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Biomedical subjects

C S Lieber

Publications and source records attributed to C S Lieber.

At least 37 records · Page 2Linked to original sources
PubMed2000

Alcohol and the liver: metabolism of alcohol and its role in hepatic and extrahepatic diseases.

UNLABELLED: Dr. Charles S. Lieber conducted clinical and experimental studies for more than four decades (three at Mount Sinai and the Bronx VA Medical Centers) with emphasis on liver, nutrition and GI pathophysiology. His major contributions include elucidation of the pathogenesis of alcoholic liver disease, by demonstrating the toxic role of alcohol and describing associated metabolic disorders. This was achieved through judicious clinical studies and newly-developed rodent and primate models with the administration of ethanol in liquid diets. The mechanisms of various pathological and metabolic effects of ethanol were clarified, including hyperlipemia (with the rise in HDL), hyperuricemia, the role of acetaldehyde toxicity and alcohol-induced oxidative stress. The latter, including glutathione depletion, was corrected by S-adenosyl-1-methionine given to alcohol-fed baboons; the compound is now being used successfully for the treatment of patients with alcoholic liver disease in Europe. Alcoholic cirrhosis was produced for the first time in nonhuman primates and shown to be fully prevented by polyenylphosphatidylcholine, which is now being tested in a multicenter clinical trial. Lieber also discovered a new (microsomal) pathway of ethanol metabolism, responsible for the tolerance to ethanol and for several clinically important toxic interactions with other drugs (e.g., acetaminophen), anesthetics, industrial solvents, carcinogens, as well as retinol and b-carotene, with narrowing of their therapeutic window. His work defined the role of the stomach in ethanol metabolism, description of corresponding gender differences, cloning (for the first time) of the gene for sigma ADH (a newly-recognized gastric alcohol dehydrogenase isozyme) with its chromosomal localization, and the discovery of the effects of commonly used medications (e.g., H2 blockers and aspirin) on the activities of the enzyme and on blood alcohol levels in social drinkers. Lieber was among the first to use antibiotics for the elimination of gastric bacterial urease and its ammonia production in man, thereby alleviating chronic gastritis and hypoacidity, with attenuation of hepatic encephalopathy in cirrhotics. He promoted early detection and treatment of heavy drinkers before their social or medical disintegration, by defining precirrhotic lesions and markers of alcohol consumption. CONCLUSIONS: The research of Dr. Lieber and his group yielded a better understanding of the pathogenesis of common hepatic, gastric and nutritional disorders, with elucidation and prevention of serious toxic alcohol-drug interactions and the development of methods for early recognition and more effective approaches to prevent and treat liver and gastrointestinal diseases.

Animals↗
PubMed2000

Polyenylphosphatidylcholine protects against alcohol but not iron-induced oxidative stress in the liver.

BACKGROUND: We reported before that, in baboons, the alcohol-induced oxidative stress in the liver is associated with depletion of dilinoleoylphosphatidylcholine [the major component of polyenylphosphatidylcholine (PPC)] and that both can be corrected by the administration of PPC, but we did not determine whether this protection extended to iron-induced oxidative stress. METHODS: To compare the effects of PPC on alcohol- and iron-induced hepatic oxidative stress, 56 Sprague Dawley male rats were pair-fed nutritionally adequate liquid diets containing ethanol (36% of energy) or isocaloric carbohydrate and PPC (3 mg/ml) or safflower oil (2.73 mg/ml), with or without 5 mg/ml carbonyl iron for 2 months. Markers of oxidative stress (4-hydroxynonenal and reduced glutathione), antioxidants (vitamin E, ubiquinol-9, and ubiquinol-10), and phosphatidylcholine (PC) species were assessed by HPLC and/or gas chromatography/mass spectrometry. RESULTS: Alcohol feeding increased hepatic 4-hydroxynonenal 3-fold and decreased glutathione by 19%, ubiquinol-10 by 53%, and PC species containing arachidonate (palmitoyl- and stearoylarachidonoylphosphatidylcholines by 24% and 21%, respectively) and total phospholipids by 14%. PPC feeding prevented the rise of 4-hydroxynonenal, restored glutathione, and increased the hepatic content of dilinoleoylphosphatidylcholine and of some other PC carrying polyunsaturated fatty acids. Administration of iron alone increased hepatic iron, doubled 4-hydroxynonenal and glutathione, whereas it decreased vitamin E, ubiquinol-9, total phospholipids, and several polyunsaturated PC. Alcohol given with iron further exacerbated the hepatic oxidative stress, as documented by the increase of 4-hydroxynonenal and the decrease in glutathione and ubiquinols-10. PPC did not prevent this oxidative stress, although it increased hepatic glutathione. Hepatic dilinoleoylphosphatidylcholine content was comparable with and without dietary iron. CONCLUSIONS: PPC prevents the alcohol-induced oxidative stress but only in the absence of iron overload.

Animals↗
PubMed2000

Attenuation of alcohol-induced apoptosis of hepatocytes in rat livers by polyenylphosphatidylcholine (PPC).

BACKGROUND: Alcohol consumption increases apoptosis of hepatocytes. This effect appears to be mediated by the induction of hepatic cytochrome P-4502E1(CYP2E1) and its generation of free radicals, which results in an enhanced lipid peroxidation that initiates apoptosis. Because polyenylphosphatidylcholine (PPC), a soybean extract rich in polyunsaturated phosphatidylcholines, decreases the induction of ethanol-specific CYP2E1 and opposes oxidative stress, we hypothesized that PPC supplementation may attenuate hepatocyte apoptosis caused by ethanol ingestion. METHODS: Twenty-eight male Sprague Dawley rats were pair-fed Lieber-DeCarli liquid diets containing 36% of energy as alcohol or an isocaloric amount of carbohydrate for 28 days. Half of the rats were given PPC (3 g/liter), whereas the other half received the same amount of linoleate (as safflower oil) and of choline as the bitartrate. An additional dose of alcohol (3 g/kg) was given intragastrically 90 min before the livers were removed. We assessed apoptosis in formalin-fixed, paraffin-embedded liver sections by using the TUNEL (terminal transferase dUTP nick end labeling) assay. Apoptotic hepatocytes were identified by positive TUNEL staining in conjunction with condensation of nucleoplasm or margination of chromatin. In each rat, 20,000 to 60,000 hepatocytes were counted by light microscopy by using Image-Pro Plus computer software, and the incidence of apoptosis was expressed as the percentage of total hepatocytes. RESULTS: Alcohol feeding resulted in a 4.5-fold increase in apoptosis of hepatocytes compared to pair-fed control rats; PPC supplementation decreased the alcohol-induced apoptosis to less than half. No difference in the incidence of apoptosis between the control and PPC-supplemented rats was found in the absence of alcohol. Apoptosis was distributed randomly in the liver lobules of the rats fed the control diet, whereas the alcohol-induced apoptosis was significantly increased in the perivenular area. PPC supplementation strikingly reduced this effect. CONCLUSIONS: PPC attenuates alcohol-induced apoptosis of hepatocytes; this effect may provide a mechanism for PPC's protection against liver injury, possibly in association with its antioxidative action via the down-regulation of ethanol-mediated CYP2E1 induction.

Animals↗
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

Dilinoleoylphosphatidylcholine selectively modulates lipopolysaccharide-induced Kupffer cell activation.

Polyenylphosphatidylcholine (PPC), a mixture of polyunsaturated phosphatidylcholines extracted from soybeans, protects against alcoholic and non-alcoholic liver injury. Because Kupffer cells mediate liver injury, we hypothesized that PPC may modulate their activation. The activation of Kupffer cells by lipopolysaccharide (LPS) leads to an enhanced production of cytokines. Among these, tumor necrosis factor-alpha(TNF-alpha) exerts mainly a hepatotoxic effect, whereas interleukin-1beta (IL-1beta) appears to be hepatoprotective. The present study evaluated whether dilinoleoylphosphatidylcholine (DLPC), the main component of PPC (40% to 52%), affects LPS-induced Kupffer cell activation in vitro. For comparison, palmitoyl-linoleoylphosphatidylcholine (PLPC), the other major component of PPC (23% to 24%), and distearoylphosphatidylcholine (DSPC), the saturated counterpart of DLPC, were also tested. Rat Kupffer cells were cultured in serum-free RPMI-1640 medium containing 10 micromol/L of either DLPC, PLPC, or DSPC in the presence or absence of LPS (1 microg/mL). After 20 hours in culture, the media were collected for cytokine measurements by enzyme-linked immunosorbent assays. LPS significantly stimulated TNF-alpha and IL-1beta production by 62% and 328%, respectively. Treatment of Kupffer cells with LPS plus DLPC decreased the production of TNF-alpha by 23% (12.17+/-1.83 pg/ng DNA vs 15.72 +/-2.74 pg/ng DNA, P < .05, n = 6) and increased that of IL-1beta by 17% (1.80 +/- 0.16 pg/ng DNA vs 1.54 +/- 0.08 pg/ng DNA, P< .05, n = 6). No effect of PLPC or DSPC on LPS-induced TNF-alpha or IL-1beta generation was observed, thereby illustrating the selective effect of DLPC in this process. Thus DLPC selectively modulates the LPS-induced activation of Kupffer cells by decreasing the production of the cytotoxic TNF-alpha while increasing that of the protective IL-1beta. This dual action of DLPC on cytokines may provide a mechanism for the protective effect against liver injury, but its significance still needs to be determined by in vivo studies.

Animals↗
PubMed1999

Carbohydrate deficient transferrin in alcoholic liver disease: mechanisms and clinical implications.

Carbohydrate-deficient transferrin (CDT) is now considered to be the most sensitive and specific biological marker of alcohol abuse. The mechanism by which chronic alcohol consumption causes an elevation of CDT levels in serum is discussed. The sensitivity and specificity of various test procedures are compared, with special emphasis on the impact of liver disease. Clinical applications are reviewed, including the utility of CDT as a marker of relapse in alcoholic patients, and the use of CDT for the systematic screening of drinking in vulnerable populations as part of a public health approach to alcoholism.

Alcoholism↗
PubMed1999

Alcohol-induced pancreatic oxidative stress: protection by phospholipid repletion.

Oxidative stress is considered to be a forerunner of pancreatitis. Since we had found polyenylphosphatidylcholine, a mixture of polyunsaturated phosphatidylcholines extracted from soybeans, to protect against hepatic oxidative stress, we now tested its effects on the pancreas. Sprague-Dawley rats were pair-fed for two months nutritionally adequate liquid diet containing ethanol (36% of energy) or isocaloric carbohydrate, with either polyenylphosphatidylcholine (3 g/1000 kcal) or safflower oil, with or without 5 g/1000 kcal carbonyl iron. Parameters of oxidative stress (F2-isoprostanes, 4-hydroxynonenal, reduced glutathione), ubiquinol-10, ubiquinol-9 and vitamin E, as well as phosphatidylcholine species, were assessed by GC/MS and/or HPLC. Alcohol feeding increased pancreatic 4-hydroxynonenal three-fold, F2-isoprostanes and ubiquinol-9 by more than 70%, whereas it decreased total phospholipids, several phosphatidylcholine species, ubiquinol-10 and glutathione, especially in iron fed rats. Polyenylphosphatidylcholine prevented the rise in 4-hydroxynonenal and F2-isoprostanes, the decrease in dilinoleoylphosphatidylcholine and oleoyllinoleoylphosphatidylcholine and opposed the alcohol-induced decrease of glutathione; alpha-tocopherol remained unchanged. Iron had no significant effect except for decreasing ubiquinol-10 in the pancreas and increasing aminotransferases in the plasma. Thus, the alcohol-induced oxidative stress in the pancreas was shown to be prevented by polyenylphosphatidylcholine which may act, in part, by correcting the depletion of several phosphatidylcholine species.

Alcoholism↗
PubMed1999

Alcohol, vitamin A, and beta-carotene: adverse interactions, including hepatotoxicity and carcinogenicity.

Isozymes of alcohol and other dehydrogenases convert ethanol and retinol to their corresponding aldehydes in vitro. In addition, new pathways of retinol metabolism have been described in hepatic microsomes that involve, in part, cytochrome P450s, which can also metabolize various drugs. In view of these overlapping metabolic pathways, it is not surprising that multiple interactions between retinol, ethanol, and other drugs occur. Accordingly, prolonged use of alcohol, drugs, or both, results not only in decreased dietary intake of retinoids and carotenoids, but also accelerates the breakdown of retinol through cross-induction of degradative enzymes. There is also competition between ethanol and retinoic acid precursors. Depletion ensues, with associated hepatic and extrahepatic pathology, including carcinogenesis and contribution to fetal defects. Correction of deficiency through vitamin A supplementation has been advocated. It is, however, complicated by the intrinsic hepatotoxicity of retinol, which is potentiated by concomitant alcohol consumption. By contrast, beta-carotene, a precursor of vitamin A, was considered innocuous until recently, when it was found to also interact with ethanol, which interferes with its conversion to retinol. Furthermore, the combination of beta-carotene with ethanol results in hepatotoxicity. Moreover, in smokers who also consume alcohol, beta-carotene supplementation promotes pulmonary cancer and, possibly, cardiovascular complications. Experimentally, beta-carotene toxicity was exacerbated when administered as part of beadlets. Thus ethanol, while promoting a deficiency of vitamin A also enhances its toxicity as well as that of beta-carotene. This narrowing of the therapeutic window for retinol and beta-carotene must be taken into account when formulating treatments aimed at correcting vitamin A deficiency, especially in drinking populations.

Animals↗
PubMed1999

Polyenylphosphatidylcholine opposes the increase of cytochrome P-4502E1 by ethanol and corrects its iron-induced decrease.

Dietary iron overload damages membrane phospholipids and decreases microsomal cytochromes P-450. We wondered whether this might also pertain to cytochrome P-4502E1 (2E1) and whether polyenylphosphatidylcholine (PPC), a 94-96% pure mixture of linoleate-rich polyunsaturated phosphatidylcholines that protects against alcohol-induced liver injury, also affects 2E1, either in the presence or absence of iron. Accordingly, rats were fed for 8 weeks our standard liquid diet containing ethanol (36% of energy) or isocaloric carbohydrates, with either PPC (3 g/1000 Cal) or equivalent amounts of linoleate (as safflower oil). 2E1 was assessed by Western blots and by two of its characteristic enzyme activities: the microsomal ethanol oxidizing system (MEOS), evaluated by the conversion of ethanol to acetaldehyde (determined by head space GC), and p-nitrophenolhydroxylase (PNP) activity, measured by HPLC with UV detection of 4-nitrocatechol. With ethanol (36% of energy) replacing carbohydrates, 2E1 content increased 10-fold, with a corresponding increase in PNP and MEOS activities, but when carbonyl iron (5 g/1000 Cal) was added, the induction was significantly reduced. This iron-induced decrease was corrected by PPC. PPC is rich in linoleate, but when the latter was given as triglycerides (safflower oil), there was no effect, whereas hepatic nonheme iron content was the same in both these groups. It also was found that in the absence of iron, the ethanol-mediated induction of 2E1 and its corresponding enzyme activities were significantly less with PPC (< 0.001) than with safflower oil. In addition, in alcohol-fed animals, PPC decreased the oxidative stress (as determined by F2-isoprostanes), which reflects yet another hepatoprotective effect of PPC.

Animals↗