Biomedical subjects

C S Lieber

Publications and source records attributed to C S Lieber.

At least 73 records · Page 4Linked to original sources

PubMed1997

Polyenylphosphatidylcholine prevents carbon tetrachloride-induced lipid peroxidation while it attenuates liver fibrosis.

BACKGROUND/AIMS: Polyenylphosphatidylcholine protects against alcoholic cirrhosis in the baboon and carbon tetrachloride-induced cirrhosis in rats. This study addresses the possible mechanism of the protective effect of polyenylphosphatidylcholine. METHODS: For 8 weeks, rats were injected with either carbon tetrachloride in peanut oil or peanut oil alone (control), and pair-fed nutritionally adequate liquid diets with equivalent amounts of linoleic acid either as polyenylphosphatidylcholine or as safflower oil. Other rats were injected for 9 weeks with heterologous albumin and fed the same liquid diets. Lipid peroxidation was measured by F2-isoprostanes and 4-hydroxynonenal. RESULTS: Carbon tetrachloride-induced lipid peroxidation was strikingly attenuated with polyenylphosphatidylcholine supplementation. Levels of hepatic F2-isoprostanes and 4-hydroxynonenal paralleled liver fibrotic scores and collagen accumulation. Polyenylphosphatidylcholine also attenuated the fibrosis induced in rats with human albumin, but in this case, levels of hepatic 4-hydroxynonenal did not change, nor were they significantly affected by polyenylphos-phatidylcholine. Neither carbon tetrachloride injection nor polyenylphosphatidylcholine treatment changed the arachidonic acid content (a major precursor of F2-isoprostanes and 4-hydroxynonenal) in liver phospholipids, and hepatic vitamin E was not significantly altered. CONCLUSIONS: The hepatic protection of polyenylphosphatidylcholine against carbon tetrachloride appears to be due, at least in part, to an antioxidant effect, whereas the protection against heterologous albumin-induced fibrosis suggests that an additional mechanism, such as stimulation of collagenase activity, may also be responsible.

Analysis of Variance↗

PubMed1997

Role of oxidative stress and antioxidant therapy in alcoholic and nonalcoholic liver diseases.

The main pathway for the hepatic oxidation of ethanol to acetaldehyde proceeds via ADH and is associated with the reduction of NAD to NADH; the latter produces a striking redox change with various associated metabolic disorders. NADH also inhibits xanthine dehydrogenase activity, resulting in a shift of purine oxidation to xanthine oxidase, thereby promoting the generation of oxygen-free radical species. NADH also supports microsomal oxidations, including that of ethanol, in part via transhydrogenation to NADPH. In addition to the classic alcohol dehydrogenase pathway, ethanol can also be reduced by an accessory but inducible microsomal ethanoloxidizing system. This induction is associated with proliferation of the endoplasmic reticulum, both in experimental animals and in humans, and is accompanied by increased oxidation of NADPH with resulting H2O2 generation. There is also a concomitant 4- to 10-fold induction of cytochrome P4502E1 (2E1) both in rats and in humans, with hepatic perivenular preponderance. This 2E1 induction contributes to the well-known lipid peroxidation associated with alcoholic liver injury, as demonstrated by increased rates of superoxide radical production and lipid peroxidation correlating with the amount of 2E1 in liver microsomal preparations and the inhibition of lipid peroxidation in liver microsomes by antibodies against 2E1 in control and ethanol-fed rats. Indeed, 2E1 is rather "leaky" and its operation results in a significant release of free radicals. In addition, induction of this microsomal system results in enhanced acetaldehyde production, which in turn impairs defense systems against oxidative stress. For instance, it decreases GSH by various mechanisms, including binding to cysteine or by provoking its leakage out of the mitochondria and of the cell. Hepatic GSH depletion after chronic alcohol consumption was shown both in experimental animals and in humans. Alcohol-induced increased GSH turnover was demonstrated indirectly by a rise in alpha-amino-n-butyric acid in rats and baboons and in volunteers given alcohol. The ultimate precursor of cysteine (one of the three amino acids of GSH) is methionine. Methionine, however, must be first activated to S-adenosylmethionine by an enzyme which is depressed by alcoholic liver disease. This block can be bypassed by SAMe administration which restores hepatic SAMe levels and attenuates parameters of ethanol-induced liver injury significantly such as the increase in circulating transaminases, mitochondrial lesions, and leakage of mitochondrial enzymes (e.g., glutamic dehydrogenase) into the bloodstream. SAMe also contributes to the methylation of phosphatidylethanolamine to phosphatidylcholine. The methyltransferase involved is strikingly depressed by alcohol consumption, but this can be corrected, and hepatic phosphatidylcholine levels restored, by the administration of a mixture of polyunsaturated phospholipids (polyenylphosphatidylcholine). In addition, PPC provided total protection against alcohol-induced septal fibrosis and cirrhosis in the baboon and it abolished an associated twofold rise in hepatic F2-isoprostanes, a product of lipid peroxidation. A similar effect was observed in rats given CCl4. Thus, PPC prevented CCl4- and alcohol-induced lipid peroxidation in rats and baboons, respectively, while it attenuated the associated liver injury. Similar studies are ongoing in humans.

Acetaldehyde↗

PubMed1997

beta-Carotene beadlets potentiate hepatotoxicity of alcohol.

Administration of beta-carotene in beadlets to baboons potentiates alcohol-induced liver injury. To determine whether this also occurs in other species, and whether the beadlet carrier itself contributes to the toxicity, rats were given for 2 mo vitamin A (1.4 U/J), beta-carotene (4.8, 12.0, and 24.0 U/J, with or without beadlets), or corresponding amounts of beadlets without beta-carotene, in diets containing either carbohydrates or equivalent amounts of ethanol. Isoenergetic substitution of ethanol (36% of total energy) for carbohydrates reduced hepatic vitamin A by 80%, and such a depletion was also observed with beta-carotene as vitamin A precursor. By contrast, ethanol raised hepatic beta-carotene, which was further increased by beadlets. Thus, whereas alcohol promoted hepatic depletion of vitamin A, it had the opposite effect on beta-carotene. Ethanol seems to affect the homeostasis of beta-carotene. Furthermore, the ethanol-induced oxidative stress, assessed by an increase in hepatic 4-hydroxynonenal and F2-isoprostanes (measured by gas chromatography-mass spectrometry), was not improved despite a concomitant rise in hepatic antioxidants (beta-carotene and vitamin E). Moreover, beadlets resulted in proliferation of the smooth endoplasmic reticulum and in leakage of the mitochondrial glutamate dehydrogenase into the plasma, reflecting mitochondrial injury (both documented by electron microscopy). Thus, in rats given ethanol, beta-carotene is not an efficient vitamin A precursor. Its bioavailability was improved by beadlets, but the ethanol-induced oxidative stress was not attenuated and there was associated hepatotoxicity that now needs to be assessed in humans.

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

Gastric ethanol metabolism and gastritis: interactions with other drugs, Helicobacter pylori, and antibiotic therapy (1957-1997)--a review.

The stomach provides some protection against the penetration of ethanol into the body by contributing to the metabolism of ethanol. The latter is attenuated by various drugs and, although the magnitude of this effect is still the subject of debate, patients should be warned of the corresponding possible increase in blood alcohol levels. Furthermore, oxidation of ethanol generates acetaldehyde, a toxic metabolite. In addition, chronic alcohol abuse seems to favor colonization by Helicobacter pylori, which produces ammonia that also contributes to the commonly associated chronic gastritis. Because antibiotics were shown over the last 4 decades to effectively eliminate gastric ammonia, they should be considered for the routine treatment of such chronic gastritis in the way they are now being used for ulcer therapy.

Alcohol Dehydrogenase↗

PubMed1997

Cytochrome P-4502E1: its physiological and pathological role.

The role of the microsomal ethanol-oxidizing system (MEOS) in hepatic ethanol metabolism is reviewed, with focus on its constitutive, ethanol-inducible cytochrome P-4502E1 (2E1). The MEOS was purified and reconstituted using 2E1, phospholipids, and cytochrome P-450 reductase and shown to oxidize ethanol to acetaldehyde, mainly as a monooxygenase and secondarily via hydroxyl radicals, with transcriptional and posttranscriptional regulation. Polymorphism of 2E1 was recognized, and enzymology (including cofactors, role of lipids, inducers, and inhibitors) as well as cellular and tissue distribution were chartered. Physiological functions involve lipid metabolism and ketone utilization in starvation, obesity, and diabetes. The most significant role of 2E1 is its adaptive response to high blood ethanol levels with a corresponding acceleration of ethanol metabolism. The associated free radical production, however, contributes to liver injury in the alcoholic. Most importantly, 2E1 has a unique capacity to activate many xenobiotics (85 of which are listed) to hepatotoxic or carcinogenic products. Induction of 2E1 also results in enhanced production of acetaldehyde, a highly reactive and toxic metabolite. The proliferation of the endoplasmic reticulum associated with 2E1 induction is also accompanied by enhanced activity of other cytochrome P-450s, resulting in accelerated metabolism of, and tolerance to, other drugs, as well as increased degradation of retinol and its hepatic depletion. Some substrates and metabolites, however, are innocuous and may eventually be used as markers of heavy drinking. Recently discovered effective 2E1 inhibitors also have great therapeutic potential.

Animals↗

PubMed1997

Gastritis and Helicobacter pylori: forty years of antibiotic therapy.

Helicobacter pylori has now been propelled into the forefront of gastroenterology, particularly the treatment of gastroduodenal ulcer, whereas its role in gastritis is still widely ignored, although this disease sparked much of the original observations. Forty years ago, it was shown for the first time that antibiotics can eliminate gastric ammonia production in man which suggested that this was due to eradication of bacterial urease activity. It was also found that the gastric juice ammonia concentration correlates with hypo- or anacidity in uremics and with mucosal inflammation in subjects with gastritis. In patients with nonalcoholic and alcoholic gastritis, the histology as well as the symptoms of gastritis were strikingly improved by antibiotic treatment. Beneficial effects of eradication of gastric urease activity and the resulting decreased ammonia production were also shown in patients with hepatic encephalopathy. Broader studies and clinical applications of these earlier findings are now warranted.

Ammonia↗

PubMed1997

Polyenylphosphatidylcholine decreases alcohol-induced oxidative stress in the baboon.

Diets supplemented with polyunsaturated fatty acids or triglycerides exacerbate alcohol-induced liver injury in rats, whereas, in baboons, polyenylphosphatidylcholine (PPC) protects against alcohol-induced fibrosis and cirrhosis. Because the aggravation in rats was attributed to enhanced lipid peroxidation, the present study was undertaken to assess parameters of oxidative stress in percutaneous liver biopsies of baboons fed alcohol, with or without PPC (2.8 g per 1000 calories). F2-isoprostanes and 4-hydroxynonenal, breakdown products of lipid peroxidation, were determined by gas chromatography/mass spectrometry, and alpha-tocopherol was measured by HPLC with electrochemical detection. Hepatic 4-hydroxynonenal was significantly increased in animals fed alcohol, but this was fully prevented by PPC. F2-isoprostanes were also significantly lower after PPC and ethanol than after ethanol alone, and the alcohol-induced glutathione decrease was attenuated. All of these parameters were normal in the animals withdrawn from alcohol, even with persistence of significant liver disease. Because peroxidation products are fibrogenic, their decrease could contribute to the antifibrogenic property of the phospholipids. In conclusion, PPC significantly attenuates ethanol-induced oxidative stress, which may explain, at least in part, its protective effect against alcoholic liver injury.

Alcoholism↗

PubMed1997

Gastric juice urease activity as a diagnostic test for Helicobacter pylori infection.

OBJECTIVE: An ideal assay (inexpensive, sensitive, specific, and readily available) for Helicobacter pylori is lacking. Urease activity is an important characteristic of the organism and is employed in the rapid urease and urea breath tests. In this study, we assessed whether a simpler test, namely, measurement of gastric juice urease activity, would provide comparable results. METHODS: Gastric juice was analyzed for urea and ammonia in 57 patients evaluated with rapid urease test and histology. Urease activity was assessed by the fraction of urea hydrolyzed to ammonia. RESULTS: Thirty-five subjects were H. pylori positive and 22 were H. pylori negative. Compared with noninfected subjects, H. pylori-positive patients had lower urea levels (0.52 +/- 0.10 vs. 2.77 +/- 0.48 mM, p < 0.01), higher ammonia concentrations (6.59 +/- 1.06 vs. 1.64 +/- 0.25 mM, p < 0.01), and higher gastric urease activity (0.83 +/- 0.03 vs. 0.24 +/- 0.14, p < 0.01). In H. pylori-negative patients, there was a correlation between blood and gastric urea (r = 0.61, p < 0.01). However, in H. pylori-positive patients, no such relationship existed (r = 0.30, p = 0.11). The ratio of gastric to blood urea was lower in infected patients (0.11 +/- 0.02 vs. 0.45+/- 0.04, p < 0.01). The sensitivity and specificity of gastric urease activity for diagnosis of H. pylori were 91% and 100%, respectively, and for the ratio of gastric to blood urea, 89% and 95%, respectively. CONCLUSION: Gastric juice urease activity is a simple, sensitive, and specific means to detect H. pylori.

Ammonia↗

PubMed1997

Immunohistochemical determination of hepatic cytochrome P-4502E1 in formalin-fixed, paraffin-embedded sections.

Cytochrome P-4502E1 (2E1) is inducible by chronic ethanol consumption that results in enhanced activation of anesthetics and commonly used drugs (such as acetaminophen) to hepatotoxins. Therefore, assessment of hepatic 2E1 is needed in prescribing these drugs for the management of alcoholic patients. Currently, measurement of 2E1 requires either immunohistochemistry on frozen sections or Western blot (WB) analysis of homogenized tissue in excess of that needed for pathology. To obtain a more widely applicable method, we developed a procedure to detect 2E1 by immunohistochemistry in formalin-fixed, paraffin-embedded liver biopsies obtained routinely for diagnosis. Data were collected from rats fed ethanol-containing or control liquid diets for 3 weeks. Immunostaining was performed using anti-human rabbit 2E1 antibody as the primary antibody, and the immunoreaction was detected by the avidin-biotin immunoperoxidase method after treating sections with target unmasking fluid, an antigen retrieval buffer that enhanced the staining of 2E1. In control rats, 2E1 staining was weak and perivenular. After ethanol feeding, it showed a lobular gradient, strongest perivenular and weakest periportal, similar to that seen in frozen sections. The staining intensity was scored as: 0 (no staining) to 3 (strong staining). The zonal staining was scored as follows: 1 = perivenular zonal staining, 2 = midzonal, and 3 = panlobular. With the product of the two scores, a significant difference was found between alcohol-fed and control rats (5.1 +/- 0.3 vs. 0.8 +/- 0.2, p < 0.001). 2E1 assessments by WB were also significantly different for these rat pairs (68.5 +/- 2.1 vs. 7.9 +/- 0.8 arbitrary units/mg protein, p < 0.001), with a parallel increase of immunostaining scores and WB measurement of 2E1 content. This immunohistochemical method was then validated in 14 paraffin-embedded percutaneous human liver biopsy samples. In livers of nonalcoholics, 2E1 staining was seen in the perivenular zone only, whereas in samples of alcoholics, the staining was perivenular to midzonal and sometimes periportal. A significant correlation between the zonal staining scores (rs = 0.67, p < 0.005) or intensity x zonal staining scores (rs = 0.79, p < 0.001) and WB analysis was found. The immunohistochemical assessments of 2E1 expression in formalin-fixed, paraffin-embadded sections from livers of alcoholics was found to correlate with WB analysis, and lobular distribution was consistent with that seen in frozen sections. The proposed method should therefore be useful for the assessment of 2E1 content in paraffin-embedded liver samples, thereby aiding in the management of heavy drinkers.

Adult↗

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↗

PubMed1997

F2-isoprostane and 4-hydroxynonenal excretion in human bile of patients with biliary tract and pancreatic disorders.

OBJECTIVE: To assess parameters of lipid peroxidation in bile of patients with hepatobiliary and pancreatic diseases. METHODS: F2-isoprostanes (F2-IPs) and 4-hydroxynonenal (4-HNE) were measured in bile collected during 31 ERCP procedures using gas chromatography/mass spectrometry. RESULTS: In 11 subjects with normal ERCP (controls), bile contained significant amounts of F2-IPs (188 +/- 27 pg/ml) and 4-HNE (37.5 +/- 8.0 ng/ml). In 10 individuals with bile duct stones, there was a 3-fold increase of F2-IPs (523 +/- 129 pg/ml; p < 0.05) and a 2.5-fold increase of 4-HNE (89.6 +/- 18.0 ng/ml; p < 0.05). In 10 patients with various pancreatic diseases, bile F2-IPs were also enhanced (545 +/- 112 pg/ml; p < 0.01). There was no significant change in alpha-tocopherol, whereas beta-carotene was decreased in biliary tract and pancreatic diseases (p < 0.05). Results of serum liver tests were normal with the exception of bilirubin, which was increased together with alkaline phosphatase. Concentrations of total lipids, phospholipids, and cholesterol did not differ significantly between the three groups. CONCLUSIONS: These data provide the first evidence in humans supporting the role of oxidative stress in the pathogenesis of biliary and pancreatic disease.

Aged↗

PubMed1996

The determination of cytochrome P450 2E1-dependent p-nitrophenol hydroxylation by high-performance liquid chromatography with electrochemical detection.

A highly sensitive, simple assay for the determination of 4-nitrocatechol formed during the P450-dependent hydroxylation of p-nitrophenol has been developed. The assay utilizes high-performance liquid chromatography with electrochemical detection. The procedure consists of enzymatic reaction, quenching with trifluoroacetic acid, precipitation of the protein by centrifugation, and direct injection of supernatant aliquots for analysis on a reverse-phase C18 column. The electrochemical detection makes it possible to detect 0.5 pmol of 4-nitrocatechol injected, 30 times less than previously reported for an ultraviolet detector. The detector response was linear with time and with protein content, down to as little as 1.0 microgram of microsomal protein. The usefulness of the method was demonstrated with hepatic microsomal as well as S-9 fractions from both ethanol-treated and control rats, and the dependency of the reaction on cytochrome P450 2E1 activity was proven by immunoinhibition experiments.

Animals↗

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

Metabolism of alcohol by human gastric cells: relation to first-pass metabolism.

BACKGROUND & AIMS: The bioavailability of orally administered alcohol is incomplete, indicating first-pass metabolism. There is debate regarding the site of first-pass metabolism and specifically whether the stomach has the metabolic capacity to account for first-pass metabolism. The aim of this study was to assess ethanol metabolism by human gastric mucosa cells in primary culture. METHODS: Cells were incubated with [1-14C]ethanol, and the quantity of ethanol oxidized was measured by the production of [1-14C]acetate. RESULTS: Gastric cells cultured from men produced 7.3 +/- 3.5 mumol acetate.10(6) cells-1.h-1, which was more than that generated in cells from women (3.2 +/- 0.6; P < 0.05). Acetate production was inhibited by 4-methylpyrazole (a class I alcohol dehydrogenase [ADH] inhibitor) and by m-nitrobenzaldehyde (a selective substrate for class IV ADH isoenzyme) but not by sodium azide (a catalase inhibitor). Cimetidine (a gastric ADH inhibitor) reduced acetate production by as much as 59%, whereas ranitidine had no significant effect. CONCLUSIONS: Human gastric cells metabolize sufficient alcohol to account for the bulk of first-pass metabolism. At least two isozymes of gastric ADH contribute to this metabolism. Cimetidine, but not ranitidine, inhibits gastric alcohol metabolism in keeping with its inhibition of in vivo first-pass metabolism.

Acetic Acid↗

PubMed1996

Polyenylphosphatidylcholine attenuates non-alcoholic hepatic fibrosis and accelerates its regression.

BACKGROUND/AIMS: Polyenylphosphatidylcholine protects against alcoholic cirrhosis in the baboon. This study assesses whether the antifibrotic effect also pertains to a species other than the baboon and to agents other than alcohol. METHODS: Rats were injected with either CC14 in peanut oil or peanut oil alone, and pair-fed nutritionally adequate liquid diets, with or without polyenylphosphatidylcholine. Other rats were injected with heterologous albumin instead of CC14. To assess whether polyenylphosphatidylcholine is active on established fibrosis, rats were also given CC14 for 8 weeks, and then divided into two groups and pair-fed a diet with or without polyenylphosphatidylcholine. RESULTS: After 8 weeks of CC14, the animals were sacrificed; chromotrope aniline blue and Sirius red stains of liver revealed fibrosis or cirrhosis in animals given CC14 alone, whereas the effect was attenuated in the polyenylphosphatidylcholine-supplemented animals. Hepatic collagen content was decreased by 25 to 32% (p < 0.05) and serum ALT and AST were significantly less increased. The expression of liver collagen type I mRNA was significantly increased in CC14 treated rats and was not significantly affected by polyenylphosphatidylcholine although there was a trend towards a lesser increase polyenylphosphatidylcholine also attenuated liver fibrosis produced by the injection of heterologous albumin. CC14-induced liver fibrosis regressed more rapidly in polyenylphosphatidylcholine-treated animals than controls, both histologically and by measurement of collagen (p < 0.05). CONCLUSIONS: Polyenylphosphatidylcholine (a) attenuates hepatic fibrosis induced by CC14 or human albumin in rats; and (b) accelerates the regression of pre-existing fibrosis.

Animals↗

PubMed1996

Induction of cytochrome P-4502E1 by ethanol in rat Kupffer cells.

Ethanol has been shown to affect several Kupffer cell functions, but the mechanisms underlying these changes are unknown. One possible mediator is cytochrome P-4502E1 (CYP2E1), an ethanol-inducible enzyme that has been associated with toxic effects in the liver, as well as in many extrahepatic organs. To assess whether CYP2E1 can be induced by ethanol in Kupffer cells, male rats pair-fed ethanol-containing or control Lieber-DeCarli diets for 3 weeks were studied. Immunoblotting experiments showed that ethanol-treatment caused a 7-fold increase in CYP2E1 content both in Kupffer cells and hepatocytes. When expressed per milligram of S9 protein, the content of CYP2E1 in Kupffer cells was, however, 10 times lower than in hepatocytes. Immunohistochemical studies revealed that CYP2E1 is located in the endoplasmic reticulum of Kupffer cells in vivo and that it is also present in isolated Kupffer cells. In both Kupffer cells and hepatocytes, ethanol feeding increased the hydroxylation of p-nitrophenol, a relatively specific substrate for CYP2E1, demonstrating that the induced CYP2E1 was catalytically active. This reaction was significantly inhibited by anti-CYP2E1 IgG in both types of cells. Although CYP2E1 may not be the predominant pathway for ethanol metabolism in hepatocytes, it is possibly the major one in Kupffer cells. Thus, the induction of CYP2E1 by ethanol in these cells could cause significant changes in intracellular acetaldehyde concentrations which, together with increased lipid peroxidation, may contribute to the development of alcoholic liver injury.

Acetaldehyde↗