Ethanol in hospital formularies.
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Alcohol Dehydrogenase↗
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Gestational ethanol exposure disrupts the expression of FGF8 and Sonic hedgehog during limb patterning.
BACKGROUND: Ethanol is known to induce a wide variety of gestational anomalies, including skeletal malformations. Gestational ethanol exposure in mice has been shown to induce postaxial digit loss (ectrodactyly). How ethanol induces limb malformations is not understood. To better understand how ethanol effects limb development, we have utilized a transgenic line of mice that expresses beta-galactosidase in the apical ectodermal ridge (AER) of the limbs throughout gestation. METHODS: Pregnant female mice were injected with 2.9, 3.4, or 3.9 gm/kg ethanol at E9.3 and E9.5; embryos were isolated at E11.25, stained for beta-galactosidase activity, and evaluated for AER defects. Based upon the pattern of defects seen, expression of FGF8 in the AER and Sonic hedgehog in the postaxial mesoderm was evaluated by in situ hybridization. RESULTS: Two distinct phenotypes were seen in response to ethanol that were dose dependent. At 2.9 gm/kg ethanol, the most prevalent phenotype was a mislocalization of the AER to regions both dorsal and ventral to the midline. A higher dosage of 3.4 gm/kg ethanol did not increase the mislocalization phenotype, but resulted in a higher frequency of postaxial loss of the AER and associated mesenchymal tissue. The highest dosage utilized (3.9 gm/kg) resulted in a high frequency of both preaxial and postaxial loss of the AER. Through in situ hybridization, we found that ethanol exposure resulted in a concomitant reduction in FGF8 expression in the AER and Sonic hedgehog expression from the zone of polarizing activity (ZPA). CONCLUSIONS: We propose a model where ethanol disrupts the AER/ZPA positive feedback loop to induce postaxial malformations. Preaxial malformations seen at higher ethanol dosage suggest FGF8 as a critical target of ethanol in producing limb defects.
Alcohol Drinking↗
Effect of ethanol on semen characteristics of vervet monkeys.
The effect of alcohol on spermatogenesis and sperm morphology has been of interest to many andrologists. Six adult male vervet monkeys were utilized to evaluate the effect of ethanol on semen quality. A decrease of the percentage of normal spermatozoa was observed after 10 months of exposure to alcohol.
Animals↗
Effect of acute ethanol intoxication on primary haemostasis, coagulation factors and fibrinolytic activity.
The effect of ethanol intoxication on haemostasis was studied by transection of mesenteric microvessels and liver resection in the rat. Plasma concentrations of alcohol were within the range of those found in ethanol intoxication in man. Bleeding time and blood loss were increased 1 h after ethanol administration, regardless of the utilized technique. A significant positive correlation existed between bleeding time following liver resection and bleeding time after simultaneous transection of a mesenteric arteriole and venule. Coagulation mechanisms, assayed by whole blood clotting time, APT time, one-stage prothrombin time, recalcification time, thrombin time, Owren's P & P test and determination of plasma factor V and fibrinogen levels, were not significantly changed in ethanol-intoxicated animals. Administration of alcohol did not affect fibrinolytic activity, while it inhibited significantly ADP and collagen-induced platelet aggregation in the rat.
Alcoholic Intoxication↗
Direct carbon versus proton heteronuclear editing of 2-13C ethanol in rabbit brain in vivo: a sensitivity comparison.
Proton NMR editing techniques were utilized to study the pharmacology of 13C-labeled ethanol in the cerebrum of the living rabbit at 4.7 T. The sensitivity of these proton spectroscopic methods was compared to direct carbon spectroscopy and a 14-fold improvement in sensitivity of 1H over 13C NMR spectroscopy was observed in vivo. This increase in sensitivity permitted the observation of the time course of the influx and afflux of this 13C-labeled compound with a time resolution of approximately 2 min per spectrum.
Animals↗
[Effect of ethanol on the enkephalinergic opioid system of the rat brain].
The effects of ethanol were examined on the main parameters of rat brain enkephalinergic neurotransmission, e.g., enkephalinase A activity, enkephalin content and specific binding of 3H-morphine and 3H-(D-Ala2, D-Leu5)-enkephalin. Administration of ethanol in a single dose led to significant changes in the tested parameters; upon chronic treatment with ethanol these changes were either less pronounced or altogether absent. The stimulating effect of ethanol on the release and utilization of enkephalins was supposed. Evidence in favour of the hypothesis on the functional relationship between the opiate receptors of the delta-type and enkephalinergic neurotransmission was obtained.
Animals↗
Bifunctional constructs of aspirin and ibuprofen (non-steroidal anti-inflammatory drugs; NSAIDs) that express antibacterial and alkylation activities.
Ibuprofen and aspirin are two common non-steroidal anti-inflammatory drugs (NSAIDs). Both NSAIDs have a carbonyl carbon [-C(O)-], which was utilized to attach a nitrogen mustard (N-mustard) ester group or a tripeptide group. The tripeptide consisted of a L-Gly-D-Ala-D-Ala sequence, where D-Ala-D-Ala is the reactive site for antibacterial activity and L-Gly serves as a linker to the NSAID carrier drug. The aspirin tripeptide and N-mustard show significant antibacterial activity at >or=5.0 x 10(-5) M against penicillin-susceptible or -resistant Escherichia coli. The partition coefficients (log Kow)log P of aspirin and ibuprofen tripeptide drugs were -1.05 and 2.23, respectively. The NSAIDs served as carrier drugs of the N-mustard group which expressed alkylation activity directed towards the nucleophilic primary amine of p -chloroaniline. Hydrolysis of the N-mustard agents yielded the parent structure of aspirin (or ibuprofen) and an N-mustard moiety, 2-[bis(2-chloroethyl)amino]ethanol. The (log Kow)log P for the N-mustard structures of aspirin and ibuprofen were 2.61 and 5.63, respectively. The (log Kow)log P value of 2-[bis(2-chloroethyl)amino]ethanol was 0.56. Fluorescamine was utilized to determine unreacted p -chloroaniline at known time intervals, which permitted calculation of rate constants and rate equations. The aspirin N-mustard agent expressed strong antibacterial activity against a penicillin-resistant bacteria and first-order alkylation kinetics. The ibuprofen N-mustard and 2-[bis(2-chloroethyl)amino]ethanol followed second-order alkylation kinetics. All N-mustard and tripeptide compounds showed zero violations of the Rule of 5. Values of TPSA (molecular polar surface area), C log P and molecular dipoles were calculated.
Anti-Inflammatory Agents, Non-Steroidal↗
Lipofection reagents prepared by a simple ethanol injection technique.
Cationic liposomes are being utilized for the delivery of DNA into mammalian cells both in vitro and in vivo. In this report, we describe a rapid, simple injection method for the preparation of cationic liposomes that requires no special equipment. We demonstrate that, using this injection method, liposomes prepared with a commercially available cationic lipid (dimethyldioctadecylammonium bromide, DDAB) or a synthetic cationic cholesterol derivative, along with a neutral lipid (dioleoyl-L-alpha-phosphatidylethanolamine, DOPE), effectively transfect a variety of cell lines in vitro. The transfection activity of liposomes prepared by this method was comparable to that obtained with liposomes prepared by the standard evaporation/sonication procedure and to that of a commercial reagent, Lipofectamine.
Cations↗
Effect of propylthiouracil treatment on NADPH-cytochrome P450 reductase levels, oxygen consumption and hydroxyl radical formation in liver microsomes from rats fed ethanol or acetone chronically.
The antithyroid drug propylthiouracil (PTU) has been shown previously to reduce hepatic oxygen utilization and to protect the liver from ethanol-induced injury. The present study examined the effect of PTU on hepatic microsomal oxygen consumption and on the activities of NADPH-cytochrome P450 reductase (CYP-reductase) and cytochrome P4502E1 (CYP2E1) in rats receiving ethanol or acetone chronically. Liver microsomes from rats treated with ethanol for 29 days displayed increases in (i) O2 consumption (70%), (ii) hydroxyl radical (.OH) production (49%) and (iii) ethanol oxidation (50%). Microsomal CYP2E1 levels were increased markedly by chronic ethanol administration, while CYP-reductase was affected marginally, but not significantly (P = 0.06). Chronic treatment with acetone for 14 days, produced similar effects, except that .OH production was not enhanced. Administration of PTU (25 mg/kg/day) to ethanol- or acetone-fed rats, for 10 and 14 days, respectively, led to a marked reduction in the levels and activity of CYP-reductase, and to a decrease in the rates of microsomal O2 consumption, .OH production and ethanol oxidation, but did not lower the levels of CYP2E1 or the metabolism of the CYP2E1 substrate N,N-nitrosodimethylamine. These data suggest that the ability of PTU to protect the liver from ethanol-induced injury may be due to a reduction in the levels of CYP-reductase, thereby minimizing the enhancement of microsomal oxygen consumption and free radical generation associated with ethanol-induced CYP2E1 activity.
Acetone↗
Metabolic mapping of the effects of oral alcohol self-administration in rats.
The functional effects of the voluntary consumption of ethanol in rats were investigated using the quantitative autoradiographic 2-[14C]deoxyglucose method for measurement of rates of local cerebral glucose utilization. A modified sucrose-substitution procedure was used to train three groups of Wistar rats to self-administer water, a 5% sucrose solution, or a 10% ethanol/5% sucrose solution in daily sessions. Once stable rates of consumption were established, the 2-[14C]deoxyglucose method was applied immediately after completion of the final test session. Rats received a dose of ethanol equivalent to 0.5 g/kg (n = 6) on the day of the procedure or a comparable volume of sucrose solution (n = 6) or water (n = 5). Rates of local cerebral glucose utilization in rats that ingested water did not differ from those that rats consumed a 5% sucrose solution. In contrast, voluntary ethanol consumption produced a highly discrete pattern of changes in rates of glucose utilization. Ethanol ingestion increased cerebral metabolism, as compared with rates of metabolism in rats that consumed either water or sucrose in the rostral pole and shell of the nucleus accumbens, medial prefrontal cortex, lateral septum, basolateral and central nuclei of the amygdala, substantia nigra, and the ventral tegmental area. This pattern of alterations in functional activity is distinctly different from that observed when equivalent doses of ethanol are administered acutely, emphasizing the importance of self-administration in determining the changes in glucose utilization. Furthermore, within the nucleus accumbens, glucose utilization was selectively augmented in the rostral pole and shell subterritories, whereas cerebral metabolism in the core was unaffected. Finally, these data demonstrate that it is the simultaneous activation of an interconnected network of limbic brain regions that serves as the substrate of the effects of voluntarily ingested ethanol.
Alcohol Drinking↗
Utilization of cellulosic materials through enzyamtic hydrolysis. I. Fermentation of hydrolysate to ethanol and single-cell protein.
Ethanol fermentation studies were conducted with Saccharomyces cerevisiae ATCC "4126, to determine the optimal conditions of oxygen tension and feed sugar concentration. In long-term continuous culture maximum ethanol production was found to occur at 0.07 mmHg oxygen tension and 10% glucose feed concentration. Preliminary process design and cost studies are developed for industrial scale fermentations to produce ethanol and torula yeast from sugars obtained by enzymatic hydrolysis of newsprint.
Biodegradation, Environmental↗
Utilization and metabolic effects of a solution of amino acids, sorbitol, and ethanol in parenteral nutrition.
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Acid-Base Equilibrium↗
Direct and efficient production of ethanol from cellulosic material with a yeast strain displaying cellulolytic enzymes.
For direct and efficient ethanol production from cellulosic materials, we constructed a novel cellulose-degrading yeast strain by genetically codisplaying two cellulolytic enzymes on the cell surface of Saccharomyces cerevisiae. By using a cell surface engineering system based on alpha-agglutinin, endoglucanase II (EGII) from the filamentous fungus Trichoderma reesei QM9414 was displayed on the cell surface as a fusion protein containing an RGSHis6 (Arg-Gly-Ser-His(6)) peptide tag in the N-terminal region. EGII activity was detected in the cell pellet fraction but not in the culture supernatant. Localization of the RGSHis6-EGII-alpha-agglutinin fusion protein on the cell surface was confirmed by immunofluorescence microscopy. The yeast strain displaying EGII showed significantly elevated hydrolytic activity toward barley beta-glucan, a linear polysaccharide composed of an average of 1,200 glucose residues. In a further step, EGII and beta-glucosidase 1 from Aspergillus aculeatus No. F-50 were codisplayed on the cell surface. The resulting yeast cells could grow in synthetic medium containing beta-glucan as the sole carbon source and could directly ferment 45 g of beta-glucan per liter to produce 16.5 g of ethanol per liter within about 50 h. The yield in terms of grams of ethanol produced per gram of carbohydrate utilized was 0.48 g/g, which corresponds to 93.3% of the theoretical yield. This result indicates that efficient simultaneous saccharification and fermentation of cellulose to ethanol are carried out by a recombinant yeast cells displaying cellulolytic enzymes.
Cellulase↗
Use of measurements of ethanol absorption from stomach and intestine to assess human ethanol metabolism.
Controversy exists concerning the site (stomach vs. liver) and magnitude of first-pass metabolism of ethanol. We quantitated gastric and total ethanol absorption rates in five male subjects and utilized these measurements to evaluate first-pass metabolism. Gastric emptying of ethanol (0.15 g/kg) was determined via a gamma camera and gastric absorption from the ratio of gastric ethanol to [14C]polyethylene glycol. Gastric absorption accounted for 30% and 10% of ethanol administered with food and water, respectively. With food, estimated gastric mucosal ethanol concentrations fell from 19 to 5 mM over 2 h. Calculations using these concentrations and kinetic data for gastric alcohol dehydrogenase showed <2% of the dose underwent gastric metabolism. Application of observed ethanol absorption rates to a model of human hepatic ethanol metabolism indicated that only 30% and 4% of the dose underwent first-pass metabolism when administered with food and water, respectively. We conclude that virtually all first-pass ethanol metabolism occurs in the liver and first-pass metabolism accounts for only a small fraction of total clearance.
Absorption↗
Ethanol-induced alterations of glucose tolerance, postglucose hypoglycemia, and insulin secretion in normal, obese, and diabetic subjects.
Ethanol at an average blood concentration of 1 mg. per milliliter enhanced the immediate (first-phase) and prolonged (second-phase) insulin response to an intravenous glucose load in nonfasting normal human subjects. Simultaneously, the glucose disposal rate was increased and the postglucose hypoglycemia was accentuated, resulting in definite hypoglycemic symptoms in some individuals. Oral glucose tolerance was not changed by ethanol administration, but the thirty-minute blood glucose and plasma insulin values were increased, suggesting that alcohol might accelerate the absorption of glucose from the gut. Ethanol given orally during evening hours (1.5 gm. per kilogram) caused a nocturnal hyperinsulinemia and a decrease of blood glucose, but not an actual hypoglycemia. Oral glucose tolerance and plasma insulin response tested the next morning, when ethanol had disappeared from the blood, were not influenced by drinking the previous evening. The K-value of intravenous glucose was increased at this time, however. When alcohol was administered for one week at a dose corresponding to 25 per cent of daily calories and substituting for fat, both the oral and intravenous glucose tolerances were impaired in each subject but the insulin response remained unchaged. In obese nondiabetic subjects, ethanol did not potentiate the early insulin response to intravenous glucose but it increased the second phase of insulin secretion in response to sustained hyperglycemia. In contrast to conditions in nonobese subjects, the glucose disposal rate was not incresed and postglucose hypoglycemia was not accentuated by ethanol in overweight subjects. In insulin-deficient diabetic patients the absent early insulin response could not be restored by ethanol, and the late component of insulin release was little increased by alcohol infusion. Ethanol did not improve the glucose utilization of diabetic patients.
Adult↗
Effect of chronic ethanol consumption on respiratory and glycolytic activities of rat periportal and perivenous hepatocytes.
Previous studies (Ivester et al., Arch. Biochem. Biophys. 322, 14-21, 1995) have established that periportal and perivenous hepatocytes isolated from ethanol-fed rats demonstrate lower ATP concentrations than those in control preparations when the cells are maintained at very low oxygen tension. In the present investigation, experiments were implemented with periportal and perivenous hepatocytes to determine the effects of chronic ethanol consumption on cellular respiratory and glycolytic activities, since both contribute to maintenance of the energy state of the liver cell. Both periportal and perivenous hepatocytes from ethanol-fed rats demonstrated significantly increased, rather than decreased, respiratory activity when monitored with oxygen concentrations ranging from 16 to 140 microM. Whole liver hepatocytes from control and ethanol-fed animals demonstrated equivalent oxygen utilization, however. Glycolytic activity, monitored by lactate + pyruvate concentrations obtained after both anaerobic and aerobic incubation protocols, was decreased in both cell types from ethanol-fed animals. The glycogen concentrations in freshly isolated periportal and perivenous hepatocytes were also decreased eight- and sevenfold, respectively, as compared with control preparations. Incubation under anaerobic conditions resulted in almost complete depletion of glycogen in both cell types. These observations suggest the possibility that the decreased energy state observed in hepatocytes from ethanol-fed animals is related to a depression in anaerobic glycolysis due to depletion of the endogenous substrate, glycogen.
Adenosine Triphosphate↗
Biological role of alcohol dehydrogenase in the tolerance of Drosophila melanogaster to aliphatic alochols: utilization of an ADH-null mutant.
The toxicity of the first eight primary alcohols and of four secondary alcohols was compared in a wild-type strain (having active ADH) and an ADH-negative mutant. Differences between LC50 measured in the two strains allowed an evaluation of the biological activity of the enzyme. In vitro, ADH is mainly active on secondary alcohols, while in vivo its main role is the detoxification and metabolism of ethanol. These observations suggest that originally ADH was involved in unknown metabolic pathways and that its utilization in ethanol metabolism could be a recent event.
Alcohol Oxidoreductases↗
Metabolic engineering of Saccharomyces cerevisiae for xylose utilization.
Metabolic engineering of Saccharomyces cerevisiae for ethanolic fermentation of xylose is summarized with emphasis on progress made during the last decade. Advances in xylose transport, initial xylose metabolism, selection of host strains, transformation and classical breeding techniques applied to industrial polyploid strains as well as modeling of xylose metabolism are discussed. The production and composition of the substrates--lignocellulosic hydrolysates--is briefly summarized. In a future outlook iterative strategies involving the techniques of classical breeding, quantitative physiology, proteomics, DNA micro arrays, and genetic engineering are proposed for the development of efficient xylose-fermenting recombinant strains of S. cerevisiae.
Biological Transport↗