Rate Of Ethanol Metabolism Research Articles

The fructose-dependent acceleration of ethanol metabolism

The aim of the present study was to elucidate how fructose is able to increase the rate of ethanol metabolism in the liver, an observation previously termed the fructose effect. Previous studies suggest that an increase in ATP consumption driven by glucose synthesis from fructose stimulates the oxidation of NADH in the mitochondrial respiratory chain, allowing faster oxidation of ethanol by alcohol dehydrogenase; however, this idea has been frequently challenged. We tested the effects of fructose, sorbose and tagatose both in vitro and in vivo. Both ethanol and each sugar were either added to isolated hepatocytes or injected intraperitoneally in the rat. In the in vitro experiments, samples were taken from the hepatocyte suspension in a time-dependent manner and deproteinized with perchloric acid. In the in vivo experiments, blood samples were taken every 15 min and the metabolites were determined in the plasma. These metabolites include ethanol, glucose, glycerol, sorbitol, lactate, fructose and sorbose. Ethanol oxidation by rat hepatocytes was increased by more than 50% with the addition of fructose. The stimulation was accompanied by increased glucose, glycerol, lactate and sorbitol production. A similar effect was observed with sorbose, while tagatose had no effect. The same pattern was observed in the in vivo experiments. This effect was abolished by inhibiting alcohol dehydrogenase with 4-methylpyrazole, whereas inhibition of the respiratory chain with cyanide did not affect the fructose effect. In conclusion, present results provide evidence that, by reducing glyceraldehyde and glycerol and fructose to sorbitol, respectively, NADH is consumed, allowing an increase in the elimination of ethanol. Hence, this effect is not linked to a stimulation of mitochondrial re-oxidation of NADH driven by ATP consumption.

385 Ethanol Metabolism in a Group of Experienced Users

Alcohol intoxication is a common reason for emergency department (ED) visits. Although it is known that the blood alcohol concentration does not correlate well with symptoms of intoxication, clinical and legal decisions are often made based upon this objective lab value. Knowledge of the rate of ethanol (EtOH) metabolism is therefore important to plan a patient’s ED course, and may have a legal role after discharge. Prior studies in ED patients demonstrated an EtOH elimination rate of about 20 mg/dL/hr, slightly higher than studies in healthy, nonalcoholic volunteers. This may be due to the disproportionately high number of chronic EtOH users among ED patients. It has been speculated that there is a difference in the rate of metabolism between the episodic and chronic EtOH user, due upregulation of hepatic enzymes involved in alcohol metabolism. Prior studies of the rate of EtOH metabolism in chronic users have been limited by small sample sizes and conflicting results. Our objective was to describe the rate of EtOH metabolism in a group of chronic users presenting to the ED. We conducted a multi-site, retrospective chart review at 2 public hospitals in Los Angeles and Atlanta. Each site has more than 75,000 adult ED visits annually. Subjects were identified via review of the electronic health record (EHR), and were eligible for inclusion if they had an initial serum ethanol (sEtOH) > 300 mg/dL, a prior documented alcohol-related encounter, and a repeat sEtOH obtained during the visit. Subjects were excluded if the repeat sEtOH was drawn < 1 or > 24 hours after the first, if the repeat sETOH was < 50 mg/dL, or if there was evidence of EtOH consumption after arrival. If subjects had more than one visit meeting inclusion criteria, only data from the first visit was included in the overall calculation of EtOH metabolism. Demographics were recorded and t-tests were used to compare groups. 87 encounters meeting inclusion criteria were identified by screening of the EHR: 58 from Los Angeles and 29 from Atlanta. After manual chart review for the above criteria and to exclude subsequent visits by 4 subjects with more than 1 visit during the study period, the final data set contained 62 subjects: 41 from Los Angeles and 21 from Atlanta. The mean age was 43.6 years; 76% of subjects were male. The mean rate of EtOH clearance was 23.3 ± 6.1 mg/dL/hr. There was a significant difference in this rate (p=0.02) between the study sites. No significant difference was found based upon sex (p=0.86). Subjects with 2 presentations did not all have consistent metabolic rates between presentations. This study supports the notion that chronic alcohol users metabolize EtOH slightly faster than occasional users, though with a wide variance. We did not expect to find a difference between study sites, but hypothesize that this may be related to genetic differences in each site’s patient population. Further study is needed to evaluate this hypothesis.Table 1Individual study site dataSiteSubjectsMaleFemaleMetabolic rate (mean ± SD)Los Angeles4134724.5 ± 6.2Atlanta2113820.7 ± 5.3Total62471523.3 ± 6.1Metabolic rates are in mg/dL/hr Open table in a new tab

Alcohol metabolism in hangover sensitive versus hangover resistant social drinkers

BackgroundPrevious research demonstrated that urinary ethanol concentrations were significantly lower in hangover resistant individuals compared to drinkers who reported having a hangover. This finding suggests that the rate of ethanol metabolism is faster in drinkers who do not experience an alcohol hangover. This study aimed to directly compare alcohol metabolism after administering a low dose of ethanol to hangover sensitive drinkers and hangover resistant drinkers. MethodsSocial drinkers who previously participated in hangover trials at Utrecht University were invited to participate. It was aimed to include 12 hangover resistant drinkers and 12 hangover sensitive drinkers. Participants consumed alcohol to reach a breath alcohol concentration (BrAC) of 0.05%. Every 5 min BrAC was determined, until BrAC reached zero. Every 15 min, the Karolinska Sleeping Scale (KSS) was administered to assess subjective sleepiness, and subjective intoxication was measured. ResultsData of N = 23 participants with a mean age of 22.4 (±1.9) years was included in the analyses. No significant difference in BrAC over time was found between the hangover resistant group and the hangover sensitive group. In line, subjective sleepiness scores and subjective intoxication ratings did not significantly differ between the groups at any point in time after alcohol consumption. ConclusionHangover resistant individuals and hangover sensitive drinkers did not significantly differ on BrAC, subjective sleepiness, and subjective intoxication after consuming a moderate amount of alcohol. These findings suggest that drinkers who usually experience hangovers after a heavy drinking occasion do not experience alcohol intoxication differently than hangover resistant drinkers.

The galanin-3 receptor antagonist, SNAP 37889, suppresses alcohol drinking and morphine self-administration in mice

The neuropeptide, galanin, is widely expressed in the central and peripheral nervous systems and is involved in a range of different functions including nociception, neurogenesis, hormone release, reproduction, cognitive function and appetite. Given the overlap between galanin expression and reward circuitry in the brain, galanin has been targeted for alcohol use disorder (AUD) and opioid dependency. Furthermore, the galanin-3 receptor (GAL3) specifically regulates emotional states and plays a role in motivation, reward and drug-seeking behaviour. We have previously shown that the GAL3 antagonist, SNAP 37889, reduces ethanol self-administration and cue-induced re-instatement in alcohol-preferring (iP) rats with no alterations in locomotor activity or anxiety-like behaviour. The aim of this study was to investigate whether SNAP 37889 reduces binge drinking and/or self-administration of morphine in mice. Using the Scheduled High Alcohol Consumption (SHAC) procedure, SNAP 37889 (30 mg/kg) treated mice drank significantly less ethanol, sucrose and saccharin than vehicle treated mice. Using an operant paradigm, SNAP 37889 reduced morphine self-administration but failed to impact cue-induced relapse-like behaviour. SNAP 37889 had no significant effect on locomotor activity, motor co-ordination, anxiety, nor was SNAP 37889 itself positively reinforcing. Liver assays showed that there was no alteration in the rate of hepatic ethanol metabolism between SNAP 37889 and vehicle treated mice suggesting that the reduction in ethanol intake via SNAP 37889 is due to a central effect of GAL3 signalling. This study implicates the GAL3 receptor in consummatory drive which may have wider implications for the treatment of different addictions.

Ethanol elimination rates at low concentrations based on two consecutive blood samples

IntroductionFor ethanol, the elimination curve change from apparent zero to apparent first order kinetics at low blood alcohol concentrations (BACs). This is less studied than elimination at higher BACs, and knowledge about this low BAC elimination is especially missing in drunk drivers representing a population with a high frequency of heavy drinkers with increased rate of ethanol metabolism. The aim of this study was to investigate the point at which elimination rates turns from zero to first order kinetics and the exact elimination rates at the very low BAC intervals in drunk drivers. MethodsTwo consecutively collected samples from suspected drunk drivers were used. All samples were analyzed by two headspace gas chromatography flame ionization detector methods (limit of quantification=0.04g/kg). The elimination rates at BACs below 0.25g/kg (study group, n=175) was studied in detail, and compared to the elimination rates in a moderate BAC reference group (n=789) as well as a high BAC reference group (n=4435). ResultsThere were no differences in age, gender and drivings occurring during night-time between the study group and the reference groups. The mean elimination rates were stable at 0.18–0.19g/kg/h from a BAC of 4.0g/kg and until BAC in the first blood sample fell below 0.19g/kg. At BACs below 0.19g/kg, the mean elimination rate gradually declined from 0.163g/kg/h to the lowest elimination rate of 0.083g/kg/h. There was no relation between the concentration of ethanol and elimination rate at BACs above 0.19g/kg (Pearson's r=0.035, p=0.3), but there was a strong relation between concentration of ethanol and elimination rate at BACs below 0.19g/kg (Pearson's r=0.56, p<0.001). ConclusionIn conclusion, the present study showed that in a population of drunk drivers, the shift from zero order to first order kinetics occurs when BAC falls below 0.19g/kg. Below this points, the present study indicate that drunk drivers show elimination rates comparable to the normal population. These results could assist in back-calculations in cases of drunk driving involving low BACs.

Impact of Trauma, Massive Blood Loss and Administration of Resuscitation Fluids on a Person's Blood-Alcohol Concentration and Rate of Ethanol Metabolism.

Excessive drinking and drunkenness are tightly linked to many types of intentional and unintentional injuries involving trauma and blood loss, which often necessitate emergency medical intervention. This article considers the impact of trauma, massive blood loss, and the administration of life-saving replacement fluids on a person's blood alcohol concentration (BAC) and rate of ethanol metabolism. Both German and English language journals were reviewed and results from animal experiments, human studies, and actual victims of trauma undergoing life-saving treatment were considered. If trauma-related bleeding occurs when some ingested alcohol remains unabsorbed in the stomach, then under these circumstances continued absorption into portal venous blood is delayed, owing to altered splanchnic circulation. Hemodilution caused by administration of replacement fluids has only minimal effects on a preexisting BAC, because ethanol distributes into the total body water (TBW) compartment, which represents 50-60% of body weight. After hypovolemia there is a transfer of fluids from tissue compartments into the blood, which becomes more like plasma in composition with lower hematocrit and hemoglobin content. Unless the trauma or emergency treatment impedes hepatic blood flow, the rate of ethanol metabolism is not expected to differ from normal values, namely 0.10-0.25 g/L/h (0.01-0.025 g% per h). If ethanol is fully absorbed and distributed in all body fluids and tissues, neither massive blood loss nor administration of resuscitating fluids is expected to have any significant effect on a preexisting BAC or the rate of ethanol metabolism.

Combination of genetic and humanitarian (cross-cultural) methods for the identification of human genes involved in the process of adaptation to evolutionary new environmental factors

Human settlement from the African ancestral home was accompanied by cultural and genetic adaptation to new habitat conditions (climate, infections, diet, etc.). We previously suggested for the first time an approach to the identification of human genes presumably involved in adaptation to evolutionary new environmental factors based on a combination of genetic and humanitarian methods of study. In order to search for the genes involved in adaptation and for environmental factors (to which this adaptation occurs), we attempted to find correlations between the population allele frequencies of the studied gene and formalized descriptions of peculiarities of the habitat of ethnic groups given in "Ethnographic Atlas" by G. P. Murdock. In the presented review, we summarized our own data on an experimental determination of the allele frequencies for lactase (LCT*), apolipoprotein E (APOE), and alcohol dehydrogenase (ADH1B) genes in populations of Russia. Based on these data and available materials of other investigators, we developed maps of worldwide allele frequency distribution for these genes. We detected a correlation of allele frequencies of these genes in populations with the presence of certain factors of the environment that these populations inhabit. It was also confirmed that the evolutionarily young LCT*-13910T allele, which determines lactase persistence and the possibility of milk consumption in adults, is distributed in populations for which dairy animal husbandry is typical. During the analysis of 68 populations, we for the first time demonstrated that the frequency of the APOE e4 allele (which is ancestral for humans and influences the lipid metabolism) is higher in groups with a high contribution of hunting and gathering. Our data are in favor of the hypothesis that it was exactly the e4 allele that was a subject for selection, while the e3 allele was less important for adaptation. We also for the first time demonstrated that the evolutionarily young ADH1B*48His allele (which determines a high rate of ethanol metabolism into acetaldehyde) is presented with a large frequency in those populations where filariasis is endemic. The obtained data indicate the possible involvement of endogenous ADH1B gene substrates or their metabolites in the resistance to filaria and open a new path to the development of drugs for this widespread human disease.

352 Effect of High-Carbohydrate Meals on the Rate of Ethanol Metabolism

352 Effect of High-Carbohydrate Meals on the Rate of Ethanol Metabolism

Drosophila highwire gene modulates acute ethanol sensitivity in the nervous system

Animals exhibit behavioral differences in their sensitivity to ethanol, a trait that is at least in part due to genetic predispositions. This study has implicated a large neuronal protein involving Highwire, a Drosophila E3 ubiquitin ligase (Hiw, a homolog of Pam, a protein associated with Myc found in humans) in acute sensitivity to ethanol sedation. Flies lacking Hiw were hypersensitive to the sedating effect of ethanol whereas those overexpressing Hiw showed decreased sensitivity to ethanol. Furthermore, RNAi functional knockdown of Hiw in adult neurons or ellipsoid body neurons showed increased sensitivity to ethanol sedation. None of these manipulations of the hiw gene caused changes in the rate of ethanol absorption and/or metabolism. These results suggest a previously unknown role for this highly conserved gene in regulating the behavioral responses to an addictive drug.

Metabotropic glutamate 5 receptors regulate sensitivity to ethanol in mice

The metabotropic glutamate receptor 5 (mGlu5) has been implicated in ethanol- and drug-seeking behaviours in rodent studies. Here we examine a number of ethanol-related behavioural assays in mice lacking mGlu5 and wild-type littermates. In a two-bottle free-choice paradigm, mGlu5-deficient mice consumed less ethanol with a reduced preference compared to wild-type mice. Indeed, mGlu5-deficienct mice were ethanol-avoiding at both concentrations of ethanol proffered (5% and 10% v/v). However, there was no difference in the rate of hepatic ethanol and acetaldehyde metabolism between genotypes and consumption of saccharin was similar. In a conditioned place preference study, mGlu5-deficient mice displayed a place preference for ethanol when conditioned with a low dose (1g/kg) of ethanol. Thus, while mGlu5-deficient mice consume less ethanol (with a reduced preference) than wild-type mice, this is not apparently related to impaired hepatic metabolism or a lack of reward from ethanol. Rather, we provide evidence that deletion of the mGlu5 receptor increases sensitivity to centrally mediated effects of ethanol.

Rates of ethanol metabolism decrease in sons of alcoholics following a priming dose of ethanol

Rapid changes in rates of ethanol metabolism in response to acute ethanol administration have been observed in animals and humans. To examine whether this phenomenon might vary by risk for alcoholism, 23 young men with a positive family history of alcoholism (family history positive [FHP]) were compared to 15 young men without a family history of alcoholism (family history negative [FHN]). Rates of ethanol metabolism were measured in all subjects first after an initial ethanol dose (0.85 g/kg) and then, several hours later, a second dose (0.3 g/kg), and the two rates were compared. The two groups of subjects were similar in their histories of ethanol consumption. FHP subjects demonstrated faster initial rates of ethanol metabolism, 148 ± 36 mg/kg/h, compared to FHN subjects, 124 ± 18 mg/kg/h, P = .01. However, FHN subjects increased their rate of metabolism by 10 ± 27% compared to a decrease of −15 ± 24% in FHP subjects, P = .007. Fifty-two percent of the FHP and none of the FHN subjects exhibited a decline in metabolic rate of 20% or more, P = .0008. Since a significant proportion of FHP subjects exhibited a decrease in the second rate of ethanol metabolism, these preliminary data might help to partly explain why FHP individuals differ in their sensitivity to ethanol and are more likely to develop alcohol dependence.

Zinc Supplementation Prevents Alcoholic Liver Injury in Mice through Attenuation of Oxidative Stress

Alcoholic liver disease is associated with zinc decrease in the liver. Therefore, we examined whether dietary zinc supplementation could provide protection from alcoholic liver injury. Metallothionein-knockout and wild-type 129/Sv mice were pair-fed an ethanol-containing liquid diet for 12 weeks, and the effects of zinc supplementation on ethanol-induced liver injury were analyzed. Zinc supplementation attenuated ethanol-induced hepatic zinc depletion and liver injury as measured by histopathological and ultrastructural changes, serum alanine transferase activity, and hepatic tumor necrosis factor-alpha in both metallothionein-knockout and wild-type mice, indicating a metallothionein-independent zinc protection. Zinc supplementation inhibited accumulation of reactive oxygen species, as indicated by dihydroethidium fluorescence, and the consequent oxidative damage, as assessed by immunohistochemical detection of 4-hydroxynonenal and nitrotyrosine and quantitative analysis of malondialdehyde and protein carbonyl in the liver. Zinc supplementation suppressed ethanol-elevated cytochrome P450 2E1 activity but increased the activity of alcohol dehydrogenase in the liver, without affecting the rate of blood ethanol elimination. Zinc supplementation also prevented ethanol-induced decreases in glutathione concentration and glutathione peroxidase activity and increased glutathione reductase activity in the liver. In conclusion, zinc supplementation prevents alcoholic liver injury in an metallothionein-independent manner by inhibiting the generation of reactive oxygen species (P450 2E1) and enhancing the activity of antioxidant pathways.

Ethanol consumption in mice with a targeted disruption of the dopamine-3 receptor gene.

Considerable evidence suggests that the mesolimbic dopaminergic system is an important substrate for the rewarding effects of ethanol consumption. Previous data have demonstrated that pharmacological agents that alter dopamine signaling also influence the self-administration of ethanol. The present experiments were designed to assess the role of the dopamine-3 receptor (D3-R) on voluntary ethanol consumption in C57BL/6 mice. Mice with targeted disruption of the D3-R gene (D3-R - /-) were compared to wild-type controls in an ethanol intake paradigm. In Experiment 1, mice had 24-hour access to ethanol each day in a two-bottle choice paradigm for a period of 7 days per concentration. The concentrations tested were 3, 6, 10 and 15%. In Experiment 2, mice had I hour of access to ethanol each day in a two-bottle paradigm for a period of 7 days per concentration. The same concentrations in Experiment I were compared in Experiment 2. In Experiment 3 we sought to test the development of a conditioned taste aversion (CTA) after receiving an intraperitoneal (ip.) injection of 2.0 g/kg ethanol. In Experiment 4, blood ethanol levels where assessed following a 2.0 g/kg ip.injection of ethanol. Experiment 5 assessed taste preference for saccharine and quinine in wild-type and D3-R -/- mice. Contrary to our predictions, both D3-R -/- and wild-types on a CS57BL/6 background had similar intakes of ethanol, at all concentrations tested, in the 24-hour and 1-hour intake paradigms. Wild-type and D3-R -/- mice respond to injected ethanol similarly by developing a conditioned taste aversion. Metabolic analysis revealed mutant mice are slower in metabolizing a bolus injection of ethanol. Lastly, wild-type and D3-R -/- mice showed similar consumption to increasing concentration of both sweet and bitter tastes. These data suggest that deletion of the D3-R gene does not increase ethanol consumption above that found on the C57BL/6 genetic background. Furthermore, the D3-R -/- mice adequately learn a CTA to ethanol and do not ham differing taste reactivity to saccharin or quinine. However, D3-R -/- mice do appear to have a slower rate of ethanol metabolism.

Role of naringin supplement in regulation of lipid and ethanol metabolism in rats

The current study was performed to investigate the effect of naringin supplements on the alcohol, lipid, and antioxidant metabolism in ethanol-treated rats. Male Sprague-Dawley rats were randomly divided into six groups (n = 10) based on six dietary categories: ethanol and naringin-free, ethanol (50 g/L) plus low-naringin (0.05 g/L), ethanol plus high-naringin (0.125 g/L), and three corresponding pair-fed groups. The pair-fed control rats received an isocaloric diet containing dextrin-maltose instead of ethanol for 5 wks. Among the ethanol treated groups, the naringin supplements significantly lowered the plasma ethanol concentration with a simultaneous increase in the ADH and/or ALDH activities. However, among the ethanol-treated groups, naringin supplementation resulted in a significant decrease in the hepatic triglycerides and plasma and hepatic total cholesterol compared to that in the naringin-free group. Naringin supplementation significantly increased the HDL-cholesterol and HDL-C/total-C ratio, while lowering the AI value among the ethanol-treated groups. Hepatic lipid accumulation was also significantly reduced in the naringin-supplemented groups compared to the naringin-free group among the ethanol-treated groups, while no differences were found among the pair-fed groups. Among the ethanol-treated groups, the low-naringin supplementation resulted in a significant decrease in the levels of plasma and hepatic TBARS, whereas it resulted in higher SOD and GSH-Px activities and gluthathion levels in the liver. Accordingly, naringin would appear to contribute to alleviating the adverse effect of ethanol ingestion by enhancing the ethanol and lipid metabolism as well as the hepatic antioxidant defense system.

Soymilk Products Affect Ethanol Absorption and Metabolism in Rats during Acute and Chronic Ethanol Intake

In this study we evaluated the effects of soy products on ethanol metabolism during periods of acute and chronic consumption in rats. Gastric ethanol content and blood ethanol and acetaldehyde concentrations were investigated after the oral administration of ethanol (34 mmol/kg) plus soy products such as soymilk (SM) or fermented soymilk (FSM). The gastric ethanol concentration of the FSM group was greater than that of the control group, whereas portal and aortal blood ethanol concentrations of the FSM group were lower than in controls. The aortal acetaldehyde concentration in the FSM group was lower than that of the control group. The direct effect of isoflavones on liver function was investigated by using hepatocytes isolated from untreated rats. Genistein (5 micromol/L) decreased ethanol (P = 0.045) and tended to decrease acetaldehyde (P = 0.10) concentrations in the culture filtrate. Some variables of ethanol metabolism in the liver were investigated after chronic ethanol exposure for 25 d. Rats consumed a 5% ethanol fluid plus the SM diet, the FSM diet or a control diet. Microsomal ethanol oxidizing activity was significantly lower in the FSM group than the control group. Furthermore, cytosolic glutathione S-transferase activity was higher in the SM and FSM groups than in the control group. Acetaldehyde dehydrogenase activity (low K(m)) in the FSM group (P = 0.15), but not in the SM group (P = 0.31), tended to be greater than in the control group. The amount of thiobarbituric acid reacting substances in the liver of the SM and FSM groups tended to be less than that of the control group (P = 0.18 and 0.10, respectively). These results demonstrate that soymilk products inhibit ethanol absorption and enhance ethanol metabolism in rats.

Ethanol metabolism in patients with liver cirrhosis

Aspects of human metabolism of ethanol are reviewed with the main focus on the rate of ethanol clearance from blood in patients suffering from liver cirrhosis. Studies in humans and experimental animals do not support the notion of a slower rate of ethanol metabolism in patients with liver cirrhosis compared with those with normal liver function. The rate of ethanol disappearance from blood in healthy non-alcoholic subjects falls within the range 9-20 mg/dL/h and there is no compelling evidence to suggest that this should be much different in cirrhotic patients.

Ontogeny of ethanol elimination and ethanol-induced hypothermia

Ontogeny of ethanol elimination rates and ethanol-induced hypothermia were examined as possible mechanisms contributing to the marked reduction in ethanol sensitivity early in life (Little et al., 1996; Silveri & Spear, 1998) and the notable gender difference in ethanol sleep-time seen in adult animals (Silveri & Spear, 1998). Elimination rates and brain/blood ethanol levels were determined following doses of 1.5 or 4.5 g/kg ethanol in male and female Sprague–Dawley rats at postnatal days (P)16, 26, 36, or 56. Animals were sacrificed at 40, 80, or 160 min post-injection, with ethanol elimination rates estimated from the slope of the regression of blood and brain alcohol levels across the three sampling periods. P16 animals exhibited the slowest rate of ethanol metabolism, while no gender effects were evident at any age. Observed ontogenetic increases in ethanol hypothermia were not systematically related to the ontogeny of ethanol metabolism. Factors other than ontogenetic changes in ethanol metabolism, hypothermia, or the distribution of ethanol between brain and blood must underlie the relative insensitivity to ethanol often reported in young and adolescent organisms, a fruitful area for future studies given the frequent use and misuse of alcohol by human adolescents.

Dietary carbohydrate intake plays an important role in preventing alcoholic fatty liver in the rat

Background/Aims: Dietary carbohydrate intake during ethanol ingestion augments the induction of hepatic cytochrome P450 2E1 (CYP2E1) by ethanol. This study addresses the role of carbohydrate intake in the development of alcoholic fatty liver in the rat. Methods: Male Sprague-Dawley rats were pair-fed on liquid diets containing ethanol (3.5 g/day, 36% of total calories) with different amounts of carbohydrate and fat for 4 weeks, and the development of fatty liver was observed biochemically and morphologically. Results: An ethanol-containing low-carbohydrate diet (protein 17%; fat 36%; carbohydrate 11%; ethanol 36%) had more markedly adverse effects on the liver of rats than did an isocaloric ethanol-containing high-carbohydrate diet (protein 17%; fat 5%; carbohydrate 42%; ethanol 36%). The hepatic triglyceride level in the rats that consumed the low-carbohydrate diet was higher than that in the rats kept on the high-carbohydrate diet, a finding that was confirmed histologically. The ethanol-containing low-carbohydrate diet caused a marked increase in the activity of hepatic CYP2E1. The CYP2E1 protein level, as measured by Western blot analysis, matched the activity of CYP2E1, as measured by the rates of dimethylnitrosamine, p-nitrophenol and ethanol metabolism. The severity of the fatty liver was well correlated with the increased CYP2E1 activity. Conclusions: Dietary carbohydrate intake plays an important role in the development of alcoholic fatty liver by affecting CYP2E1 activity in the liver. A liquid diet containing ethanol in which the ethanol is included at the expense of fat is more acceptable to rats than a diet in which the ethanol replaces carbohydrate.

Effect of L-Carnitine on Activity of Liver Alcohol Dehydrogenase in Diabetic Rats

Supplementary L-carnitine attenuates ethanol metabolism in rats and thus offers protection to animals against ethanol-induced lipid abnormalities by decreasing the load of ethanol-derived metabolites on the liver. Experimental diabetes increases ethanol metabolism in rats by affecting the activity of liver alcohol dehydrogenase (ADH). L-carnitine has been used for treatment of diabetic neuropathy in humans. We have therefore evaluated the effect of L-carnitine on the activity of liver ADH in Wistar diabetic male rats. Two groups (n=5) of rats were rendered diabetic with alloxan (75 mg/kg) and L-carnitine (200 mg/kg day, i.p.) was given to diabetic rats starting fom the 3rd week after the induction of diabetes and lasting for 4 weeks. A third groups of rats (n=5) which was not diabetic and not supplemented with L-carnitine served as controls. The activity of ADH was determined by an enzymatic method. Liver ADH activity in diabetic rats (25±1.9 U/g protein) was significantly higher (p

Role of catalase in rat gastric mucosal ethanol metabolism in vitro.

To evaluate the possible role of catalase in gastric ethanol metabolism in rats, we studied acetaldehyde formation from ethanol by gastric mucosal homogenate under various in vitro conditions. Homogenized rat gastric mucosa produced significant amounts of acetaldehyde in a time and ethanol concentration-dependent manner, even in the absence of added NAD. Both acetaldehyde formation and catalase activity peaked around the physiological pH, whereas alcohol dehydrogenase (ADH) activity was in that pH range low and reached peak values only at a higher pH of 9 to 10. Catalase inhibitors sodium azide (SA) and 3-amino-1,2,4-triazole (3-AT) had little effect on ADH activity but markedly decreased catalase activity and acetaldehyde formation (1 mM of SA to 56 +/- 13% of control, 5 mM of 3-AT to 67 +/- 3% of control; mean +/- SE). 4-Methylpyrazole decreased ADH activity significantly, but did not affect acetaldehyde formation. Heating of the homogenate at 60 degrees C for 5 min decreased ADH activity only slightly, but totally abolished catalase activity and reduced acetaldehyde formation to 39 +/- 3% of control. Addition of a H2O2 generating system (beta-D(+)-glucose + glucose oxidase] increased acetaldehyde formation in a concentration-dependent manner up to 8-fold of the control value. Our results strongly suggest that, in addition to ADH, catalase may play a significant role in gastric ethanol metabolism in rats.