An Experimental Model of Alcohol Feeding and Liver Injury
in the Baboon

Cs, Lieber; Lm, Decarli

doi:10.1159/000459999

Cited by 219 publications

(45 citation statements)

References 20 publications

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“…Specifically, CYP2E1 mRNA levels were strikingly decreased in patients with both hepatocellular and cholestatic forms of cirrhosis (George et al, 1995). Furthermore, it was shown that in baboons that were fed alcohol chronically, MEOS induction was greater in those with simple fatty liver than in those that had progressed to more severe stages of liver disease (Lieber and DeCarli, 1974b). At what level of alcoholic liver disease CYP2E1 P-450 IN HEPATIC AND EXTRA HEPATIC PATHOLOGY induction peaks and when it starts to wane remains to be defined.…”

Section: Role Of Meos and Associated Cytochromesmentioning

confidence: 99%

Microsomal Ethanol‐Oxidizing System (MEOS): The First 30 Years (1968‐1998)–A Review

Lieber

1999

Alcoholism Clin & Exp Res

274

235

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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. After chronic ethanol consumption, the activity of the microsomal ethanol-oxidizing system (MEOS) increases, with an associated rise in cytochromes P-450, especially CYP2E1. This induction is associated with proliferation of the endoplasmic reticulum, both in experimental animals and in humans. The role of MEOS in vivo and its increase after chronic ethanol consumption was shown most conclusively in alcohol dehydrogenase-negative deer mice. Enhanced ethanol oxidation is associated with cross-induction of the metabolism of other drugs, resulting in drug tolerance. Furthermore, there is increased conversion of known hepatotoxic agents (such as CCl4) to toxic metabolites, which may explain the enhanced susceptibility of alcoholics to the adverse effects of industrial solvents. CYP2E1 also has a high capacity to activate some commonly used drugs, such as acetaminophen, to their toxic metabolites, and to promote carcinogenesis (e.g., from dimethylnitrosamine). Moreover, catabolism of retinol is accelerated and there also is induction of microsomal enzymes involved in lipoprotein production, resulting in hyperlipemia. Contrasting with the chronic effects of ethanol consumption, acute ethanol intake inhibits the metabolism of other drugs through competition for the at least partially shared microsomal pathway. In addition, metabolism by CYP2E1 results in a significant free radical release and acetaldehyde production which, in turn, diminish reduced glutathione (GSH) and other defense systems against oxidative stress. Acetaldehyde also forms adducts with proteins, thereby altering the functions of mitochondria and of repair enzymes. Increases of CYP2E1 and its mRNA prevail in the perivenular zone, the area of maximal liver damage. CYP1A2 and CYP3A4, two other perivenular P-450s, can also sustain the metabolism of ethanol, thereby contributing to MEOS activity and possibly liver injury. By contrast, CYP2E1 inhibitors oppose alcohol-induced liver damage, but heretofore available compounds were too toxic for clinical use. Recently, however, polyenylphosphatidylcholine (PPC), an innocuous mixture of polyunsaturated lecithins extracted from soybeans, was discovered to decrease CYP2E1 activity. PPC (and its active component dilinoleoylphosphatidylcholine) also oppose hepatic oxidative stress and fibrosis. PPC is now being tested clinically for the prevention and treatment of liver disease in the alcoholic.

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Section: Role Of Meos and Associated Cytochromesmentioning

confidence: 99%

Microsomal Ethanol‐Oxidizing System (MEOS): The First 30 Years (1968‐1998)–A Review

Lieber

1999

Alcoholism Clin & Exp Res

274

235

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“…No lesions in the corresponding pairfed controls. The capacity of ethanol to produce fibrosis in well fed baboons was confirmed by Porto et al [io,xx]; these lesions were less severe than those produced before [5,6,9] but the amount of alcohol administered was also smaller and the duration of the study was shorter.…”

Section: Nutritional Factorsmentioning

confidence: 76%

“…The 1 Alcohol and ethanol are used interchangeably in this review. ultimate stage of cirrhosis was achieved in subhuman primates [5]. In the aggregate of the studies conducted thus far [6][7][8][9] , production of cirrhosis was observed in x 3 of a total of 63 baboons fed ethanol for 3 years or more, with septal fibrosis developing in an additional 13 animals.…”

Section: Nutritional Factorsmentioning

confidence: 99%

Metabolism of ethanol and associated hepatotoxicity

Lieber

1991

Drug and Alcohol Review

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Over the last three decades, direct hepatotoxic effects of ethanol were established, some of which were linked to redox changes produced by NADH generated via the alcohol dehydrogenase (ADH) pathway and shown to affect the metabolism of lipids, carbohydrates, proteins, and purines. It was also determined that ethanol can be oxidized by a microsomal ethanol oxidizing system (MEOS) involving a specific cytochrome P-450; this newly discovered ethanol-inducible cytochrome P-450 (P-450 IIEi) contributes to ethanol metabolism, tolerance, energy wastage (with associated weight loss), and the selective hepatic perivenular toxicity of various xenobiotics. Their activation by P-450IIEi now provides an understanding of the increased susceptibility of the heavy drinker to the toxicity of industrial solvents, anaesthetic agents, commonly prescribed drugs, over-the-counter analgesics, and chemical carcinogens. P-450 induction also explains depletion (and toxicity) of nutritional factors such as vitamin A. As a consequence, treatment with vitamin A and other nutritional factors is beneficial, but must take into account a narrowed therapeutic window in alcoholics who have increased needs for nutrients and also display an enhanced susceptibility to some of their adverse effects. Acetaldehyde (the metabolite produced from ethanol by either ADH or MEOS) impairs hepatic oxygen utilization and forms protein adducts, resulting in antibody production, enzyme inactivation, and decreased DNA repair. It also stimulates collagen production by the vitamin A storing cells (lipocytes) and myofibroblasts, and causes glutathione depletion. Supplementation with S-adenosyl-L-methionine partly corrects the depletion and associated mitochondrial injury, whereas administration of polyunsaturated lecithin opposes the fibrosis. Thus, at the cellular level, the classic dichotomy between the nutritional and toxic effects of ethanol has now been bridged. The understanding of how the ensuing injury eventually results in irreversible scarring or cirrhosis may provide us with improved modalities for treatment and prevention.

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“…Under severe conditions, displaced lipids can accumulate in the hepatic cells, leading to a condition known as "fatty liver." Protein molecules can then envelope the insoluble lipids, resulting in enhanced secretion into blood of aqueous soluble lipoproteins (Lieber, 1973;Lieber and DeCarli, 1974). This detoxification mechanism may be one explanation of the effect of the ingestion of ethanol in increasing actinide removal, that is, soluble lipoproteins may provide binding sites for the intracellularly bound actinides.…”

Section: Discussionmentioning

confidence: 99%

“…As noted in Table 1, various diets were administered along with the alcohol. Nutritional balance was maintained during treatment period 1 by administration of the "Lieber control diet" (Lieber and DeCarli, 1974), which guaranteed fulfillment of the minimum requirements of all essential nutrients.…”

Section: Methodsmentioning

confidence: 99%

Effect of ethanol on the retention of americium‐241 in the baboon liver

Cohen

Antonelli

Sasso

et al. 1978

Journal of Toxicology and Environmental Health

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The oral administration of ethyl alcohol enhanced the excretion of 241Am from the liver of a baboon by 2.5 times that of a control animal. After ethanol administration, increases in the total content of 241Am excreted in feces were accompanied by corresponding increases in fecal volumes, although administration of nonalcoholic cathartics would not be expected to produce a similar effect. The effectiveness of ethanol as a decorporating agent may result from its ability to mobilize intracellularly bound 241Am from the liver, thereby making the nuclide more available for metabolic secretory mechanisms occurring via liver-bile-fecal route.

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An Experimental Model of Alcohol Feeding and Liver Injury in the Baboon

Cited by 219 publications

References 20 publications

Microsomal Ethanol‐Oxidizing System (MEOS): The First 30 Years (1968‐1998)–A Review

Microsomal Ethanol‐Oxidizing System (MEOS): The First 30 Years (1968‐1998)–A Review

Metabolism of ethanol and associated hepatotoxicity

Effect of ethanol on the retention of americium‐241 in the baboon liver

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