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Biomedical subjects

C S Lieber

Publications and source records attributed to C S Lieber.

At least 253 records · Page 14Linked to original sources
PubMed1987

Effects of fasting and chronic alcohol consumption on the first-pass metabolism of ethanol.

The present investigation was undertaken to evaluate what fraction of alcohol ingested in amounts during usual "social drinking" does not enter the systemic circulation. To that effect, on consecutive days, either peroral or intravenous ethanol was administered in both fed and fasted states to 7 nonalcoholic and 18 alcoholic subjects. In nonalcoholics consuming 0.15 g/kg body wt ethanol, the magnitude of first-pass metabolism of ethanol was 3.94 +/- 0.15 mmol/L X h, calculated as the difference of the areas under the curve obtained after oral and intravenous alcohol administration. The first-pass metabolism accounted for 73% of the latter. When the administered dose was increased to 0.3 g/kg body wt ethanol, the corresponding values were 6.46 +/- 0.50 mmol/L X h and 44%. Fasting decreased this effect. When alcoholics consumed 0.15 g/kg body wt ethanol, the corresponding values were 0.92 +/- 0.65 mmol/L X h and 23%. When these alcoholics were fasted, the first-pass metabolism again decreased and it was significantly lower than in the nonalcoholics tested under the same conditions. We conclude that in humans a significant fraction of ingested alcohol undergoes first-pass metabolism but that this effect is reduced in alcoholics and by fasting. The magnitude of this process determines the bioavailability of alcohol and thus modulates its potential toxicity.

Administration, Oral↗
PubMed1987

Potentiation of ethanol-induced hepatic vitamin A depletion by phenobarbital and butylated hydroxytoluene.

Administration of ethanol, phenobarbital or butylated hydroxytoluene (BHT) each resulted in significantly lower hepatic vitamin A than in untreated controls. When ethanol was combined with either phenobarbital or BHT, a striking potentiation of the depletion was observed, resulting in hepatic vitamin A values of less than 5% of normal, whether expressed per gram of liver or per 100 g body wt. These effects were observed for both retinol and retinyl esters, measured by high pressure liquid chromatography. By contrast, lung levels of retinol and retinyl esters were significantly higher in rats treated with ethanol, but remained unchanged in rats treated with phenobarbital or butylated hydroxytoluene compared with control animals.

Animals↗
PubMed1987

Effect of abstinence on the blood acetaldehyde response to a test dose of alcohol in alcoholics.

Following an acute dose of alcohol (0.15 g/kg intravenously), blood levels of acetaldehyde were significantly higher in nonabstinent alcoholics than in controls. After 2 weeks of abstinence, this blood acetaldehyde response significantly decreased in alcoholics and the acetaldehyde returned towards levels comparable to those observed in nonalcoholics. These results suggest that elevated blood acetaldehyde levels in the alcoholics are secondary to the chronic alcohol consumption rather than reflecting a primary preexisting defect.

Acetaldehyde↗
PubMed1987

Serum procollagen type III N-terminal peptides and laminin P1 peptide in alcoholic liver disease.

The appearance of perivenular fibrosis on liver biopsy reflects the beginning of the fibrotic process that ultimately results in liver cirrhosis. To examine whether the fibrogenic activity can be detected by blood tests, we evaluated whole antibody radioimmunoassay (RIA) of procollagen type III N-terminal peptides (P-III-P), RIA of these peptides using Fab fragments (Fab-P-III-P), and RIA of the laminin P1 peptide in alcoholics within 1 week of alcohol abstinence. The Fab-P-III-P levels in subjects with perivenular fibrosis were significantly higher than those in patients with simple fatty liver. Values in 63% of subjects with perivenular fibrosis exceeded the upper limit of the fatty liver group. Patients with simple fatty liver had significantly lower values than nonalcoholic controls. Serum levels of P-III-P and laminin were elevated in patients with alcoholic hepatitis and correlated well with the degree of inflammation. With abstinence, Fab-P-III-P levels increased in all alcoholics. P-III-P values increased in patients with normal P-III-P values on admission. By contrast, the values of laminin decreased during abstinence. Therefore, to interpret serum levels of Fab-P-III-P, P-III-P, and laminin, the duration of abstinence must be taken into consideration. P-III-P, Fab-P-III-P and laminin measurements in the serum within 1 week of abstinence can contribute to the detection of alcoholic liver disease and the determination of its stage.

Adult↗
PubMed1987

The microsomal ethanol oxidizing system and its interaction with other drugs, carcinogens, and vitamins.

The interaction of ethanol with the oxidative drug-metabolizing enzymes present in liver microsomes results in a number of clinically significant side effects in the alcoholic. Following chronic ethanol consumption, the activity of the microsomal ethanol oxidizing system (MEOS) increases. This enhancement of MEOS activity is primarily due to the induction of a unique microsomal cytochrome P-450 isozyme, which has a high capacity for ethanol oxidation, as shown in reconstituted systems. Normally present in liver microsomes at low levels, this form of cytochrome P-450 increases dramatically after chronic ethanol intake in many species, including baboons. The in-vivo role of cytochrome P-450 in hepatic ethanol oxidation, especially following chronic ethanol consumption, has been conclusively demonstrated in deer-mice lacking liver ADH. Induction of microsomal cytochrome P-450 by ethanol is associated with the enhanced oxidation of other drugs as well, resulting in metabolic tolerance to these agents. There is also increased cytochrome P-450-dependent activation of known hepatotoxins such as carbon tetrachloride and acetaminophen, which may explain the greater susceptibility of alcoholics to the toxicity of industrial solvents and commonplace analgesics. In addition, the ethanol-inducible form of cytochrome P-450 has the highest capacity of all known P-450 isozymes for the activation of dimethylnitrosamine, a potent (and ubiquitous) carcinogen. Moreover, cytochrome P-450-catalyzed oxidation of retinol is accelerated in liver microsomes, which may contribute to the hepatic vitamin A depletion seen in alcoholics. In contrast to chronic ethanol consumption, acute ethanol intake inhibits the metabolism of other drugs via competition for shared microsomal oxidation pathways. Thus, the interplay between ethanol and liver microsomes has a profound impact on the way heavy drinkers respond to drugs, solvents, vitamins, and carcinogens.

Alcohol Dehydrogenase↗
PubMed1987

Microsomal ethanol-oxidizing system.

Advances in our knowledge of the microsomal metabolism of ethanol enable us to understand a number of complications that develop in the alcoholic. After chronic ethanol consumption, microsomal ethanol-oxidizing system (MEOS) activity increases with an associated rise in microsomal cytochrome P-450, including a form different from that induced by phenobarbital and methylcholanthrene and which has a high affinity for ethanol, as shown in reconstituted systems. The role of this MEOS in vivo and its increase after chronic ethanol consumption was most conclusively shown in alcohol dehydrogenase-negative deer mice. Microsomal induction is also associated with enhanced metabolism of other drugs, resulting in metabolic drug tolerance. Furthermore, there is increased conversion to toxic metabolites of known hepatotoxic agents (such as CCl4), which may explain the enhanced susceptibility of alcoholics to the toxicity of industrial solvents. Furthermore, the ethanol-induced form of cytochrome P-450 has a high capacity for the conversion to toxic metabolites of some commonly used drugs, such as acetaminophen, and also carcinogens, such as dimethylnitrosamine which is activated at concentrations much lower than those required for other microsomal inducers. Moreover, catabolism of retinol is accelerated through a newly discovered microsomal pathway, thereby contributing to hepatic vitamin A depletion and possibly vitamin A toxicity. There is also induction of microsomal enzymes involved in lipoprotein production, resulting in hyperlipemia. Contrasting with the chronic effects of ethanol consumption, acutely, ethanol inhibits the metabolism of other drugs through competition for an at least partially shared microsomal detoxification pathway.

Alcoholism↗
PubMed1987

Acute and chronic effects of ethanol and its metabolites on vascular production of prostacyclin in rats.

The cutaneous vasodilation produced by ethanol is exaggerated when acetaldehyde levels are increased after aldehyde dehydrogenase inhibition, producing a flushing reaction, the mechanism of which is unknown. The authors investigated whether ethanol and its metabolites affect the vascular release of prostacyclin, a potent vasodilator, and whether such an effect might be modified by chronic alcohol consumption. Aortic rings from rats fed Chow ad libitum or pair-fed liquid diets containing either ethanol (36% of energy) or isocaloric carbohydrate for 4 to 5 weeks were incubated in Krebs-Ringer bicarbonate supplemented with saturating amounts of arachidonate (10-20 microM) in the presence of ethanol (10-100 mM), acetaldehyde (10-100 microM) or acetate (1.25-5 mM). Prostacyclin was measured by the radioimmunoassay of 6-keto-prostaglandin F1 alpha. Acetaldehyde produced a concentration-dependent stimulation of prostacyclin production both in alcohol-fed and control rats, whereas acetate did not. This effect was associated with increased conversion of arachidonate (either exogenous or released with A23187) and of prostaglandin endoperoxide H2 to prostacyclin. Ethanol did not affect prostacyclin release in control rats, but, in aortas from alcohol-fed animals, 50 mM ethanol did stimulate prostacyclin formation. These effects may contribute to the cardiovascular responses associated with high blood acetaldehyde levels in flushers and with high ethanol levels in alcoholics. In conclusion, acetaldehyde is a potent stimulant of vascular prostacyclin production. This effect is due, at least in part, to enhanced activity of prostacyclin synthase. Ethanol acquires such a stimulatory effect on prostacyclin formation after chronic alcohol consumption.

Acetaldehyde↗
PubMed1987

Transport of acetaldehyde in red blood cells.

Alcohol intake caused a much greater elevation of acetaldehyde in red blood cells than in plasma. During ethanol oxidation, most of this metabolite was released from the splanchnic areas and circulated reversibly bound to intracellular components of the erythrocyte. Acetaldehyde was then taken up by extra-splanchnic tissues from both plasma and erythrocytes. Thus, an amount of acetaldehyde much larger than previously thought by measurements in plasma becomes available to exert extra-splanchnic toxicity. The contribution of this route for acetaldehyde transport is markedly enhanced in alcoholics.

Acetaldehyde↗
PubMed1987

Ethanol metabolism in alcohol dehydrogenase deficient deermice is mediated by the microsomal ethanol oxidizing system, not by catalase.

The participation of the microsomal ethanol oxidizing system (MEOS) and catalase in total ethanol metabolism is reviewed. Non-alcohol dehydrogenase (ADH) dependent pathways contribute to in vivo ethanol metabolism, but the respective role of each has long been debated. The principal data supporting a role for catalase is an occasionally reported moderate depression of ethanol metabolism after aminotriazole. In deermice lacking ADH, we observed a slight (though not statistically significant) decrease in basal ethanol metabolism of hepatocytes after aminotriazole. However, this decrease was found to parallel a similar inhibition of MEOS by aminotriazole, and thus may not reflect catalase mediated peroxidation in this animal. 1-butanol, a competitive inhibitor of ethanol oxidation by MEOS and not a substrate for catalase, decreased ethanol metabolism by hepatocytes in a concentration dependent manner. These results, as well as those from other investigators, indicate that MEOS mediates virtually all of non-ADH ethanol metabolism in vivo.

1-Butanol↗
PubMed1987

Potentiation by ethanol consumption of tracheal squamous metaplasia caused by vitamin A deficiency in rats.

The effect of ethanol (CAS: 64-17-5) consumption on the development of squamous metaplasia of the trachea caused by vitamin A deficiency was assessed in rats. To that effect, weanling male Sprague-Dawley rats were fed for 8-12 weeks either a nutritionally adequate liquid diet containing a standard amount of vitamin A or a diet lacking vitamin A. Littermates were pair-fed the same diets with ethanol (36% of total calories) isocalorically replacing part of the carbohydrates. In rats fed the vitamin A-deficient diets with or without ethanol, plasma vitamin A was very low (5.3 +/- 0.9 and 5.9 +/- 1.5 micrograms/dl; n = 20 pairs), while liver and tracheal vitamin A was unmeasurable. Squamous metaplasia was noted in 9 of 20 rats fed the vitamin A-deficient diet and in 13 of 20 rats fed the same diet plus ethanol. Severe lesions (those showing keratinization) were present in 42% of the tracheal sections from rats fed the vitamin A-deficient diet plus ethanol compared to 6% of the sections from rats fed the diet without ethanol (P less than .001). In the ethanol-fed group, 37% of all the sections showed metaplasia occupying more than 50% of the tracheal epithelium, whereas in the absence of ethanol, 14% of the sections had lesions occupying more than 50% of the epithelium (P less than .001). When the histologic grade and extent of the lesions were expressed as the percentage of rats affected, the differences between the 2 groups of animals were not statistically significant. Ethanol feeding resulted in a 70% increase in the labeling index of basal cells in squamous metaplasia (30.7 +/- 3.5 vs. 17.3 +/- 1.5%; P less than .02). The number of [3H]thymidine-labeled suprabasal cells was not altered after ethanol feeding. In ciliated cells of the tracheal epithelium that were not as yet involved in the formation of metaplasia, ciliary abnormalities and an increased number of lysosomes were observed in rats that had consumed ethanol.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1987

Use of the triolein breath test in alcoholics with liver damage.

The triolein breath test (TBT) is a simple, noninvasive technique for the evaluation of steatorrhea. However, because it depends on intermediary hepatic processes, and because both liver damage and pancreatic dysfunction often co-exist in the alcoholic, the overall usefulness of the test in patients with liver injury was reassessed. We found that even in the absence of steatorrhea, a majority of patients with advanced liver injury (alcoholic hepatitis, cirrhosis, or both) had abnormal TBT results that failed to correct with pancreatic extract. In contrast, patients with less severe lesions (steatosis) had results that were not significantly different from those in normal controls. Inasmuch as the abnormal TBT results in patients with advanced alcohol-induced lesions did not correct with pancreatic extract, the test may not accurately differentiate pancreatic from nonpancreatic steatorrhea in some alcoholics.

Breath Tests↗
PubMed1986

Interaction of drugs and retinol.

In liver microsomes of ethanol-fed rats, retinol competitively inhibited the hydroxylation of aniline, the demethylation of dimethylnitrosamine, and the oxidation of ethanol to acetaldehyde, whereas the inhibition of benzphetamine demethylation was of the mixed type in microsomes of phenobarbital-treated, ethanol-treated or control rats. Conversely, benzphetamine exerted a striking inhibition of the 4-hydroxylation of retinol in microsomes of phenobarbital-treated rats. At the concentration used, ethanol (100 mM) and dimethylnitrosamine (10 mM) had no such effect. In vivo administration of phenobarbital resulted in a 9-fold increase in the Vmax of the microsomal retinol 4-hydroxylase activity, with a 3-fold increase of the Km, whereas ethanol feeding resulted in a doubling of the Vmax with no significant change in the Km. The induction of this microsomal retinol-metabolizing system may contribute to the hepatic vitamin A depletion that has been reported previously after either ethanol or drug administration. Conversely, the observed inhibition, by retinol, of microsomal drug metabolism, including the demethylation of dimethylnitrosamine, may be of significance with regards to the interaction of retinol with carcinogenesis.

Animals↗
PubMed1986

Assessment of the role of non-ADH ethanol oxidation in vivo and in hepatocytes from deermice.

Deermice genetically lacking alcohol dehydrogenase (ADH-) were used to quantitate the effect of 4-methylpyrazole (4-MP) on non-ADH pathways in hepatocytes and in vivo. Although primarily an inhibitor of ADH, 4-methylpyrazole was also found to inhibit competitively the activity of the microsomal ethanol-oxidizing system (MEOS) in deermouse liver microsomes. The degree of 4-MP inhibition in ADH- deermice then served to correct for the effect of 4-MP on non-ADH pathways in deermice having ADH (ADH+). In ADH+ hepatocytes, the percent contributions of non-ADH pathways were calculated to be 28% at 10 mM and 52% at 50 mM ethanol. When a similar correction was applied to in vivo ethanol clearance rates in ADH+ deermice, non-ADH pathways were found to contribute 42% below 10 mM and 63% at 40-70 mM blood ethanol. The catalase inhibitor 3-amino-1,2,4-triazole, while reducing catalase-mediated peroxidation of ethanol by 83-94%, had only a slight effect on blood ethanol clearance at ethanol concentrations below 10 mM, and no effect at all at 40-70 mM ethanol. These results indicate that non-ADH pathways (primarily MEOS) play a significant role in ethanol oxidation in vivo and in hepatocytes in vitro.

Alcohol Dehydrogenase↗
PubMed1986

Liver fibrosis in alcoholics. Detection by Fab radioimmunoassay of serum procollagen III peptides.

Radioimmunoassays were used to measure serum levels of laminin and of procollagen III peptides, both with the intact antibody and with the Fab fragments, within one week of alcohol withdrawal in 83 alcoholics admitted for detoxification and/or treatment of concomitant medical problems. All patients underwent a diagnostic liver biopsy, which revealed simple fatty liver in 22, perivenular fibrosis in 20, septal fibrosis in 21, and cirrhosis in 20. Although all three serum measurements correlated significantly with the degree of fibrosis, only the Fab radioimmunoassay of procollagen III peptides discriminated between simple fatty liver and perivenular fibrosis in a significant number of subjects.

Adult↗