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Biomedical subjects

C S Lieber

Publications and source records attributed to C S Lieber.

At least 307 records · Page 17Linked to original sources
PubMed1984

Decreased cytochrome oxidase activity in hepatic mitochondria after chronic ethanol consumption and the possible role of decreased cytochrome aa3 content and changes in phospholipids.

In ethanol-fed baboons, hepatic mitochondrial cytochrome oxidase activity and cytochrome aa3 content were significantly decreased by 58.3 and 50.5%, respectively, compared to their pair-fed controls. However, there was no significant correlation between the two, suggesting that other factors in addition to cytochrome aa3 may be responsible for the depression in cytochrome oxidase activity. The total phospholipid content of the mitochondrial membranes was significantly decreased (0.24 +/- 0.03 mumol of phospholipid phosphorus/mg of protein vs. 0.32 +/- 0.04 in controls). This change was accounted for, in part, by the significant decrease in the levels of phosphatidylcholine and cardiolipin. In addition, the fatty acid pattern of the phospholipids was changed. There was a marked increase in the relative amounts of oleic and linoleic acids and a decrease in arachidonic acid. These changes were associated with an increase in the activity of phospholipase A2. The reactivation rate of phospholipid-depleted cytochrome oxidase by endogenous phospholipids from ethanol-fed baboons was significantly lower than that by phospholipid from pair-fed controls, when measured at an optimal phospholipid to protein ratio. Thus, it appears that alterations in the phospholipid composition of the mitochondrial membranes are responsible, at least in part, for the depression of cytochrome oxidase activity produced by chronic ethanol consumption.

Animals↗
PubMed1984

Characterization of three highly purified cytochromes P-450 from hepatic microsomes of adult male rats.

Three hepatic microsomal cytochromes P-450 (P-450f, P-450g, and P-450h) have been purified to electrophoretic homogeneity from both untreated and ethanol-treated adult male rats. By all criteria examined, the hemoproteins isolated from untreated rats are indistinguishable from the corresponding enzymes purified from rats administered ethanol. Highly purified cytochromes P-450f, P-450g and P-450h are characterized by minimum Mr of 51,000, 50,000, and 51,000, respectively, and unique coordinates in two-dimensional isoelectric focusing-sodium dodecyl sulfate-polyacrylamide gels. The CO-reduced spectral maxima of cytochromes P-450f and P-450g are at 447-448 nm, and the peak of cytochrome P-450h is at 451 nm. Cytochrome P-450h is a versatile catalyst exhibiting high activity toward benzphetamine, hexobarbital, and estradiol-17 beta and moderate activity toward benzo[alpha]pyrene and zoxazolamine. In contrast, cytochromes P-450f and P-450g have low metabolic activity for these substrates. The three hemoproteins catalyze the metabolism of testosterone with different regio- and stereospecificities and overall rates. Both cytochromes P-450f and P-450h catalyze the hydroxylation of testosterone at the 16 alpha-position; however, cytochrome P-450h also oxidizes the steroid at the 2 alpha- and 17 beta-position (androstenedione formation). Testosterone is oxidatively metabolized at the 6 beta-, 15 alpha- and an unknown position by cytochrome P-450g. Peptide maps, generated by proteolytic or chemical digestion of the hemoproteins, indicate that cytochromes P-450f, P-450g, and P-450h differ structurally from each other and five previously characterized rat hepatic microsomal cytochromes P-450 (P-450a, P-450b, P-450c, P-450d, and P-450e). Cytochromes P-450f, P-450g, and P-450h do not react with antibodies directed against these inducible hemoproteins by Ouchterlony immunodiffusion in the presence of detergent; however, in the absence of detergent, cytochrome P-450f cross-reacts weakly with anti-P-450b. Results of this study indicate that rat hepatic microsomal cytochromes P-450 are composed of at least four hemoproteins with CO-reduced absorbance maxima between 447-448 nm. Furthermore, a minimum of four microsomal cytochromes P-450 are now known to 16 alpha-hydroxylate testosterone.

Animals↗
PubMed1984

The effect of chronic alcohol feeding on lipid peroxidation in microsomes: lack of relationship to hydroxyl radical generation.

Chronic alcohol feeding causes microsomal induction including increased generation of hydroxyl radicals. Ethanol induced liver injury may be mediated by lipid peroxidation for which hydroxyl radicals have been proposed as major mediators. Ethanol promotes lipid peroxidation when given acutely but also may serve as a hydroxyl radical scavenger. Therefore, we studied the acute and chronic effects of alcohol on microsomal lipid peroxidation and hydroxyl radical generation. Chronic alcohol feeding in rats increased microsomal generation of hydroxyl radicals but lipid peroxidation of endogenous lipid was inversely related to hydroxyl radical generation. Ethanol (50mM) had a slight inhibitory effect on hydroxyl radical production in peroxidizing microsomes, no effect on endogenous lipid peroxidation and enhanced the lysis of RBCs added as targets of peroxidation. Enhanced microsomal generation of hydroxyl radicals following chronic alcohol feeding is not an important mediator of lipid peroxidation.

Alcoholism↗
PubMed1984

NH2-terminal sequence analyses of four rat hepatic microsomal cytochromes P-450.

Cytochromes P-450f, P-450g, P-450h, and P-450i are four hepatic microsomal hemoproteins that have been purified from adult rats. Whereas cytochromes P-450g and P-450h appear to be male-specific hemoproteins, cytochrome P-450i is apparently a female-specific enzyme purified from untreated adult female rats. Cytochrome P-450f has been purified from adult male and female rats with equivalent recoveries. Amino-terminal sequence analyses of the first 15-20 amino acid residues of each of these cytochromes P-450 has been accomplished in the current investigation. Each protein possesses a hydrophobic leader sequence consisting of 65-87% hydrophobic amino acids, and only one charged amino acid (Asp) in the amino-terminal region. Although differences in the amino-terminal sequences of cytochromes P-450f, P-450g, P-450h, and P-450i are identified, these hemoproteins all begin with Met-Asp, and marked structural homology is observed among certain of these enzymes. Cytochromes P-450g and P-450h, two male-specific proteins, have 11-12/15 identical residues with cytochrome P-450i, a female-specific isozyme. Cytochromes P-450f and P-450h have 16/20 identical amino-terminal residues. Only limited sequence homology is observed between the amino-terminal sequences of cytochromes P-450f-i compared to rat liver cytochromes P-450a-e. The results demonstrate that cytochromes P-450f, P-450g, P-450h, and P-450i are isozymic to each other and five additional rat hepatic microsomal cytochrome P-450 isozymes (P-450a-e).

Amino Acid Sequence↗
PubMed1984

Retinoic acid metabolism by a system reconstituted with cytochrome P-450.

Feeding rats with a diet containing a hundred times the normal amount of vitamin A resulted, within 2 to 3 weeks, in an increase in total hepatic microsomal cytochrome P-450 content. This was associated, in isolated microsomes, with an enhanced conversion of all-trans-retinoic acid to polar metabolites, including a two- to threefold increased production of 4-hydroxy- and 4-oxo-retinoic acid, whether expressed per microsomal protein or per cytochrome P-450. Unlike effects of other inducers (e.g., phenobarbital or methylcholanthrene), activities of benzphetamine, aminopyrine, and ethylmorphine demethylases or benzopyrene hydroxylase were not increased. Furthermore, the CO-reduced difference spectral peak was shifted towards 449 nm. On sodium dodecyl sulfate-gel electrophoresis, one band was increased with electrophoretic mobility identical to that of cytochrome P-450f, a recently isolated new form which has a CO-reduced difference spectral peak at 448 nm. In a system reconstituted with NADPH-cytochrome P-450 reductase, NADPH, and phospholipid, purified cytochromes P-450f and b were discovered to promote conversion of retinoic acid to polar metabolites, including 4-hydroxy-retinoic acid.

Animals↗
PubMed1984

Depression, suicide, and aggression in alcoholics and their relationship to plasma amino acids.

In an earlier study we found an association in alcoholic patients between depression and low ratios of tryptophan over amino acids sharing with it the same transport carrier into the brain. A decreased tryptophan ratio has been shown to be correlated with lower brain tryptophan and serotonin. Because it has been postulated that altered serotonin metabolism may be a highly significant contributing factor not only to depression but also to aggressive and suicidal behavior, we decided to assess the existence of possible associations between amino acid abnormalities and these behaviors in a population of alcoholics. We observed a significant association between histories of aggression and depression. In addition, depressed patients with a history of aggression were found to have the lowest tryptophan ratio values. These values differed significantly from those found in depressed patients with no aggression history and from those observed in patients with no history of aggression and depression. Two of the three suicide attempters in the study fell also in the group of patients with an aggression history. Our data suggest the existence of a subgroup of alcoholics with marked amino acid abnormalities at risk for manifestations of depression, suicide, and aggression.

Adult↗
PubMed1984

Metabolism and metabolic effects of alcohol.

The author provides an excellent overview of the three major pathways for the metabolism of ethanol. Many of the toxic effects of ethanol can be attributed to two specific products, hydrogen and acetaldehyde, and these effects are explored in detail.

Acetaldehyde↗
PubMed1984

Decreased hepatic vitamin A after drug administration in men and in rats.

Eleven patients with moderate drug-induced liver changes were found to have extremely low hepatic vitamin A levels (less than 10% of normal). Their serum vitamin A, retinol-binding protein, and transthyretin were only slightly affected. In rats, two representative drugs (phenobarbital and methylcholanthrene) produced a significant depression of hepatic vitamin A, whereas plasma vitamin A levels remained normal. The livers of drug-treated animals showed no abnormalities except for the expected proliferation of the smooth endoplasmic reticulum and induction of microsomal enzymes and cytochrome P-450 (phenobarbital) and P-448 (methylcholanthrene). These findings suggest that the decrease in hepatic vitamin A may be secondary, at least in part, to enhanced microsomal metabolism.

Animals↗
PubMed1984

Normal testicular structure and reproductive function in deermice lacking retinol and alcohol dehydrogenase activity.

It was found that a strain of deermice (Peromyscus maniculatus), which genetically lacks liver alcohol dehydrogenase activity also displays no such activity in the testis and is devoid of the enzyme activity that converts retinol to retinal, both in liver and in the testis; nevertheless, these animals exhibit normal reproduction and testicular histology. Therefore, one must reconsider the theory that the testicular atrophy and aspermatogenesis commonly found in alcoholics is due, at least in part, to interaction of ethanol with these enzyme activities in the testis.

Alcohol Dehydrogenase↗
PubMed1984

Decrease in microviscosity and cholesterol content of rat liver plasma membranes after chronic ethanol feeding.

This investigation was performed to determine whether chronic ethanol feeding alters the lipid composition or the fluidity of liver plasma membranes. Male Sprague-Dawley rats were pair-fed nutritionally adequate liquid diets containing ethanol as 36% of energy or an isocaloric amount of carbohydrate for 4-5 wk. Contrasting with other membranes, chronic ethanol feeding resulted in an increase in hepatic plasma membrane fluidity as assessed by fluorescence anisotropy. This alteration was associated with a decrease in plasma membrane cholesterol content.

Animals↗
PubMed1984

Relationship between changes in plasma amino acids and depression in alcoholic patients.

The authors studied the relationship between changes in amino acid precursors of biogenic amines and depression in 42 alcoholic patients with a secondary depression. Tryptophan and amino acids competing with it for brain entry were measured in the plasma of depressed alcoholics, nondepressed alcoholics, and control subjects. The ratio of tryptophan to its competitors was significantly lower in depressed patients than in nondepressed patients and controls. The decreased ratio was due primarily to decreased tryptophan and increased tyrosine and phenylalanine values. A decreased tryptophan ratio is known to result in decreased brain tryptophan and may contribute to depression through a deficiency of brain serotonin.

Adult↗
PubMed1984

Acetaldehyde and lactate stimulate collagen synthesis of cultured baboon liver myofibroblasts.

Cells with electron-microscopic characteristics of myofibroblasts were isolated from baboon liver biopsy specimens by collagenase digestion and Percoll density gradient centrifugation and then cultured. The cultures consisted of only one cell type. By immunofluorescence, these cells synthesized collagen types I, III, and IV and laminin. Typical features of myofibroblasts were maintained throughout many passages in the culture. To study the effects of ethanol (and its oxidation product acetaldehyde and associated metabolite lactate) on myofibroblast collagen synthesis, the cell cultures were incubated for 24 h in a medium containing either 50 mM ethanol, 200 microM acetaldehyde, or 5 mM lactate. The cells did not contain significant alcohol dehydrogenase activity. Acetaldehyde stimulated significantly (p less than 0.05) myofibroblast collagen synthesis without changing noncollagen protein synthesis or proline pools. Lactate caused a significant (p less than 0.02) increase in intracellular proline pool and collagen synthesis. Ethanol itself did not have any effect on collagen synthesis of myofibroblasts. The stimulation of collagen synthesis of hepatic myofibroblasts by acetaldehyde and lactate may contribute to the development of alcoholic liver fibrosis, as alcohol intake is known to elevate acetaldehyde and lactate in tissues and blood.

Acetaldehyde↗
PubMed1984

Hepatic triacylglycerol synthesizing activity during progression of alcoholic liver injury in the baboon.

To study the effects of alcoholic liver injury on the ability of ethanol to promote hepatic fat accumulation and hyperlipemia, baboons were pair-fed liquid diets containing 50% of energy either as ethanol or as additional carbohydrate (controls) for 1 to 7 years. Alcohol consumption produced triacylglycerol accumulation in the liver, hypertriacylglyceridemia, and various degrees of liver injury, including cirrhosis. At the early stages of fatty liver (with or without perivenular fibrosis), there was increased activity of microsomal diacylglycerol acyltransferase and of both microsomal and cytosolic phosphatidate phosphohydrolase, with no changes in glycerol-3-phosphate acyltransferase. With progression of the liver injury and development of septal fibrosis and/or cirrhosis, the rate of hepatic triacylglycerol accumulation and the magnitude of the hyperlipemia decreased, despite continuous ethanol intake. These changes were associated with disappearance of the increases in microsomal diacylglycerol acyltransferase and cytosolic phosphatidate phosphohydrolase activities, whereas those of microsomal phosphatidate phosphohydrolase remained elevated and glycerol-3-phosphate acyltransferase was unaffected. Thus, changes in the activity of two enzymes of the triacylglycerol-synthesizing pathway, namely the microsomal diacylglycerol acyltransferase and the cytosolic phosphatidate phosphohydrolase, may contribute to the differences in the rate of hepatic triacylglycerol accumulation and the degree of hyperlipemia during progression of the alcoholic liver damage.

Acyltransferases↗
PubMed1984

Ethanol potentiates squamous metaplasia of the rat trachea caused by vitamin A deficiency.

The effect of ethanol consumption on the development of squamous metaplasia of the trachea caused by vitamin A deficiency was studied in rats fed for 8-14 weeks with either normal vitamin A-containing diets or diets lacking vitamin A. Littermates were pair-fed the same diets with carbohydrates (36% of energy) replaced by ethanol. In rats fed the normal vitamin A diet with or without ethanol the tracheal mucosa was lined by a pseudostratified ciliated columnar epithelium; no squamous metaplasia was observed. Serum vitamin A was normal in both groups. Squamous metaplasia was noted in 4 of 7 rats fed the vitamin A-free diet and in 6 of 7 animals fed the vitamin A-free diet plus ethanol; the lesions were present in 48 and 68% of all the sections, respectively. Furthermore, the most severe lesions were seen only in the vitamin A-free diet plus ethanol group. Serum vitamin A was low in both groups. Ethanol consumption also results in lysosomal and ciliary abnormalities in the ciliated cells of the tracheal epithelia that were not as yet involved in the formation of squamous metaplasia. Thus, these synergistic effects of vitamin A deficiency and ethanol could contribute to the enhanced incidence of respiratory cancer seen in the alcoholic.

Animals↗
PubMed1984

Alcoholic liver injury in baboons: transformation of lipocytes to transitional cells.

Ultrastructure of the lipocytes (the main perisinusoidal cells) and their alterations in the progression of hepatic fibrosis were studied in liver biopsy specimens of baboons pair-fed with diets containing alcohol, or isocaloric carbohydrate, for up to 112 mo. In control baboons, 97% of the cells in the Disse space were lipocytes characterized by a volume density of lipid droplets occupying greater than 20% of the cell volume and by the presence of microfilament bundles with associated dense bodies and pinocytic vesicles. Intercellular junctions of the adherens type were present between lipocytes and hepatocytes. After alcohol consumption, the number of lipocytes (as assessed by light microscopy) was significantly decreased in fatty livers and at various stages of hepatic fibrosis; this was associated with a decreased hepatic vitamin A content. In baboons fed alcohol, only 48% of cells were lipocytes, whereas 52% were transitional cells defined by a volume of lipid droplets less than 20% of the cell. Like the lipocytes, transitional cells exhibited microfilament bundles, dense bodies, and pinocytic vesicles, and were attached to the hepatocytes by cell junctions. The rough endoplasmic reticulum in transitional cells was conspicuous and had an area significantly greater than that in lipocytes of controls and alcohol-fed animals (69% and 37%, respectively). There was a significant correlation between the percentage of transitional cells as well as the area of their rough endoplasmic reticulum and the degree of hepatic fibrosis. Thus, in baboons fed alcohol, the progression of hepatic fibrosis is associated with transformation of lipocytes to transitional cells characterized by a depletion of lipid droplets and a hypertrophy of the rough endoplasmic reticulum; these transitional cells may play a role in promoting hepatic fibrosis in alcoholic liver injury.

Adipose Tissue↗
PubMed1984

Reevaluation of the effects of alcohol consumption on rat liver microtubules: effects of feeding status.

The ability of total, free and microtubule-derived tubulins to bind colchicine was studied (using 4 different methods) in the liver of 12 male rat littermates pair-fed liquid diets containing 36% of energy either as ethanol or as additional carbohydrate and kept in the fed state up to the time of sacrifice. In the alcohol fed rats, we found a reproducible decrease in microtubule-derived tubulin and in the percentage of total tubulin present in the polymerized form. This was due to an alteration of the microtubular protein rather than to inhibitory factors of the liver supernatants. An equal group of pair-fed rats was tested after a 24-hour fast. Fasting decreased microtubule-derived tubulin and abolished the inhibitory effect of ethanol, probably by decreasing the rate of ethanol oxidation.

Animals↗