Ethanol interactions with other cytochrome P450 substrates including drugs, xenobiotics, and carcinogens

Chronic ethanol abuse is associated with increased activity of the microsomal ethanol-oxidizing system. This effect is due primarily to induction by ethanol of a specific cytochrome P450 (CYP2E1) responsible for enhanced oxidation of ethanol and other P450 substrates and, consequently, for metabolic tolerance to these substances. Furthermore, cytochrome 450 induction increases the activation of numerous xenobiotics to toxic metabolites and of chemical carcinogens to reactive metabolites, thereby accelerating their adverse effects. Microsomal enzyme induction has been associated with increased reactive oxygen species production and enhanced lipid peroxidation, as well as with decreased enzymatic and nonenzymatic scavenger activity, providing another possible explanation for ethanol-mediated toxicity. Yet another effect of chronic alcohol abuse is chronic immune system activation, which is the mechanism underlying alcohol-related liver disease. The metabolism of steroids and vitamins is catalyzed by P450 and is altered in chronic alcoholics. This article reviews recent advances in the understanding of ethanol interactions with drugs, toxic agents, and carcinogens, as well as with steroids and vitamins.     

Ethylene glycol poisoning with a normal anion gap caused by concurrent ethanol ingestion: importance of the osmolal gap

Ethylene glycol poisoning classically presents as a metabolic acidosis with an increased anion gap. Metabolism of ethylene glycol to organic acids, and increased production of lactate, are responsible for the increased gap. We report the case of an alcohol user who consumed ethanol and ethylene glycol concurrently, and presented without acidosis, with a normal anion gap. Several hours later, when his serum ethanol level had declined, he developed severe acidosis with an elevated anion gap. An increased osmolal gap, not accounted for by the serum ethanol level, proved to be an important clue to the diagnosis. In this patient, ingestion of ethanol inhibited the hepatic metabolism of ethylene glycol to organic acids, obscuring the diagnosis. In intoxicated alcohol users, even in the absence of metabolic acidosis, serum osmolality measurements and calculation of the osmolal gap may facilitate the rapid diagnosis of ethylene glycol poisoning.     

Wine versus ethanol in human nutrition. I. Nitrogen and calorie balance

There are implications in the literature that wine is different from other alcoholic beverages and that it may even have a beneficial effect on the nutritional process. A metabolic study was undertaken in an attempt to document the effects of wine versus ethanol on absorption of various nutrients. Nitrogen and caloric data are presented here. During each of four 18-day experimental periods, six healthy, young men were given, in random order, a liter per day of the following test beverages: Zinfandel wine (9.3% w/v alcohol); dealcoholized Zinfandel wine; pure ethanol (9.3% w/v aqueous alcohol solution); and deionized water. These beverages were divided into four equal feedings and administered with a carefully controlled isocaloric diet over a 12-hr period. The subjects tended to lose weight on alcohol-containing regimens, suggesting that calories from alcohol may not be as efficient as those from fat and carbohydrate. Urinary excretion of nitrogen was significantly greater during wine and ethanol administration than during feeding of the other test beverages. This was reflected in an increase in uric acid and urea nitrogen output, primarily, the latter, suggesting that alcohol may directly affect protein catabolism. There was no significant difference in fecal nitrogen excretion between experimental periods.     

Effect of lipid solubility on the development of chronic cross-tolerance between ethanol and different alcohols and barbiturates

Tolerance to ethanol and cross-tolerance to other alcohols (n-propanol, n-butanol, t-butanol, isobutanol, t-amyl alcohol, n-amyl alcohol, and benzyl alcohol) and barbiturates (pentobarbital, secobarbital, amobarbital, thiopental, barbital and phenobarbital) that differ in lipid:water partition coefficient was examined in rats after chronic pretreatment with ethanol. Tolerance and cross-tolerance were studied with three different measures (hypothermia, tilt-plane, and rotarod). Tolerance to ethanol resulted in significant cross-tolerance to alcohols with low lipid solubility (n-propanol and t-butanol), whereas no cross-tolerance was seen with alcohols of high lipid solubility (isobutanol, n-amyl alcohol, t-amyl alcohol and benzyl alcohol). Cross-tolerance to n-butanol (which has intermediate lipid solubility) appeared to be metabolic rather than functional. Tolerance to ethanol also resulted in significant cross-tolerance to barbital and phenobarbital, but not to pentobarbital, secobarbital, amobarbital or thiopental. These studies suggest that lipid solubility is an important factor in relation to specificity of cross-tolerance to alcohols and barbiturates.     

Prolonged isolation and alcohol effect on avoidance learning in two strains of mice

Prolonged isolation in mice is known to induce several behavioral changes, among which impairment of learning was also reported. On the other hand, alcohol is known to have either stimulant or depressant effects on behavior. Further, alcohol effect is also known to depend on strain-linked characteristics and on emotional ground of animals. Since prolonged isolation may differently change the emotional setting of mice, according to the strain, the behavioral effects of alcohol on avoidance learning, have been studied in two strains of male mice differentially housed. Evidences were obtained that ethanol can either improve or worsen learning performances according to the strain and the housing conditions adopted.     

Ethanol preference and behavioral tolerance in mice: Biochemical and neurophysiological mechanisms.

Determinations were made of ethanol preference and behavioral tolerance in 4 experiments with inbred strains of mice. High- and low-preference strains were compared on neural tolerance to ethanol and metabolic capacity. High preference for ethanol was accompanied by higher behavioral and neural tolerance than that found in low-preference Ss. Differences in metabolism of ethanol between high- and low-preferring Ss were small. However, low-preference Ss did not metabolize acetaldehyde as rapidly as high-preference Ss. Differences in preference for propylene glycol were in the same direction and as extreme as those for ethanol. Both substances are CNS depressants; but unlike alcohol, propylene glycol is not metabolized to a toxic metabolite that might induce a conditioned aversion. This finding in addition to the difference observed in neural tolerance suggests that neural sensitivity may play a part in the acceptance or rejection of ethanol and propylene glycol. (30 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

AIDS-related dementia

Dementia is a common process in which there is gradual decrease in mental function due to disease of either cortical or subcortical structures. The numerous causes of dementia can be divided into those in which dementia is the primary manifestation, as in Alzheimer's disease, or secondary to chronic disease, neoplasms, endocrine and metabolic disorders and chronic infections. The dementia in AIDS is usually part of the syndrome of acquired immunodeficiency and may be its first manifestation.     

Groupdrink: The effects of alcohol on intergroup competitiveness.

Alcohol is often consumed in group settings. The present article examines the effect of alcohol on intergroup competitiveness through the use of a prisoner's dilemma game. One hundred fifty-eight college students participated in the study, either individually or as a member of a 4-person experimental single-sex group. Participants consumed either alcohol (1.13 g ethanol/kg body weight) or a placebo. Results show no effect of alcohol on cooperative choice within individuals. However, groups were significantly less cooperative after consuming alcohol than they were after consuming a placebo. In addition, after consuming alcohol, groups were less cooperative than were individuals. Results are discussed in terms of the way alcohol may affect focus of attention on group-level cues. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Influenza virus hemagglutinin: hydrodynamic properties and molecular weight

Following acute alcohol administration (80-160 mg/100 g body weight) histamine levels of rat brain cortex and thalamus were elevated and histidine decarboxylase activity was decreased. The effect was less pronounced after chronic alcohol treatment (15% v/v in drinking water for 4 weeks). In the striatum there was no change in the metabolic pattern of histamine. Histamine-N-methyltransferase was unaffected in either case. Depolarisation-induced release of histamine was inhibited by alcohol in the hypothalamus, thalamus and cortex. The results indicate that ethanol affects the histamine metabolism and release processes in the histaminergic pathway of the brain.     

Increased production of reactive oxygen species by rat liver mitochondria after chronic ethanol treatment

Rat liver microsomes and, to a lesser extent, nuclei were previously shown to produce reactive oxygen species at elevated rates after chronic ethanol treatment. The ability of intact rat liver mitochondria to interact with iron and either NADH or NADPH, and the effects of ethanol treatment, on production of reactive oxygen intermediates was determined. In the presence of ferric-ATP, NADH or NADPH catalyzed mitochondrial lipid peroxidation. Rates were elevated two- to threefold with mitochondria from ethanol-fed rats with both reductants. Mitochondrial lipid peroxidation was insensitive to superoxide dismutase, catalase, or hydroxyl radical scavengers but was sensitive to GSH and anti-oxidants such as trolox. Mitochondrial generation of hydroxyl radical-like species (assayed by oxidation of chemical scavengers) was increased after chronic ethanol treatment, as was H2O2 production. Modifiers of mitochondrial metabolism such as rotenone, cyanide, or an uncoupling agent, had no effect on mitochondrial production of reactive oxygen intermediates. The membrane-impermeable thiol reagent, p-chloromercuribenzoate, was complete inhibitory with both mitochondrial preparations. The activity of the rotenone-insensitive NADH-cytochrome c reductase, an enzyme of the outer mitochondrial membrane, was increased 40 to 60% by the ethanol treatment. These results suggest that NADH acting via the outer membrane NADH reductase can catalyze an iron-dependent production of oxygen radicals by rat liver mitochondria. The outer mitochondrial membrane fraction, prepared by digitonin fractionation, displayed increased rotenone-insensitive NADH-cytochrome c reductase activity after ethanol treatment and was more reactive in catalyzing scission of pBR322 DNA from the supercoiled form to the open circular forms. Rates of oxygen radical production by mitochondria and the extent of increase produced by chronic ethanol treatment are similar to those previously found with microsomes when NADH is the cofactor. Oxidation of ethanol by alcohol dehydrogenase generates NADH, and NADH-dependent production of reactive oxygen species by various organelles is increased after chronic ethanol treatment. These acute metabolic interactions coupled to induction by chronic ethanol treatment may play an important role in the development of a state of oxidative stress in the liver by ethanol.     

Increased sensitivity to the aversive effects of ethanol in PKCε null mice revealed by place conditioning.

Determining the intracellular signaling pathways that mediate the rewarding effects of ethanol may help identify drug targets to curb excessive alcohol consumption. Mice lacking the epsilon isoform of protein kinase C (PKCε) voluntarily consumed less ethanol than wild-type mice in two-bottle choice and operant self-administration assays. Decreased consumption may reflect either increased or decreased sensitivity to the rewarding effects of ethanol. Alternatively, decreased voluntary consumption may reflect a change in sensitivity to the aversive effects of ethanol. The authors used place conditioning to determine that PKCε null mice have an increased sensitivity to the aversive effects of ethanol but a decreased sensitivity to the rewarding effects of ethanol. Together these data suggest that PKCε null mice voluntarily consume less ethanol because they derive less reward and are more sensitive to the aversive effects of ethanol. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Dehydrogenation of 3-phenoxybenzyl alcohol in isolated perfused rabbit skin, skin homogenate and purified dehydrogenases

The formation of 3-phenoxybenzoic acid from 3-phenoxybenzyl alcohol was determined in (a) rabbit ears, single-pass perfused with a protein-free buffer, pH 7.4; (b) the microsomal fraction and its supernatant from homogenized rabbit skin; and (c) purified alcohol dehydrogenase from horse liver and baker's yeast. The inhibition of product formation in (a) was about 60% by various 4-methylpyrazole concentrations, but metyrapone had no effect. Following ultracentrifugation, only the supernatant of homogenized skin showed product formation (apparent Vmay: 32 pmol/min per cm2 skin; apparent Km: 64 microM). 3-Phenoxybenzyl alcohol and ethanol dehydrogenation was similar by alcohol dehydrogenase from horse liver (apparent Km: 0.7 vs. 0.4 mM; apparent Vmax: 0.3 vs. 0.2 U/ microg protein). In baker's yeast, the apparent Km of 3-phenoxybenzoic acid formation was several times larger than that for ethanol dehydrogenation. The KI of 4-methylpyrazole for alcohol dehydrogenase from horse liver was 0.6 (3-phenoxybenzyl alcohol) vs. 0.04 microM (ethanol). The KI for ethanol in baker's yeast was 470 microM. In conclusion dehydrogenation is an important metabolic pathway in the skin for xenobiotics with an aliphatic alcohol at a side chain.     

Are there structural and functional modules in the vertebrate olfactory bulb?

Each of twelve volunteers, at 2 week intervals, received 1 g of antipyrine, a test drug, and were exposed for 4 h either to toluene (375 mg/m3) or xylene (435 mg/m3) singly or in combination with ethanol (0.45 g/kg body wt. before the onset of exposure and 0.15 g/kg thrice every 1 h during exposure to maintain a steady level of ethanol in blood approximately 11 mmol/dm3). No significant differences were found in salivary antipyrine half-life (T1/2 approximately 12 h); and clearance (ClAP approximately 0.83 cm3/s) between control and groups exposed to solvents and/or ethanol. Nevertheless, a tendency to increase the metabolic rate of antipyrine in xylene-exposed group (T1/2 approximately 6.8 h; ClAP approximately 1.40 cm3/s) and counteraction of ethanol (T1/2 approximately 15 h; ClAP approximately 0.63 cm3/s) should be noted. The stimulation of lipid peroxidation in the serum as a biological effect of combined exposure to ethanol and toluene/xylene was observed.     

Ethanol consumption by rats is inversely related to hepatic alcohol dehydrogenase activity

Under normal circumstances the rate of hepatic ethanol oxidation and the rate at which ethanol is removed from the blood are dependent on the hepatic activity of alcohol dehydrogenase. It is possible that ethanol metabolism, and thus hepatic alcohol dehydrogenase, could influence ethanol consumption. In this study 11 adult female Wistar rats were provided with 20% ethanol as their sole drinking fluid and ethanol consumption was measured. After a further period of drinking tap water, the hepatic alcohol dehydrogenase activity was determined. A significant inverse relationship was found between the ethanol consumption by the rats and the hepatic activity of alcohol dehydrogenase (P < 0.05). This enzyme could therefore play a role in determining the amount of alcohol an animal will consume.     

Orbital decompression in exophthalmos due to thyroid disease. Report of 69 cases]

Preclinical studies suggest that acoustic startle amplitude is increased during ethanol withdrawal. The current study evaluated the effects of intravenous infusion of the alpha 2-adrenergic antagonist, yohimbine (0.4 mg/kg), the serotonin partial agonist m-chlorophenylpiperazine (mCPP, 0.1 mg/kg), and placebo administered to 22 male patients meeting DSM-III-R criteria for alcohol dependence and 13 male healthy subjects. Patients and healthy subjects completed 3 test days under double-blind conditions in a randomized order. Patients were sober for 12-26 days prior to testing. On each test day, participants completed startle testing 80 min following drug infusion. Stimuli with varying intensities (90, 96, 102, 108, 114 dB) were presented in a randomized order balanced across four blocks. Stimuli consisted of 40-ms bursts of white noise administered every 45-60 s for 15-20 min through headphones. Analyses indicated that patients exhibited elevated acoustic startle magnitudes on the placebo day relative to healthy subjects. In patients, the magnitude of startle amplitudes elicited at 90 dB, but not 114 dB, correlated significantly with the number of previous alcohol detoxifications. Yohimbine increased startle magnitudes and reduced startle latencies relative to placebo and mCPP in both patients and healthy subjects. mCPP did not alter startle magnitude in either group. Yohimbine also increased the probability that a 90-dB stimulus produced a startle response in healthy subjects, but not in patients. Blunting of yohimbine effects on startle probability may reflect the baseline elevations in startle probability levels in patients, but may also be consistent with other evidence of reduced postsynaptic, but not presynaptic, noradrenergic function in these same patients. These data replicate and extend previous reports indicating that yohimbine facilitates the acoustic startle response in humans. They also further implicate the number of episodes of ethanol withdrawal as a factor influencing subsequent neurobiological responsivity in chronic alcoholic patients. Based on the current data, future research should explore whether measurement of the acoustic startle response provides an objective quantitative severity measure of ethanol withdrawal.     

Effect of alcohol (ethanol) administration on sex-hormone metabolism in normal men

To determine whether ethanol per se affects testosterone metabolism, alcohol was administered to normal male volunteers for periods up to four weeks, resulting in an initial dampening of the episodic bursts of testosterone secretion followed by decreases in both the mean plasma concentration and the production rate of testosterone. The volunteers received adequate nutrition and none lost weight during the study, which tended to exclude a nutritional disturbance as the cause of the decreased testosterone levels. The changes in plasma luteinizing hormone suggested both a central (hypothalamus-pituitary) and gonadal effect of alcohol. In addition, alcohol consumption increased the metabolic clearance rate of testosterone in most subjects studied, probably owing to the combined effects of a decreased plasma binding capacity for the androgen and increased hepatic testosterone A-ring reductase activity. These results indicate that alcohol markedly affects testosterone metabolism independently of cirrhosis or nutritional factors.     

Dopamine release during ethanol drinking in AA rats

The dopamine overflow in the nucleus accumbens of rats from the high alcohol drinking AA line was measured by microdialysis before, during, and after one-half hour sessions of cued drinking of ethanol flavored with saccharin and peppermint or, as a control, saccharin-peppermint drinking. The animals had had extensive previous experience with ethanol drinking. Self-administration of the ethanol solution did not raise the dopamine level substantially: there was a small (17%) but significant increase only during the first 10 min after the onset of drinking. Giving the rats a cue for ethanol, which was part of their daily routine drinking regime, did not raise the dopamine level before ethanol was presented to the rats (i.e., during "anticipation"). The results are consistent with our previous studies showing a lack of a large ethanol-induced dopamine response in rats with previous experience of drinking ethanol and with the idea that although dopamine may play some role in alcohol drinking, it is not the central substrate producing the reinforcement from ethanol in AA rats.     

Thermodynamic and fluorescence studies of the underlying factors in benzyl alcohol-induced lipid interdigitated phase

To further investigate factors contributing to the action of alcohol in the solute-induced lipid interdigitation phase, thermodynamic and fluorescence polarization measurements were carried out to study the interaction of benzyl alcohol with dipalmitoyl phosphatidylcholine bilayer vesicles. The obtained results were compared with those previously reported for ethanol and cyclohexanol (L. G. Roth and C-H. Chen, Arch. Biochem. Biophys. 296, 207, 1992). Similar to ethanol, benzyl alcohol was found to exhibit a biphasic effect on the enthalpy (delta Hm) and the temperature (tm) of the lipid-phase transition and the steady-state fluorescence polarization (P) monitored by 1,6-diphenyl-1,3,5-hexatriene. At a total concentration of benzyl alcohol < 30 mg/ml (the alcohol concentration in lipid phase < 21 mg/ml), benzyl alcohol was found to exhibit large increases in delta Hm and P, which were correlated with the formation of a lipid interdigitated phase, as evidenced by reported X-ray diffraction data. Combining the results with benzyl alcohol and ethanol suggested that simultaneously large changes in delta Hm and P can be used as an indication of the occurrence of a solute-induced lipid interdigitated phase. The overall interacting force in the formation of this lipid phase, as derived from the interactions of the hydroxyl portion of an alcohol with the lipid phosphate head group and the hydrophobic portion of an alcohol with the lipid hydrocarbon chains, may or may not be dominated by hydrophobic interaction. Although lipid/water partition coefficients and the contribution of hydrophobic interaction to the overall interacting force were comparable between benzyl alcohol and cyclohexanol, benzyl alcohol induced lipid interdigitated phase, but not for cyclohexanol. This was due to the ability of benzyl alcohol to be more effective than cyclohexanol in simultaneously interacting with the phosphate head group and the hydrocarbon chains of lipid.     

Acid-catalyzed ethanolysis of temazepam in anhydrous and aqueous ethanol solutions

The benzodiazepines are a family of anxiolytic and hypnotic drugs. When taken concurrently with ethanol, a pharmacological interaction may occur, potentiating the central nervous system depression produced by either drug. In addition to this pharmacological interaction, this report describes a novel chemical reaction between temazepam (a 3-hydroxy-1,4-benzodiazepine) and ethanol under acidic conditions similar to those found in vivo, resulting in a 3-ethoxylated product. Optimal conditions, kinetics, equilibrium, and the mechanism of this acid-catalyzed ethanolysis are reported. The results raise the possibility that the ethanolysis reaction may occur in the stomach of people who consume alcohol and 3-hydroxy-1,4-benzodiazepine on a regular basis. The acid-catalyzed ethanol-drug reaction is a relatively unexplored area and may alter the pharmacological action of some drugs.     

Synergistic increases in rat hepatic cytochrome P450s by ethanol and isopentanol

The purpose of this study was to determine if isopentanol alone or in combination with ethanol increased CYP2B1/2, CYP2E or CYP3A in the livers of rats. Increasing doses of isopentanol (0.5, 1, 2 or 3%) were administered in combination with 5.6% ethanol in the Lieber-DeCarli liquid diet for 7 days. Doses of 0.5 or 3% isopentanol were also administered alone. Isopentanol alone caused small increases in CYP2B1/2 and CYP3A. However, when isopentanol (2 or 3%) was combined with ethanol a synergistic increase in P4502B1/2 was observed. The combined alcohol treatment also resulted in a greater increase in immunoreactive CYP3A than either alcohol alone. Ethanol alone increased CYP2E 5-fold. Inclusion of isopentanol with ethanol resulted in either small or no additional increases in CYP2E. These results confirm our previous findings in cultured hepatocytes that when isopentanol is combined with ethanol, there is a synergistic increase in CYP2B1/2. Increases in CYP2B1/2, CYP2E and CYP3A protein moieties by ethanol, and by ethanol in combination with isopentanol, were associated with increases in their mRNAs. Blood isopentanol levels were 10-fold greater in rats administered 3% isopentanol in combination with ethanol compared to rats administered 3% isopentanol alone. From these results we suggest that isopentanol, a higher chain alcohol in alcoholic beverages, can contribute to increases in hepatic cytochrome P450 observed following consumption of alcoholic beverages.