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Biomedical subjects

E Baraona

Publications and source records attributed to E Baraona.

At least 19 recordsLinked to original sources
PubMed2001

Sex difference in alcohol-related organ injury.

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were Nobuhiro Sato and Kai O. Lindros. The presentations were (1) Sex differences in ethanol pharmacokinetics, by E. Baraona; (2) Estrogen regulates the sensitivity to endotoxin in hepatic Kupffer cells, by K. Ikejima; (3) Sex difference in alcohol-related organ injury, by E. Mezey; (4) Aggravated ethanol-induced liver injury in female rats: Protection by the antiestrogen toremifene, by Harri A. Järveläinen; and (5) Alcohol metabolism in Asian subjects: Sex differences and flushing response, by V. A. Ramchandani.

Alcohol Dehydrogenase↗
PubMed2001

Gender differences in pharmacokinetics of alcohol.

BACKGROUND: The enhanced vulnerability of women to develop alcohol-related diseases may be due to their higher blood alcohol levels after drinking, but the mechanism for this effect is debated. METHODS: Sixty-five healthy volunteers of both genders drank 0.3 g of ethanol/kg of body weight (as 5%, 10%, or 40% solutions) postprandially. Blood alcohol concentrations were monitored by breath analysis and compared with those after intravenous infusion of the same dose. First-pass metabolism was quantified (using Michaelis-Menten kinetics) as the route-dependent difference in the amount of ethanol reaching the systemic blood. Gastric emptying was assessed by nuclear scanning after intake of 300 microCurie of technetium-labeled diethylene triamine pentacetic acid in 10% ethanol. The activities of alcohol dehydrogenase isozymes were assessed in 58 gastric biopsies, using preferred substrates for gamma-ADH (acetaldehyde) and for final sigma-ADH (m-nitrobenzaldehyde) and a specific reaction of chi-ADH (glutathione-dependent formaldehyde dehydrogenase). RESULTS: Women had less first-pass metabolism than men when given 10% or 40%, but not 5%, alcohol. This was associated with lower gastric chi-ADH activity; its low affinity for ethanol could explain the greater gender difference in first-pass metabolism with high rather than with low concentrations of imbibed alcohol. Alcohol gastric emptying was 42% slower and hepatic oxidation was 10% higher in women. A 7.3% smaller volume of alcohol distribution contributed to the higher ethanol levels in women, but it did not account for the route-dependent effects. CONCLUSIONS: The gender difference in alcohol levels is due mainly to a smaller gastric metabolism in females (because of a significantly lesser activity of chi-ADH), rather than to differences in gastric emptying or in hepatic oxidation of ethanol. The concentration-dependency of these effects may explain earlier discrepancies. The combined pharmacokinetic differences may increase the vulnerability of women to the effects of ethanol.

Adult↗
PubMed2000

Dilinoleoylphosphatidylcholine protects human low density lipoproteins against oxidation.

LDL oxidation may promote atherosclerosis. We found that polyenyphosphatidylcholine (PPC), a mixture of polyunsaturated phospholipids extracted from soybeans, has antioxidant effects in in vivo models of oxidative stress. To assess whether components of PPC affect the in vitro oxidizability of LDL, plasma from 15 healthy volunteers was incubated with 10 microM of either dilinoleoyl-, palmitoyl-linoleoyl-, linoleoyl-palmitoyl- or distearoyl-phosphatidylcholine as well as 10 microM and 1 mM alpha-tocopherol. LDL oxidation was initiated with 5 microM Cu(2+) sulfate and monitored by conjugated diene production, or with 2, 2'-azobis (2-amidinopropane) dihydrochloride, a free radical generator, and monitored by O(2) consumption. After addition of Cu(2+), the lag phase (indicative of resistance of LDL to oxidation) was longer (140% of controls; P<0.001) for LDL incubated with dilinoleoyl-, but not with the other phosphatidylcholine species. This effect was similar to that of 1 mM alpha-tocopherol (135%). After addition of 2,2'-azobis (2-amidinopropane) dihydrochloride, the inhibition time (also reflecting the antioxidant content of LDL) was prolonged (P<0.001) for alpha-tocopherol (206%) and dilinoleoyl-(188%), but not for distearoyl-phosphatidyl-choline. Thus, dilinoleoyl-phosphatidylcholine (the main component of PPC) protects against LDL oxidation, a possible mechanism for its reported anti-atherosclerosis effects.

Adult↗
PubMed2000

Alcohol levels are increased in social drinkers receiving ranitidine.

OBJECTIVE: Ranitidine increases blood alcohol concentrations by decreasing the first pass metabolism of ethanol. The effect of ranitidine on alcohol levels has been found to be variable when using large doses of alcohol or conditions in which its first pass metabolism is known to be minimal. Despite a consensus that the drug increases alcohol levels after small doses of ethanol, this effect has been considered inconsequential, because of the low alcohol levels. However, social drinking comprises repetitive consumption of small doses of alcohol and the ranitidine effect could thereby be potentiated. METHODS: To study this factor, alcohol levels were determined by breath analysis in nine men (social drinkers), after four drinks of 0.15 g/kg ethanol given postprandially every 45 min, before and after ranitidine (150 mg b.i.d. for 7 days). RESULTS: Their blood alcohol increased with repeated doses, reaching peak values of 24+/-3 mg/dl before ranitidine and 33+/-2 after ranitidine (p = 0.04). In seven of the nine subjects blood alcohol exceeded 25 mg/dl, a level at which impairment of judgment and of finely tuned skills occurs and which exceeds legal limits of driving in some European countries. Moreover, the high levels persisted for a longer time with than without the drug. These effects were associated with a 62% decrease in first pass metabolism. CONCLUSION: Under conditions mimicking social drinking, ranitidine increases blood alcohol to levels known to impair psychomotor skills needed for driving.

Adult↗
PubMed2000

Contribution of gastric oxidation to ethanol first-pass metabolism in baboons.

BACKGROUND: A portion of ingested alcohol does not reach the systemic blood, undergoing a first-pass metabolism (FPM) during gastric and hepatic circulation. METHODS: To determine whether the stomach can metabolize sufficient ethanol to account for the FPM, and to what extent gastric alcohol dehydrogenase (ADH) activity is responsible, the hepatic vein, the portal vein, and the aorta were cannulated nonocclusively in baboons to measure the conversion of ethanol to acetate in vivo. 14C-ethanol (300 mg/kg as a 15% solution) was given intragastrically (IG) whereas 3H-acetate was continuously infused intravenously (IV). 14C-acetate was measured after exhaustive evaporation of ethanol. Simultaneous sampling of hepatic venous, portal and arterial blood was carried out for 3 hr, at the end of which the same alcohol dose was given IV to calculate the Michaelis-Menten parameters of elimination. RESULTS: Analysis of the IV and IG ethanol curves revealed a FPM of 94+/-11 mg/kg (31% of dose). The portal-arterial differences were negative for 3H-acetate (indicating net extraction) and positive for 14C-ethanol and 14C-acetate (indicating net output). Portal acetate production (extraction plus net output multiplied by the portal plasma flow) increased with time and accounted, over the first 3 hr (82+/-13 mg/kg), for 87% of the FPM. Alcohol oxidation by gastric ADH activity (28.7+/-7.2 mg/kg) accounted for only 31% of the FPM. CONCLUSIONS: The in vivo oxidation of ethanol to acetate in the upper digestive tract accounts for the FPM of ethanol and is mediated, at least in part, by ADH activity.

Acetates↗
PubMed2000

Disulfiram treatment increases plasma and red blood cell acetaldehyde in abstinent alcoholics.

BACKGROUND: Much of alcohol's toxicity is due to its product, acetaldehyde. The role of acetaldehyde derived from endogenous sources was assessed in alcoholic patients administered disulfiram, an inhibitor of aldehyde dehydrogenase. METHODS: The first part of the study included 23 subjects without biochemical or clinical evidence of chronic liver disease who were abstinent for 2 weeks; 11 patients were started on disulfiram (250 mg/day), whereas the other 12 were not given disulfiram and served as controls. The second part of the study included 13 alcoholic patients with clinical or pathological evidence of cirrhosis who also were administered disulfiram for 2 weeks. Plasma and red blood cell (RBC) acetaldehyde as well as serum transaminases were measured at baseline and after 1 and 2 weeks of treatment. RESULTS: In the disulfiram-treated group of alcoholics without known cirrhosis, RBC acetaldehyde levels increased from the pretreatment value of 2.98+/-0.18 microM to 4.14+/-0.33 microM after 1 week and to 4.14+/-0.26 microM after 2 weeks of treatment (p < 0.001). Compared with the pretreatment values (2.07+/-0.24 microM), plasma acetaldehyde levels also increased after 1 week (3.18+/-0.32 microM) and 2 weeks (3.15+/-0.26 microM) of disulfiram treatment (p < 0.001). There were no significant differences in sequential levels measured in either plasma or RBC acetaldehyde levels in patients who were not administered disulfiram. In the group of cirrhotic patients, the mean baseline RBC acetaldehyde value (3.60+/-0.22 microM) was significantly higher than in noncirrhotics. Disulfiram therapy increased the RBC acetaldehyde after 1 week (4.63+/-0.27 microM, p < 0.001) and 2 weeks of treatment (4.06+/-0.28 microM, p < 0.05). Compared with baseline values, plasma acetaldehyde levels were significantly higher after 1 week but not after 2 weeks of disulfiram. There were no significant differences among serum transaminases in alcoholics administered disulfiram, although three cirrhotic patients did have clinically significant elevations. CONCLUSIONS: In abstaining subjects given disulfiram, acetaldehyde concentrations increase, possibly due to diminished catabolism of endogenously generated acetaldehyde. Disulfiram should be given cautiously, especially in patients with cirrhosis.

Acetaldehyde↗
PubMed1999

Mechanism of the aspirin-induced rise in blood alcohol levels.

Aspirin increases blood alcohol levels after post-prandial alcohol consumption in men. This was attributed to a decrease in first pass metabolism secondary to inhibition of gastric alcohol dehydrogenase. Since accelerated gastric emptying, decreased volume of distribution or delayed elimination could also result in higher blood alcohol levels, we investigated the effect of aspirin (1 g taken with a meal) on these parameters. Aspirin did not change the volume of ethanol distribution or the rate of its elimination. Moreover, it did not have a significant effect on gastric emptying. The half-time of 99Tc-DTPA loss was 65.5+/-5.4 minutes without and 71.3+/-6.5, with aspirin. Despite a trend for slower gastric emptying with aspirin, the alcohol bioavailability increased and was associated with a 39% decrease in the first pass metabolism of alcohol (from 106+/-4 to 65+/-19 mg/kg, p<0.05), consistent with the inhibition of gastric ADH activity. In keeping with this interpretation, the effect of aspirin was virtually absent in women, who have a much smaller first pass metabolism available for inhibition by aspirin.

Administration, Oral↗
PubMed1999

Gender differences in medium-chain dicarboxylic aciduria in alcoholic men and women.

PURPOSE: Women appear to be more vulnerable to developing alcoholic liver disease than men. In rats, we previously found that the response of certain pathways of fatty acid metabolism to alcohol feeding was less efficient in females than in males, resulting in striking accumulation of fatty acids in the liver of the female rats. We sought to determine whether similar differences occurred in humans. PATIENTS AND METHODS: Urinary excretion of medium chain (C6-C10) dicarboxylic acids (final products of fatty acid omega-oxidation) was determined in 40 recently drinking alcoholic subjects (24 men and 16 women) and 21 nonalcoholic subjects (12 men and nine women). Sebacic (C10), suberic (C8), and adipic (C6) acids were measured in urine by gas chromatography/mass spectrometry, and their excretion was expressed per mg of creatinine. RESULTS: In nonalcoholic subjects, there was no gender difference in dicarboxylic aciduria. By contrast, alcoholic men (but not alcoholic women) developed dicarboxylic hyperaciduria. Alcoholic men had a marked increase in adipic acid excretion and in the adipic/sebacic (C6/C10) ratio (an index of peroxisomal beta-oxidation), whereas the values in alcoholic women did not differ from those in nonalcoholic women. CONCLUSIONS: The lack of response in alcoholic women could contribute to an aggravation of liver injury by promoting deleterious accumulation of fatty acids.

Adult↗
PubMed1999

Dilinoleoylphosphatidylcholine decreases hepatic stellate cell activation.

The prevention of cirrhosis in alcohol-fed baboons by the administration of a soybean extract-43% to 50% of which was dilinoleoyl-phosphatidylcholine (DLPC) and 24% of which was 1,palmitoyl 2,linoleoyl-phosphatidylcholine (PLPC)-was associated with a significant reduction in the number of stellate cells transformed to myofibroblast-like cells. To study whether these two major phospholipids affect the similar transformation that occurs by culturing stellate cells on uncoated plastic, we assessed their effects on proliferation (by (methyl-3H)-thymidine incorporation into DNA), expression of alpha-smooth muscle actin and type I procollagen (by densitometry of Western blots), and collagen synthesis (by incorporation of tritiated proline into collagenase-digestible proteins). These manifestations of stellate cell activation were decreased by 10 micromol/L DLPC but not by 10 micromol/L PLPC when compared with controls incubated either with 17 mmol/L ethanol (used as solvent for the phospholipids) or without addition. These agents did not affect cell viability, contamination with other cells, or the capacity of stellate cells to synthesize protein. Thus DLPC specifically decreases the in vitro activation of stellate cells, as judged by the decreases in proliferative activity, alpha-smooth muscle actin and procollagen I expressions, and collagen synthesis, whereas PLPC did not show such effects. alpha-Procollagen (type I) mRNA was not affected by DLPC, suggesting a post-translational effect. The reduction in the activation of hepatic stellate cells by DLPC may be responsible for, or at least contribute to, the prevention of fibrosis by the polyenylphosphatidylcholine mixture administered in vivo.

Actins↗
PubMed1999

Oxidation of LDL in baboons is increased by alcohol and attenuated by polyenylphosphatidylcholine.

Alcohol taken in moderation may prevent atherosclerosis, whereas heavy drinking has the opposite effect, in part by promoting oxidation of low density lipoproteins (LDL), a pathogenetic factor in atherogenesis. We assess here: 1 ) whether similar alterations can be reproduced in baboons fed 50% of energy as ethanol (the average intake of alcoholics) for 7- 8 years, and 2 ) whether such alterations are affected by supplementation with polyenylphosphatidylcholine (PPC), a mixture of polyunsaturated phosphatidylcholines, shown to prevent alcoholic fatty liver, fibrosis, and cirrhosis. Ten animals were given the ethanol-containing diet and ten were pair-fed isocaloric control diets. In half of the pairs, the diets were supplemented with 2.8 g of polyenylphosphatidylcholine/1000 kcal. Alcohol feeding increased LDL-lipoperoxides and made LDL-proteins more negatively charged, changes that were attenuated or prevented by PPC. The oxidizability of LDL was determined in vitro by the formation of conjugated dienes after oxidation with copper. Alcohol shortened the lag time (which measures LDL antioxidant capacity); this effect was normalized by PPC supplementation. By contrast, PPC produced no changes in the controls. Thus polyenylphosphatidylcholine, by markedly attenuating the ethanol-induced increase in LDL oxidation, opposes one of the effects whereby alcohol promotes atherosclerosis.

Animals↗
PubMed1998

Alcohol and lipids.

Alcoholic fatty liver and hyperlipemia result from the interaction of ethanol and its oxidation products with hepatic lipid metabolism. An early target of ethanol toxicity is mitochondrial fatty acid oxidation. Acetaldehyde and reactive oxygen species have been incriminated in the pathogenesis of the mitochondrial injury. Microsomal changes offset deleterious accumulation of fatty acids, leading to enhanced formation of triacylglycerols, which are partly secreted into the plasma and partly accumulate in the liver. However, this compensatory mechanism fades with progression of the liver injury, whereas the production of toxic metabolites increases, exacerbating the lesions and promoting fibrogenesis. The early presence of these changes confers to the fatty liver a worse prognosis than previously thought. Alcoholic hyperlipemia results primarily from increased hepatic secretion of very-low-density lipoprotein and secondarily from impairment in the removal of triacylglycerol-rich lipoproteins from the plasma. Hyperlipemia tends to disappear because of enhanced lipolytic activity and aggravation of the liver injury. With moderate alcohol consumption, the increase in high-density lipoprotein becomes the predominant feature. Its mechanism is multifactorial (increased hepatic secretion and increased extrahepatic formation as well as decreased removal) and explains part of the enhanced cholesterol transport from tissues to bile. These changes contribute to, but do not fully account for, the effects on atherosclerosis and/or coronary heart disease attributed to moderate drinking.

Alcohol Drinking↗
PubMed1997

Polyenylphosphatidylcholine decreases alcoholic hyperlipemia without affecting the alcohol-induced rise of HDL-cholesterol.

In ethanol-fed rats, supplementation of the diet with soybean polyenylphosphatidylcholine (3 g/liter for 21 days) markedly decreased postprandial VLDL-triglycerides and both VLDL- and LDL-cholesterol levels, whereas it maintained high levels of HDL-cholesterol, compared to an equivalent intake of choline and polyunsaturated fatty acids. By contrast, there were no changes in the serum lipoproteins of the pair-fed controls. The prevention of alcoholic hypertriglyceridemia was associated with marked attenuation of the alcoholic fatty liver and it occurred despite a slight increase in fat absorption. Thus, the administration of polyenylphosphatidylcholine not only attenuates the hepatotoxicity of ethanol, but also increases the HDL/LDL cholesterol ratio, which may be beneficial for the prevention of atherosclerosis and coronary heart disease.

Animals↗
PubMed1997

Polyenylphosphatidylcholine attenuates alcohol-induced fatty liver and hyperlipemia in rats.

Chronic administration of a soybean-derived polyenylphosphatidylcholine (PPC) extract prevents the development of cirrhosis in alcohol-fed baboons. To assess whether this phospholipid also affects earlier changes induced by alcohol consumption (such as fatty liver and hyperlipemia), 28 male rat littermates were pair-fed liquid diets containing 36% of energy either as ethanol or as additional carbohydrate for 21 d, and killed 90 min after intragastric administration of the corresponding diets. Half of the rats were given PPC (3 g/l), whereas the other half received the same amount of linoleate (as safflower oil) and choline (as bitartrate salt). PPC did not affect diet or alcohol consumption [15.4 +/- 0.5 G/(kg.d)], but the ethanol-induced hepatomegaly and the hepatic accumulation of lipids (principally triglycerides and cholesterol esters) and proteins were about half those in rats not given PPC. The ethanol-induced postprandial hyperlipemia was lower with PPC than without, despite an enhanced fat absorption and no difference in the level of plasma free fatty acids. The attenuation of fatty liver and hyperlipemia was associated with correction of the ethanol-induced inhibition of mitochondrial oxidation of palmitoyl-1-carnitine and the depression of cytochrome oxidase activity, as well as the increases in activity of serum glutamate dehydrogenase and aminotransferases. Thus, PPC attenuates early manifestations of alcohol toxicity, at least in part, by improving mitochondrial injury. These beneficial effects of PPC at the initial stages of alcoholic liver injury may prevent or delay the progression to more advanced forms of alcoholic liver disease.

Animals↗
PubMed1997

Collagen synthesis by liver stellate cells is released from its normal feedback regulation by acetaldehyde-induced modification of the carboxyl-terminal propeptide of procollagen.

Acetaldehyde stimulates collagen synthesis in stellate cells and forms adducts with procollagen in the liver of alcoholics. To assess the possibility that modification of the carboxyl-terminal propeptide by acetaldehyde affects its capacity to exert a feedback inhibition of collagen synthesis after splitting from procollagen, the propeptide was prepared by gel filtration of the bacterial collagenase digests of procollagen type I (obtained from 10(9) calvaria fibroblasts of newborn rats) and reacted with either 250 mM acetaldehyde and 100 mM CNBH3 or with 170 microM acetaldehyde without reducing agents, to mimick in vivo conditions. The unmodified propeptide produced a concentration-dependent inhibition of collagen synthesis by Ito cells. By contrast, the acetaldehyde-modified propeptide produced a lesser inhibition of procollagen synthesis in the cells, associated with a greater accumulation of collagen in the media. The incubation with 170 microM acetaldehyde and, to a lesser extent, 50 mM ethanol produced collagenase-digestible adducts in stellate cells. Thus, the formation of acetaldehyde adducts with the carboxyl-terminal propeptide of procollagen may account, at least in part, for the stimulatory effect of acetaldehyde on collagen synthesis by stellate cells and may lead to collagen accumulation through a decrease of the normal feedback regulation of collagen synthesis by the propeptide.

Acetaldehyde↗
PubMed1996

Molecular cloning and chromosomal localization of the ADH7 gene encoding human class IV (sigma) ADH.

The ADH7 gene encoding human Class IV (sigma) alcohol dehydrogenase (ADH) was cloned from a Caucasian genomic DNA library and characterized. It has nine exons and eight introns that span about 22 kb, and its intron insertion is identical to that of the other ADH genes (ADH1 to ADH5). The nucleotide sequences of the exons encoding 374 amino acids are identical to the previously reported cDNA sequence of sigma ADH. Fluorescence in situ hybridization analysis showed that ADH7 is located on human chromosome 4q23-q24, close to the ADH cluster locus (4q21-q25). These data are consistent with the view that Class IV ADH is a member of the ADH family and is phylogenetically close to the other ADHs.

Alcohol Dehydrogenase↗
PubMed1996

Ranitidine increases the bioavailability of imbibed alcohol by accelerating gastric emptying.

To investigate the mechanism of the increase in alcohol bioavailability by ranitidine, we determined by nuclear scan the changes in gastric emptying of a 10% ethanol solution (containing 0.3 g ethanol/kg body weight and 300 microCi of technetium-labeled diethylene triamine pentacetic acid) in 8 normal men, before and after treatment with 300 mg ranitidine orally each evening for 1 week. We compared these changes with those of ethanol bioavailability, calculated by integration of the Michaelis-Menten function over the entire alcohol curves after random i.v. and, on a separate day, oral administration of the same ethanol dose, pre- and post-ranitidine. With ranitidine, we found an acceleration of gastric emptying in 7 of 8 subjects, with 20% shortening of the time to 50% emptying (51.8 +/- 4.1 min vs 64.3 +/- 3.4, without ranitidine; P < .001 by paired t test). Despite the disappearance (from the stomach) of most of the dose by the end of the blood alcohol curves, only 83 +/- 4% reached the systemic blood vs 64 +/- 4% without ranitidine (P < .02), most likely because of a shortened exposure of alcohol dehydrogenase to optimal ethanol concentrations. As a result, after oral but not intravenous alcohol administration, ranitidine increased blood alcohol concentrations (29 +/- 4 mg/dl vs 22 +/- 3, without ranitidine; P < .02), with a corresponding decrease in first pass metabolism of ethanol from 107 +/- 16 mg/kg to 47 +/- 16 (P < .01).

Adult↗
PubMed1996

Ethnic differences in gastric sigma-alcohol dehydrogenase activity and ethanol first-pass metabolism.

We assessed whether the low sigma-alcohol dehydrogenase (ADH) activity in Japanese (compared with Caucasians) affects the first-pass metabolism of ethanol. ADH isozyme activities were determined in endoscopic biopsies of the gastric corpus from 24 Japanese and 41 Caucasian men by starch gel electrophoresis and by comparing the reduction of m-nitrobenzaldehyde (a preferred substrate of sigma-ADH) with that of acetaldehyde (a preferred substrate of gamma-ADH) and the glutathione-dependent formaldehyde oxidation (a specific reaction of chi-ADH). Alcohol pharmacokinetics was compared in 10 Japanese and 10 Caucasians after administration of ethanol (300 mg/kg of body weight) intravenously or orally, using 5 and 40% oral solutions. Japanese exhibited lower sigma-ADH activity than Caucasians, with no difference in the other gastric isozymes. With 5% ethanol, first-pass metabolism was strikingly lower in Japanese than in Caucasians. Blood alcohol levels were similar because of the high elimination rate in Japanese due to the hepatic beta 2-ADH variant. With 40% ethanol, the first-pass metabolism increased in both groups to comparable levels, suggesting an additional contribution by chi-ADH at high ethanol concentrations. These results indicate that sigma-ADH activity contributes significantly to gastric ethanol oxidation and its lower activity in Japanese is associated with lesser first-pass metabolism.

Alcohol Dehydrogenase↗