ALCOHOL: its metabolism and interaction with nutrients.

In the past, alcoholic liver disease was attributed exclusively to dietary deficiencies, but experimental and judicious clinical studies have now established alcohol's hepatotoxicity. Despite an adequate diet, it can contribute to the entire spectrum of liver diseases, mainly by generating oxidative stress through its microsomal metabolism via cytochrome P4502E1 (CYP2E1). It also interferes with nutrient activation, resulting in changes in nutritional requirements.

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.

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).

Blood group antigen expression in the rat colon II. Modulation by dietary ethanol consumption.

In the accompanying article, we established that in the rat distal colon expression of H, B, and Le(b) blood group antigens by goblet cells is phenotypically fetal in nature. Because of the cocarcinogenic property of ethanol, the present study examined the effects of dietary ethanol consumption, fasting, and withdrawal on the expression of these antigens in the adult rat colon. To that effect, male adult Sprague-Dawley rats were pair-fed ethanol-containing or control Lieber-DeCarli liquid diets for 3 weeks.

Blood group antigen expression in the rat colon I. age-dependent and region-related changes.

The blood group antigens H, A, B, and Le(b) are oncofetal antigens of the human distal colon. Although these antigens are present in the digestive mucosa of the rat, little is known about their ontogenic expression in the developing rat colon. The present study was undertaken to assess age-dependent and region-related changes of blood group antigens during colonic development and maturation with the aim of determining their fetal phenotype.

Alcoholic liver disease: new insights in pathogenesis lead to new treatments.

Much progress has been made in the understanding of the pathogenesis of alcoholic liver disease, resulting in improvement of prevention and therapy, with promising prospects for even more effective treatments. The most successful approaches that one can expect to evolve are those that deal with the fundamental cellular disturbances resulting from excessive alcohol consumption. Two pathologic concepts are emerging as particularly useful therapeutically.

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.

Alcohol levels are increased in social drinkers receiving ranitidine.

Objective: Ranitidine increases blood alcohol concentrations by decreasing the first pass metabolism of ethanol. The effect of ranitidine on alcohol levels has been found to be variable when using large doses of alcohol or conditions in which its first pass metabolism is known to be minimal. Despite a consensus that the drug increases alcohol levels after small doses of ethanol, this effect has been considered inconsequential, because of the low alcohol levels.

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.

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.

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.

Microsomal ethanol-oxidizing system (MEOS): the first 30 years (1968-1998)--a review.

Oxidation of ethanol via alcohol dehydrogenase (ADH) explains various metabolic effects of ethanol but does not account for the tolerance and a number of associated disorders that develop in the alcoholic. These were elucidated by the discovery of the microsomal metabolism of ethanol. The physiologic role of this system comprises gluconeogenesis from ketones, fatty acid metabolism, and detoxification of xenobiotics, including ethanol.

Prevention and treatment of liver fibrosis based on pathogenesis.

Multiple agents have been proposed for the prevention and treatment of fibrosis. S-adenosylmethionine was reported to oppose CCl4-induced fibrosis in the rat, to attenuate the consequences of the ethanol-induced oxidative stress, and to decrease mortality in cirrhotics. Anti-inflammatory medications and agents that interfere with collagen synthesis, such as inhibitors of prolyl-4-hydroxylase and antioxidants, are also being tested.

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

Alcohol taken in moderation may prevent atherosclerosis, whereas heavy drinking has the opposite effect, in part by promoting oxidation of low density lipoproteins (LDL), a pathogenetic factor in atherogenesis. We assess here: 1 ) whether similar alterations can be reproduced in baboons fed 50% of energy as ethanol (the average intake of alcoholics) for 7- 8 years, and 2 ) whether such alterations are affected by supplementation with polyenylphosphatidylcholine (PPC), a mixture of polyunsaturated phosphatidylcholines, shown to prevent alcoholic fatty liver, fibrosis, and cirrhosis. Ten animals were given the ethanol-containing diet and ten were pair-fed isocaloric control diets.

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.

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.

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.

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).

Respective roles of human cytochrome P-4502E1, 1A2, and 3A4 in the hepatic microsomal ethanol oxidizing system.

The microsomal ethanol oxidizing system comprises an ethanol-inducible cytochrome P-4502E1, but the involvement of other P-450s has also been suggested. In our study, human CYP2E1, CYP1A2, and CYP3A4 were heterologously expressed in HepG2 cells, and their ethanol oxidation was assessed using a corresponding selective inhibitor: all three P-450 isoenzymes metabolized ethanol. Selective inhibitors-4-methylpyrazole (CYP2E1), furafylline (CYP1A2), and troleandomycin (CYP3A4)-also decreased microsomal ethanol oxidation in the livers of 18 organ donors.

Chlorzoxazone pharmacokinetics as a marker of hepatic cytochrome P4502E1 in humans.

Objective: Previous in vitro studies have demonstrated that hepatic P4502E1 metabolizes chlorzoxazone (CZX, a commonly used muscle relaxant) to 6-hydroxychlorzoxazone (6-OH-CZX). We thus assessed whether measurement of the plasma 6-OH-CZX/CZX ratio after a CZX challenge could serve as a marker of hepatic P4502E1 content.

Methods: Three subject groups were included: recently drinking alcoholics (N = 6), abstinent alcoholics (N = 5), and nonalcoholic subjects with liver disease (N = 5) undergoing liver biopsy.

Gastritis in the alcoholic: relationship to gastric alcohol metabolism and Helicobacter pylori.

Chronic gastritis is common in the alcoholic. It is characterized by histological inflammation of the gastric mucosa and is associated with variable symptomatology. Its etiology is still the subject of debate.

Microsomal acetaldehyde oxidation is negligible in the presence of ethanol.

The microsomal ethanol oxidizing system (MEOS), inducible by ethanol and acetone, oxidizes ethanol to acetaldehyde, which causes many toxic effects associated with excess ethanol. Recent studies reported that rat liver microsomes also oxidize acetaldehyde, thereby challenging the validity of the assessment of MEOS activity by measuring acetaldehyde production and suggesting that MEOS activity results in the accumulation not of acetaldehyde but, rather, of its less toxic metabolite, acetate. To address these issues, we compared both metabolic rates of ethanol and acetaldehyde and the effect of ethanol on the acetaldehyde metabolism.

Analysis of risk factors for chronic hepatic encephalopathy: the role of Helicobacter pylori infection.

Objective: Elevated blood ammonia is an important pathogenic factor of hepatic encephalopathy. Although colonic bacteria are considered the main source of ammonia, the stomach in subjects with urease-producing Helicobacter pylori (H. pylori) is an alternative site.

Inducibility of cytochromes P-4502E1 and P-4501A1 in the rat pancreas.

Cytochrome P-450 (CYP) isoenzymes have been incriminated in the toxicity and carcinogenicity of various xenobiotics in different tissues, but prior measurements of their activity in pancreatic microsomes have been disappointing. We now applied new isolation methods and a highly sensitive procedure to assay for the metabolism of p-nitrophenol and 7-ethoxyresorufin, specific substrates for CYP2E1 (2E1) and CYP1A1 (1A1), respectively. 2E1 and 1A1 content was estimated with high-resolution chemiluminescent Western blots using recombinant 2E1 and 1A1 as standards.