The effects of ethanol on blood toluene concentrations

The metabolism of toluene was found to be inhibited by a large dose of alcohol in seven volunteers exposed to 80 ppm of toluene under experimental conditions. When alcohol was taken during exposure, blood toluene concentrations were 42.5% greater on average than during exposure with no alcohol. This is probably due to competition for alcohol dehydrogenase which is required for the breakdown of both ethanol and toluene. In men exposed to toluene at work, it was found that blood toluene concentrations were lowest in those who drank regularly. These results suggest that continued alcohol intake increases the metabolism of toluene, presumably by inducing the microsomal oxidising enzyme system in the liver.     

Polymorphism of aldehyde dehydrogenase and ethanol elimination

The influence of polymorphism of aldehyde dehydrogenase (ALDH) on ethanol elimination was investigated. Japanese healthy male volunteers were divided into two groups, i.e., a normal ALDH group of 52 subjects with the low Km isozyme of ALDH, and a deficient group of 48 subjects without it. The subjects of the normal group were given 0.4, 0.8, 1.2, 1.6 or 2.0 g/kg of ethanol, while those in the deficient group ingested 0.4, 0.8 or 1.2 g/kg of ethanol. Widmark's factors (beta 60, Co and r) and ethanol elimination rate (ER) were compared between the two groups. In the deficient group, beta 60 and ER were not clearly elevated with the increase of ethanol dose, while those in the normal ALDH group increased depending on the blood ethanol level. Blood acetaldehyde level was elevated with the increase of the ethanol dose in the deficient group, but not in the normal group. In the experiment of the repeated ingestion of ethanol in the deficient group, the second peak of blood acetaldehyde level was lower than that of the first one.     

Acetaldehyde, a metabolite of ethanol, activates the hypothalamic-pituitary-adrenal axis in the rat

Cyanamide is a potent inhibitor of aldehyde dehydrogenase (ALDH: EC 1.2.1.3) used in the treatment of alcoholics. In the presence of ethanol, cyanamide causes an accumulation of acetaldehyde, a highly toxic metabolite of ethanol, with unpleasant side-effects. A similar accumulation is seen in some Oriental people with low ALDH activity. We have investigated the effects of ethanol and cyanamide administration on the activation of the hypothalamic-pituitary-adrenal (HPA) axis using in situ hybridization histochemistry and radioimmunoassay. Ethanol plus cyanamide resulted in a significant increase in corticotrophin-releasing factor and arginine vasopressin mRNA in the paraventricular nucleus, and pro-opiomelanocortin mRNA in the anterior pituitary. Plasma corticosterone concentrations were also significantly elevated following ethanol plus cyanamide administration. The blood concentration of acetaldehyde in the ethanol plus cyanamide group increased significantly. These results suggest that acetaldehyde, induced by blocking ethanol metabolism, is able to activate the HPA axis operating through a central mechanism.     

Taurine modulates catalase, aldehyde dehydrogenase, and ethanol elimination rates in rat brain

Chronic administration of either the sulphonated amino acid taurine (0.32 or 0.62 g/kg for 2 weeks) or the catalase inhibitor, 3-amino, 1,2,4-triazole (AT: 0.5 or 1.0 g/kg for 5 days) significantly reduced catalase activities both in the brain and liver of male Wistar rats. The total brain activity of aldehyde dehydrogenase was significantly increased after the lower dose of taurine and after administration of both doses of AT. Hepatic alcohol dehydrogenase activity was not altered by either AT or taurine administration. In taurine-supplemented rats, a significant increase in the ethanol elimination rates (EER) was discernible in the livers after a 2 g/kg dose of ethanol. In contrast, significant decreases in the EER were observed in both plasmas and livers of rats in which catalase was inhibited by AT. However, the brain EERs were comparable in both catalase-inhibited and taurine-supplemented rats, both showing a decrease by comparison to controls. The similar psychopharmacological effects induced by both of these compounds on ethanol-induced effects might indicate that this is mediated in part via the catalase pathway. Since both catalase and the EERs are diminished in the brain after the administration of either of these compounds, this may be an important factor in the moderation of ethanol-induced behaviour.     

Harman (1-methyl-beta-carboline) in blood plasma and erythrocytes of nonalcoholics following ethanol loading

Eleven subjects having no history of substance abuse or dependence who agreed to abstain from alcohol for one week prior to the investigation were selected to participate in the present study. On two occasions, separated by four to six weeks, blood was drawn over an 8-hour period (0, 0.5, 1, 2, 4 and 8 hours). On the first occasion, subjects were given an oral dose of ethanol (1 g/kg) after the first blood sample was drawn (ethanol-loading condition). On the second occasion no ethanol was administered (control condition). On both occasions no detectable harman was found in the plasma of subjects. In the control condition harman was detected in the erythrocytes of 7 subjects which remained relatively stable over time. In the ethanol-loading condition, however, a time-dependent increase of harman in the erythrocytes was observed. The concentration of ethanol, acetaldehyde, and erythrocyte-harman showed a parallel trend over time. These findings demonstrate an increased level of harman following ethanol loading in humans.     

Effects of chronic ethanol intoxication on aldehyde dehydrogenase in mouse liver.

Effects of chronic ethanol treatment with liquid diet (ethanol constituted 28% of the calories) on hepatic aldehyde dehydrogenase (ALDH) isozymes were studied in mice. One week of ethanol feeding caused 66% loss of mitochondrial low Km ALDH activity and 80% loss of mitochondrial high Km ALDH activity, compared with the control-fed group. However, these decreases recovered after 4 weeks of ethanol feeding. The cytosolic ALDH activity increased up to 140% after 10 weeks of ethanol feeding, compared with the control-fed group. Effects of acute ethanol injection on ALDH activity after prolonged ethanol feeding were studied. The severe acute ethanol injection (4.5 g/kg body wt) after 4 weeks of ethanol feeding caused a drastic decrease of the mitochondrial low Km ALDH activity; however, that did not affect the ethanol-fed group. After 10 weeks of ethanol feeding, acute ethanol injection (4.5 g/kg body wt) caused about twofold increase in mitochondrial low Km ALDH activity. From the agarose IEF study, it was found that ethanol intoxication does not affect the number and pI value of ALDH isozymes.     

Blood and brain ethanol concentrations during absorption and distribution in long-sleep and short-sleep mice

It is often assumed that blood ethanol content accurately reflects brain ethanol content. In previous studies we have found that at the time of regaining the righting response blood and brain ethanol levels were identical, and blood ethanol could be used to predict brain ethanol level. It is likely, however that shortly after the administration of ethanol, blood and brain ethanol levels would differ. For this study, venous blood (orbital sinus) and brain ethanol levels were measured in long-sleep and short-sleep mice within the first 30 min following ethanol administration (2.5-6.0 g/kg). Ethanol was administered intraperitoneally or intragastrically. For both lines of mice and for every dose, brain ethanol concentrations were significantly greater (as much as 100 mg/dl) than blood ethanol levels for the first 6 min, and peak blood and brain ethanol levels were reached 4 to 6 min after dosing. Approximately 6 to 10 minutes (depending on dose and line of mouse) was required for blood and brain concentrations to reach equilibrium. At the time of loss of the righting response, brain ethanol levels were significantly higher than blood ethanol levels. These results indicate that within the first 6 min after administration of ethanol, blood ethanol level is not suitable for the assessment of brain ethanol content.     

G cells and gastrin in chronic alcohol-treated rats.

Numerous reports have described gastric mucosal injury in rats treated with high ethanol concentrations. However, to the best of our knowledge, ultrastructural characteristics of G cells and antral gastrin levels have not been previously reported, either in rats that chronically consumed alcohol or in human alcoholics. The goal of this study was to examine the effect of ethanol consumption (8.5 g/kg) over a 4-month period, under controlled nutritional conditions, on antral and plasma levels of gastrin, ultrastructure of G cells, morphometric characteristics of G cells by stereological methods, and analysis of endocrine cells in the gastric mucosa by immunohistochemistry. The chronic alcohol consumption resulted in a nonsignificant decrease in gastrin plasma levels and unchanged antral gastrin concentrations. A slightly damaged glandular portion of the gastric mucosa and dilatation of small blood vessels detected by histological analysis, suggests that ethanol has a toxic effect on the mucosal surface. Chronic alcohol treatment significantly decreased the number of antral G cells per unit area, and increased their cellular, nuclear, and cytoplasmatic profile areas. In addition, the volume density and diameter of G-cell granules, predominantly the pale and lucent types, were increased, indicating inhibition of gastrin release. Ethanol treatment also decreased the number of gastric somatostatin-, serotonin-, and histamine-immunoreactive cells, except the somatostatin cells in the pyloric mucosa, as well as both G: D: enterochromaffin cells (EC) cell ratios in the antrum and D: ECL cell ratios in the fundus. These results indicate that the change of morphometric parameters in G cells may be related to cellular dysfunction. Our findings also suggest that regulation of G-cell secretion was not mediated by locally produced somatostatin in ethanol-consuming rats, but may involve gastric luminal content and/or neurotransmitters of gastric nerve fibers.     

Selenium blood concentrations in patients undergoing elective cardiac surgery and receiving perioperative sodium selenite

ObjectivesWe recently reported that cardiac surgical patients in our institution exhibited low selenium blood levels preoperatively, which were further aggravated during surgery and independently associated with the development of postoperative multiorgan failure. Low circulating selenium levels result in a decreased antioxidant capacity. Both can be treated effectively by sodium-selenite administration. Little is known about the kinetics of exogenously administered sodium-selenite during acute perioperative oxidative stress. The aim of this study was to assess the effects of perioperative high-dose sodium-selenite administration on selenium blood concentrations in cardiac surgical patients.MethodsOne hundred four cardiac surgical patients were enrolled in this prospective observational trial. Patients received an intravenous bolus of 2000 μg selenium after an induction of anesthesia and 1000 μg selenium every day further during their intensive care unit (ICU) stay. Selenium blood levels were measured at regular intervals.ResultsPreoperative sodium-selenite administration increased selenium blood concentrations to normal values on ICU admission, but failed to prevent a significant decrease of circulating selenium on the first postoperative day. During the further ICU stay, selenium blood levels were normalized by the administration strategy and did not exceed the German reference range. No acute selenium-specific side effects occurred. When matching the participating patients to a historical control group without sodium-selenite administration, the chosen strategy was associated with a decrease in SAPS II (23 ± 7 versus 29 ± 8, P = 0.005) and SOFA scores (4 ± 3 versus 7 ± 2, P = 0.007) on the first postoperative day, but was unable to improve the postoperative outcome in patients staying >1 d in ICU.ConclusionsDespite preemptive high-dose sodium-selenite administration, cardiac surgical patients experienced a significant decrease in circulating selenium levels on the first postoperative day.     

Relationship between blood, liver and brain pyridoxal phosphate and pyridoxamine phosphate concentrations in mice

Plasma pyridoxal 5'-phosphate (PLP) concentrations are considered to be the most reliable single indicator of vitamin B-6 nutritional status and are thought to reflect tissue PLP and pyridoxamine 5'-phosphate (PMP) levels. We investigated the relationship between dietary level of pyridoxine hydrochloride (PN-HCl) and concentrations of PLP in blood and PLP and PMP in liver and brain of mice. Female heterogeneous stock mice, 60 to 90 d old, were fed purified diets containing 0.5, 1.0, 2.0, 3.0, 5.0, or 7.0 mg PN-HCl/kg diet for 5 wk. PLP and PMP concentrations were determined by a spectrophotometric apotryptophanase assay. PLP content of plasma, erythrocytes, whole blood, liver and brain and PMP levels in liver and brain were highly correlated with dietary level of PN-HCl (r values ranged from 0.81 to 0.94, n per correlation = 32 to 43). By using the entire range of dietary levels of PN-HCl, both plasma and erythrocyte PLP were found to be significantly correlated with tissue PLP and PMP concentrations. For any one dietary level, however, correlations between plasma or erythrocyte PLP and tissue PLP and PMP concentrations were low and nonsignificant. These results suggest that plasma PLP levels may be suitable to determine vitamin B-6 status of populations, but not to reliably predict tissue concentrations of PLP or PMP in individuals.     

Combined effects of ethanol and garlic on hepatic ethanol metabolism in mice.

The combined effects of ethanol and components in fresh garlic on ethanol metabolism were investigated in the livers of mice. Male, 11-wk-old C3H/HeNCrj mice were intragastrically administered 2 g ethanol/kg body weight after being administered fresh garlic juice for 8 d (garlic group), and changes in the concentrations of ethanol, acetaldehyde and acetate in the serum, and changes in the activity of hepatic enzymes related to ethanol metabolism in mice were examined. The increases in the concentrations of acetaldehyde and acetate in the serum after ethanol administration tended to be diminished following garlic administration. The microsomal ethanol-oxidizing system (MEOS) in the livers of the garlic groups was significantly lower than that of the control microsomes at 2 h after ethanol administration. It therefore seems that the decrease of MEOS in hepatic microsomes caused a smaller increase in the acetaldehyde concentration in the serum of the garlic groups because cytosolic alcohol dehydrogenase showed no significant difference between the control and garlic groups. After ethanol administration, the content of cytochrome P-450 in the hepatic microsomes of the control groups increased, while that of the garlic groups did not change although cytochrome P-450 (CYP) 2E1 and 1A2 in the hepatic microsomes of the garlic groups increased. These results indicate that the induction of isozymes of cytochrome P-450 other than CYP 2E1 and 1A2 was inhibited following garlic administration. Cytosolic high Km and total aldehyde dehydrogenase (AIDH) in the liver of the garlic groups tended to be lower than those activities of the control groups at 1 and 2 h after ethanol administration. It therefore seems that the decreases of AIDH in the hepatic cytosols diminished the increase of acetate in the serum of the garlic groups after ethanol administration. These results suggest that the ethanol metabolism in the mouse liver is controlled by components in fresh garlic juice.     

Lack of differences in blood and tissue concentrations of endogenous ethanol in conventional and germfree rats

Headspace gas chromatography was used to determine the concentrations of endogenous ethanol in blood and tissue of conventional and germfree rats. In all biological specimens analysed, the four principal volatile endogenous substances were identified as methanol, acetaldehyde, ethanol and acetone. No statistically significant differences in the concentrations of endogenous ethanol were noted between conventional and germfree animals. In whole blood, liver, kidney, and brain of germfree rats the concentrations of endogenous ethanol were 4.2 +/- 0.19 microM, 5.1 +/- 0.55 microM, 8.2 +/- 0.59 microM and 4.4 +/- 0.17 microM (means +/- SE), respectively. The higher concentration in kidney was also observed in conventional rats. Our results suggest that ethanol is a normal metabolic intermediate in rats and does not exclusively arise from microbial fermentation reactions in the gastrointestinal tract.     

Age dependent development of ethanol drinking in rats after inhibition of aldehyde dehydrogenase.

The purpose of this experiment was to determine the temporal characteristics associated with the age-related development of volitional consumption of ethanol induced by the pharmacological inhibition of aldehyde dehydrogenase (AlDH). To induce preference for ethanol, the AlDH inhibitor, cyanamide, was administered to male Sprague-Dawley rats which were 30 days of age. Cyanamide (n = 8) was injected subcutaneously twice daily in a dose of 10 mg/kg over a period of 3 days while the control group (n = 6) received the saline vehicle solution according to the same schedule. Then at 50, 70, 90, and 110 days of age, both groups of rats were given a standard 11-day test of preference for water versus ethanol offered in concentrations ranging from 3% through 30%. The results showed that at 70 days of age the preference for ethanol increased above the level of the 50-day test in terms of absolute g/kg intakes and proportion of ethanol to water consumed over the lower range of 3% through 15% concentrations. During the tests at 90 and 110 days of age, the cyanamide-treated rats further increased their preference for ethanol significantly over the levels at the 70-day test in terms of both g/kg and proportional intakes. The pattern of drinking of ethanol offered in the higher concentrations of 25% and 30% was unrelated to the age of the rats and the overall intakes were significantly higher than those of the lower concentrations. These findings demonstrate that the enzymatic inhibition of AlDH systematically acts in a delayed fashion to shift the pattern of preference for ethanol which is contingent on the maturation of the animal. In this instance, the volitional intake of ethanol in the cyanamide-treated rats reached its maximal level by 90-110 days of age. It is proposed that an endocrine mechanism involved in gonadal maturation may function in the intense shift in alcohol drinking.     

Cotinine concentrations in semen, urine, and blood of smokers and nonsmokers.

Cotinine levels in the semen, urine, and blood of 88 male smokers and nonsmokers, aged 18 to 35, were analyzed via radioimmunoassay. Detectable cotinine levels were found in all three body fluids, and cotinine levels in all three fluids were highly correlated. Cotinine levels in semen and blood were of similar magnitude; cotinine levels in urine were an order of magnitude or more higher. In all three fluids, cotinine levels increased with an increase in cigarette smoke exposure.     

Interaction among niacin, vitamin B6 and zinc in rats receiving ethanol

The interaction of niacin, vitamin B6 and zinc was studied in Wistar rats. Seventy animals were submitted to a four-week depletion period during which they were fed a corn grits diet with no niacin, vitamin B6 or zinc added. These animals also received a 32% ethanol solution. Thirty additional rats were used as controls. After the period of depletion, the deficient animals were divided into five subgroups of 10 animals each. Each group received either the deficient diet, the deficient diet plus niacin, the deficient diet plus vitamin B6, the deficient diet plus zinc, or the control diet for the following two weeks. Five rats from each group were killed weekly after 24-hour urine collection. N'methylnicotinamide (N'MN), N'methyl-2-pyridone-5-carboxamide (2 PYR) and 4-pyridoxic acid (4 PYR) were measured in urine by HPLC. Niacin repletion increased the excretion of niacin metabolites, N'MN and 2 PYR (p less than 0.01), in relation to deficient animals. Niacin and vitamin B6 metabolites increased with vitamin B6 repletion (p less than 0.01). Repletion with zinc alone was followed by an increase in urinary excretion of N'MN (p less than 0.05), 2 PYR (p less than 0.01) and 4 PYR (p less than 0.01). When the deficient rats were fed the control diet containing the three nutrients, all three metabolites increased (p less than 0.01). The main conclusion is that zinc repletion per se caused activation of niacin metabolism, increasing the excretion of niacin metabolites. This emphasizes the role of zinc in the function of these vitamins.     

The effect of acute prolonged starvation on the concentrations of vitamin B6 aldehyde derivatives in whole blood

Since plasma pyridoxal-x-5'o-phosphate (PLP) levels are used to assess vitamin B6 status low levels are frequently interpreted to indicate B6 deficiency. However plasma PLP is in a dynamic equilibrium with pyridoxal (PL) through the action of non specific alkaline phosphatases (ALP). The object of this study was to monitor possible disturbances of this equilibrium in whole blood during acute prolonged fasting (40 hrs) and the subsequent repletion period in 16 healthy male dogs. Mean plasma PLP decreased by 15 percent (p less than 0.025) and PL increased by 20 percent (p less than 0.05) at the end of the starvation period and returned to baseline values after 48 hrs of refeeding. However total plasma aldehyde (PLP and PL) B6 vitamer concentrations remained unchanged throughout the investigation period. A 35 percent increase in haemolysate PL was the only significant change (p less than 0.0005) in PLP and PL levels observed in erythrocytes during fasting. It is concluded that the use of plasma PLP alone to assess vitamin B6 status may be misleading in conditions with a disturbed plasma PLP/PL equilibrium.     

Anxiety in mice following acute aspartame and ethanol exposure.

The purpose of the present study was to look at the effect of aspartame on the anxiolytic actions of ethanol. Previous research has shown that ethanol reliably produces an anxiolytic effect on rodent's plus-maze performance. There have been anecdotal reports that aspartame increases anxiety. CD-1 male mice were given i.p. aspartame doses of vehicle, 1000, or 2000 mg/kg, followed 30 min later by i.p. ethanol doses of 1.6 g/kg or vehicle. Animals were then placed in an open field, then tested in the plus-maze. Results determined that the aspartame condition had no significant effect on anxiety-related behavior, nor did it alter the anxiolytic actions of ethanol. Thus, acute high dose exposure to aspartame does not appear to affect anxiety-related behaviors.