Ethanol Increases Hepatic Smooth Endoplasmic Reticulum and Drug-Metabolizing Enzymes

Rubin, Emanuel; Hutterer, Ferenc; Lieber, Charles S.

doi:10.1126/science.159.3822.1469

Cited by 244 publications

(48 citation statements)

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“…Electron microscopy of the rat livers confirmed proliferation of SER as an effect of ethanol as previously described by Rubin et al (1968). The livers of female rats which received 15% ethanol in their drinking water contained more fat droplets than the livers of male rats.…”

Section: Percentage Ethanolmentioning

confidence: 56%

Growth and liver morphology after long-term ethanol consumption of rats

Wiel

Duijf²,

Pertijs³

et al. 1990

Lab Anim

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SummaryEthanol was administered to female and male Wistar rats by mixing it with their drinking water. Ethanol concentrations were gradually increased up to either 8% or 15070.Female rats receiving8070 ethanol in their drinking water consumed 5-13 g, males 4-10 g daily. The ethanol/total food caloric intake percentages were 13 to 20070and 9 to 15070for female and male rats, respectively. There was no difference in body weight and relative liver weight between treated rats and their controls.Female and male rats receiving 15070 of ethanol in their drinking water consumed 8-14 g ethanol per kg body weight per day. The percentages of ethanol/total food caloric intake were stabilized at about 25070for both sexes. Growth of the rats differed only slightly from controls; a tendency for a higher increase of body weight of the control rats was found. No difference in relative liver weight between ethanol-treated and control rats was observed. Microscopic examinations revealed that the ethanol treatment resulted in fat accumulation in the liver cells. A proliferation of the Smooth Endoplasmic Reticulum (SER) was more marked in the 15070 dosed rats than in the 8% dosed rats and more distinct in female rats than in male rats in both dosage groups.

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Section: Percentage Ethanolmentioning

confidence: 56%

Growth and liver morphology after long-term ethanol consumption of rats

Wiel

Duijf²,

Pertijs³

et al. 1990

Lab Anim

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“…The presence of bizarre shapes and giant mitochondria [61, 63] with an increased matrix density was also reported [56,66,72,97]. The changes involving the endoplasmic reticulum [109] consist of a marked proliferation of the smooth membranes with abundant vesicular structures. The alterations of the endoplasmic reticulum are, according to [56], the first morphological changes detectable in the liver cell after ethanol feeding to rats; they were observed, in fact, after few days of alcohol administration, while mitochondrial changes appeared some days later.…”

Section: Acetaldehyde Metabolismmentioning

confidence: 87%

“…However, the group of Lieber [117] and others [87] showed that (a) MEOS is active even in acatalasemic animals; (b) a reconstituted system consisting of the essential terms of drug metabolism, i.e., cytochrome P 450 , NADPH-cytochrome c reductase and synthetic phospholipids, is able to oxidize, besides benzphetamine (characteristic substrate of drug metabolism), ethanol and other alcohols too and that MEOS is adaptively increased after chronic ethanol consumption, like other drug metabolizing activities. The induction of drug metabolizing enzymes due to alcohol [56,73,108,109] and the fact that ethanol in vitro inhibits in a competitive way the same enzymes, could explain, at least in part, the increased tolerance of alcoholics to sedatives when sober and the enhanced sensitivity to sedatives when inebriated. The quantitative contribution of microsomal ethanol oxidation to the overall ethanol metabolism is another much (see in the following paragraphs), has a much higher K m for ethanol (8-10 mmol/l) compared to that of alcohol dehydrogenase (0.2-2 mmol/l); however, chronic alcohol consumption increases the activity of CYP2E1 by several times [3].…”

Section: Introductionmentioning

confidence: 99%

Ethanol-induced oxidative stress: basic knowledge

et al. 2009

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After a general introduction, the main pathways of ethanol metabolism (alcohol dehydrogenase, catalase, coupling of catalase with NADPH oxidase and microsomal ethanol-oxidizing system) are shortly reviewed. The cytochrome P 450 isoform (CYP2E1) specifically involved in ethanol oxidation is discussed. The acetaldehyde metabolism and the shift of the NAD/NADH ratio in the cellular environment (reductive stress) are stressed. The toxic effects of acetaldehyde are mentioned. The ethanolinduced oxidative stress: the increased MDA formation by incubated liver preparations, the absorption of conjugated dienes in mitochondrial and microsomal lipids and the decrease in the most unsaturated fatty acids in liver cell membranes are discussed. The formation of carbon-centered (1-hydroxyethyl) and oxygen-centered (hydroxyl) radicals during the metabolism of ethanol is considered: the generation of hydroxyethyl radicals, which occurs likely during the process of univalent reduction of dioxygen, is highlighted and is carried out by ferric cytochrome P 450 oxy-complex (P 450 -Fe 3? O 2 Á-) formed during the reduction of heme-oxygen. The ethanol-induced lipid peroxidation has been evaluated, and it has been shown that plasma F 2 -isoprostanes are increased in ethanol toxicity.

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“…Chronic ethanol consumption by rats results in a proliferation of the hepatic smooth endoplasmic reticulum and an increase in NADPH-cytochrome P-450 reductase and spectrally observable cytochrome P-450 (1)(2)(3). The induction of P-450 by ethanol is associated with an increase in the metabolism and, in some instances, in the toxicity of many compounds, including N-nitrosodimethylamine (4)(5)(6), acetaminophen (7)(8)(9), aniline (10)(11)(12), ethanol (13), and carbon tetrachloride (14)(15)(16).…”

mentioning

confidence: 99%

Immunochemical evidence for induction of the alcohol-oxidizing cytochrome P-450 of rabbit liver microsomes by diverse agents: ethanol, imidazole, trichloroethylene, acetone, pyrazole, and isoniazid.

Koop¹,

Crump²,

Nordblom³

et al. 1985

Proc. Natl. Acad. Sci. U.S.A.

171

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Isozyme 3a of rabbit liver microsomal cytochrome P-450, also termed P-450ALC, was previously isolated in this laboratory from animals administered ethanol or imidazole, and the purified cytochrome was shown to function in the reconstituted system as an oxygenase in catalyzing the oxidation of ethanol and other alcohols. Although liver microsomes from animals treated in various ways exhibit increased alcohol-oxidizing activity, evidence was not available as to whether this was due to enzyme induction or to other factors influencing the activity. Immunochemical quantitation of P-450 isozyme 3a has now been achieved by use of purified antibody to this cytochrome in NaDodSO4/PAGE/blotting and dot-blotting techniques. The specific content of isozyme 3a in liver microsomes was found to be increased from 2-to >4-fold by administration of the following agents, in increasing order of effectiveness as inducers: isoniazid, trichloroethylene, pyrazole, ethanol, imidazole, and acetone. Isozyme 3a represents about 5% of the total P-450 in control animals and is increased to as high as 27% by acetone treatment. Isozyme 3a-dependent butanol-oxidation activity, determined by the inhibitory effect of antibody on the various microsomal preparations, was found to increase proportionally with increased content of this cytochrome.Chronic ethanol consumption by rats results in a proliferation of the hepatic smooth endoplasmic reticulum and an increase in NADPH-cytochrome P-450 reductase and spectrally observable cytochrome P-450 (1-3). The induction of P-450 by ethanol is associated with an increase in the metabolism and, in some instances, in the toxicity of many compounds, including N-nitrosodimethylamine (4-6), acetaminophen (7-9), aniline (10-12), ethanol (13), and carbon tetrachloride (14-16). The treatment of rabbits with ethanol also results in an increase in hepatic microsomal aniline and ethanol hydroxylation, but the specific content of microsomal P-450 is not always significantly increased (17). Several years ago in this laboratory, a unique form of P-450, designated isozyme 3a on the basis of its relative electrophoretic mobility, was isolated from ethanol-treated rabbits and characterized (17, 18). More recently, we have purified the same cytochrome from rabbits treated with imidazole (19). Purified isozyme 3a, also referred to as P-450ALC (20), exhibits the highest activity of six purified rabbit liver isozymes toward ethanol and other alcohols as well as aniline (18), converts acetaminophen to a reactive intermediate (21), and is the only P-450 isozyme we have studied that is active in the demethylation of N-nitrosodimethylamine at low substrate concentrations (22). Isozyme 3a is responsible for the increase in oxidation of alcohols and aniline in liver microsomes from ethanol-treated rabbits, as indicated by inhibition of the induced activity with antibody prepared to the purified enzyme (23). Furthermore, the microsomal demethylation of N-nitrosodimethylamine at low substrate concentrations is completely inhi...

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Ethanol Increases Hepatic Smooth Endoplasmic Reticulum and Drug-Metabolizing Enzymes

Cited by 244 publications

References 6 publications

Growth and liver morphology after long-term ethanol consumption of rats

Growth and liver morphology after long-term ethanol consumption of rats

Ethanol-induced oxidative stress: basic knowledge

Immunochemical evidence for induction of the alcohol-oxidizing cytochrome P-450 of rabbit liver microsomes by diverse agents: ethanol, imidazole, trichloroethylene, acetone, pyrazole, and isoniazid.

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