ethanol oxidation by brain catalase in the action of this substance was given by the fact that rats pretreated with AT (1 g/kg IP) exhibited a significant shorter narcosis than untreated controls, strongly suggesting the mediation of acetaldehyde in this effect. Previous results with doses of 60 mmole/kg IP were confirmed with 70 mmole/kg IP, but not with 90 mmole/kg IP. A significant prolonging of narcosis time was observed when AT was administered after any of these doses by an unknown mechanism. Furthermore it was observed that AT pretreatment reduced significantly the lethal effect of 110 mmole/kg IP ethanol; but when AT was given after ethanol (90 mmole/kg IP) it enhanced the lethality. These results suggest that catalase peroxidative pathway might play a role not only in narcosis time but also in ethanol toxicity.

Amitrole↗
PubMedDate not supplied

Methanol-induced monoamine changes in hypothalamus and striatum of albino rats.

This paper suggests that like ethanol, methanol also produces certain changes in the steady state level of monoamines in hypothalamus and striatum of albino rats. Though, the toxic manifestations of methanol are attributed to the metabolic end product of methanol viz. formic acid by several workers, we report here that the methanol-induced brain monoamine changes, at least, could be attributed to the direct action of methanol rather than to its metabolic end products like formaldehyde or formate. Studies in the steady state level of rat brain monoamines have shown that after methanol administration (3 g/kg), there is severe depletion of dopamine level in striatum but a significant increase in the level of dopamine, serotonin and 5-hydroxy indole acetic acid in hypothalamus. At the same time, norepinephrine and epinephrine levels are reduced in hypothalamus as well as in striatum. These effects do not seem to be induced by metabolic acidosis. The changes in monoamine levels are very well correlated with the blood and brain level of methanol as evidenced by maintaining a higher methanol level either by simultaneous administration of ethanol or by blocking methanol metabolism by pretreatment with 4-methyl pyrazole and 3-amino-1,2,4-triazole. It is thus postulated that monoamine changes induced by methanol appear to be the direct effect of methanol per se on the monoaminergic neuronal membranes.

Amitrole↗
PubMedDate not supplied

Specific and nonspecific effects of ethanol vapor on plasma corticosterone in mice.

The intent of this study was to determine whether chronic ethanol (EtOH) vapor inhalation, with or without adjunct pyrazole (PYR) administration, was stressful in mice, as defined by increases in plasma corticosterone (CORT) concentration. Mice were randomly assigned to groups differentiated both on the basis of EtOH vapor exposure and the presence or absence of PYR administration. Blood samples for blood EtOH concentration (BEC) and plasma CORT concentration were obtained from mice after 72-96 hours of treatment. Mice were sacrificed after 96 hours of treatment and body and adrenal weight determined. BEC was significantly higher in PYR-treated animals and animals treated with the higher EtOH vapor concentration. Plasma CORT was elevated in proportion to BEC; however, other nonspecific stresses, in particular that of PYR administration, also elevated plasma CORT. Nonspecific stresses associated with this protocol may reduce the generality of these observations. Nevertheless, the high correlation between BEC and plasma CORT concentration in the PYR groups indicates that, with suitable control groups, the PYR-EtOH vapor inhalation approach is viable for studies concerned with EtOH effects on hypothalamic-anterior pituitary-adrenocortical function.

Administration, Inhalation↗