Skip to main content
SpringerLink
Log in

Effect ofS-adenosyl-l-methionine on ethanol cholestasis and hepatotoxicity in isolated perfused rat liver

  • Liver: Infectious, Inflammatory, and Metabolic Disorders
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

We investigated whetherS-adenosyl-l-methionine (SAMe) influences the inhibitory effect of ethanol on bile secretion and ethanol hepatotoxicity in the isolated perfused rat liver. SAMe (25 mg/kg intramuscularly three times a day) was administered for three days consecutively. Liver was then isolated and perfused with taurocholate to stabilize bile secretion and exposed to 1% ethanol for 70 min. The effect of ethanol on bile flow, bile salt biliary secretion, oxygen liver consumption, AST and LDH release in the perfusate, and hepatic concentration of glutathione, malondialdehyde, and diene conjugates was compared between SAMe-treated livers (N=11) and paired controls (N=11). Control experiments without ethanol were also performed (N=6). Exposure to 1% ethanol induced a significantly (P<0.03) higher inhibition of bile flow (−35% vs 17%) and bile salt secretion (−28% vs 16%) in untreated compared with SAMe-treated livers. During 1% ethanol exposure, the release of LDH and AST in the perfusate was significantly lowre (P<0.02) in SAMe-treated livers. Oxygen liver consumption was markedly inhibited by 1% ethanol administration (P<0.02 vs controls without ethanol), an effect almost totally prevented by SAMe treatment (P<0.02 vs ethanol controls). The hepatic concentration of total glutathione was significantly (P<0.02) decreased by 1% ethanol exposure, but this effect was less pronounced in SAMe-treated than in untreated controls (P<0.02). The hepatic levels of malondialdehyde and diene conjugates were not significantly changed by ethanol exposure in either SAMe-treated or control livers in comparison to ethanol-free controls. To evaluate if SAMe protection against ethanol cholestasis was related to an effect on vesicular exocytosis, the biliary excretion of the fluid-phase marker horseradish peroxidase was analyzed. Ethanol inhibited (P<0.04) horseradish peroxidase excretion, which, however, remained unaffected by SAMe (N=6). In conclusion, SAMe counteracted, in the IPRL, the inhibitory effect of ethanol acute administration on bile flow and bile salt secretion while failing to influence vesicular exocytosis. SAMe counteracted ethanol acute hepatotoxicity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Mato JM: Regulation of phospholipid methylation and its effect on membrane proteins.In Progress in Protein-Lipid Interactions, Vol. 2. Watts-De Pont (ed). New York, Elsevier Scientific, 1986, pp 267–302

    Google Scholar 

  2. Schachter D: Fluidity and function of hepatocyte plasma membranes. Hepatology 4:140–151, 1984

    Google Scholar 

  3. Devi GB, Henderson GI, Frosto TA, Schenker S: Effect of ethanol on rat hepatocytes: Studies on cell replication, lipid peroxidation and glutathione. Hepatology 18:648–659, 1993

    Google Scholar 

  4. Ponsoda, X, Jover R, Gomez-Lechon MJ, Castell JV: Intracellular glutathione in human hepatocytes incubates withS-adenosyl-l-methionine and GSH-depleting drugs. Toxicology 70:293–302, 1991

    Google Scholar 

  5. Montero C, Smolenski RT, Duley JA, Simmonds HA:S-Adenosylmethionine increases erythrocyte ATPin vitro by a route independent of adenosine kinase. Biochem Pharmacol 40:2617–2623, 1990

    Google Scholar 

  6. Alvaro D, Angelico M, Cantafora A, Gaudio E, Gandin C, Santini MT, Masella R, Capocaccia L: Improvement of estradiol-17β-d-glucuronide cholestasis by intravenous administration of dimethylethanolamine in the rat. Hepatology 13:1158–1172, 1991

    Google Scholar 

  7. Stramentinoli G, Di Padova C, Gualano M, Rovagnati P, Galli-Kienle M: Ethynilestradiol-induced impairment of bile secretion in the rat: Protective effects ofS-adenosyl-l-methionine and its implication in estrogen metabolism. Gastroenterology 80:154–158, 1981

    Google Scholar 

  8. Di Padova C, Di Padova F, Tritapepe R, Stramentinoli G:S-Adenosyl-l-methionine protection against alpha-naphthyl-isothiocyanate-induced cholestasis in the rat. Toxicol Lett 29:131–136, 1985

    Google Scholar 

  9. Jiménez R, Gonzàles-Buitrago JM, Munoz ME, Romàn ID, Galàn AI, Fernàndez E: Evaluation of the protective role ofS-adenosyl-l-methionine against cylosporine A-induced hepatotoxicity in rat. J Hepatol 13:S134, 1991

    Google Scholar 

  10. Schreiber AJ, Warren G, Sutherland E, Simon FR:S-Adenosyl methionine (SAMe) induced cytoprotection against bile acid-induced cholestasis. Gastroenterology 84:1395, 1983 (abstract)

    Google Scholar 

  11. Belli CD, Fournier LA, Lepage G, Yousef I. Roy CC:S-Adenosyl-l-methionine prevents total parenteral nutrition-induced cholestasis in the rat. J Hepatol 21:18–23, 1994

    Google Scholar 

  12. Frezza M, Pozzato G, Chiesa L, Stramentinoli G, Di Padova C: Reversal of intrahepatic cholestasis of pregnancy in women after high doseS-adenosyl-l-methionine administration. Hepatology 4:274–278, 1984

    Google Scholar 

  13. Frezza M, Surrenti C, Manzillo G, Fiaccadori F, Bortolini M, Di Padova C: OralS-adenosylmethionine in the symptomatic treatment of intrahepatic cholestasis. A double-blind, placebo-controlled study. Gastroenterology 99:211–215, 1990

    Google Scholar 

  14. Maddrey WC, Boyer JL: The acute and chronic effect of ethanol administration on bile secretion in the rat. J Lab Clin Med 82:215–225, 1973

    Google Scholar 

  15. Nissembaum M, Chedid A, Mendenhall C, Gartside P. Prognostic significance of cholestatic alcoholic hepatitis. VA Cooperative Study Group. Dig Dis Sci 35:891–896, 1990

    Google Scholar 

  16. Yamada S, Mak KM, Lieber CS: Chronic ethanol consumption alters rat liver plasma membranes and potentiates release of alkaline phosphatase. Gastroenterology 88:1799–1806, 1985

    Google Scholar 

  17. Lieber CS, Casini A, De Carli ML, Kim CI, Lowe N, Sasaki R, Leo MA:S-Adenosyl-l-methionine attenuates alcohol-induced liver injury in the baboon. Hepatology 11:165–172, 1990

    Google Scholar 

  18. Bruck R, Benedetti A, Strazzabosco M, Boyer JL: Intracellular alkalinization stimulates bile flow and vesicular-mediated exocytosis in IPRL. Am J Physiol 28:G347-G353, 1993

    Google Scholar 

  19. Alvaro D, Cho WK, Mennone A, Boyer JL: Effect of secretin on intracellular pH regulation in isolated rat bile duct epithelial cells. J Clin Invest 92:1314–1325, 1993

    Google Scholar 

  20. Beuers U, Nathanson MH, Iseles CM, Boyer JL: Tauroursodeoxycholic acid stimulales hepatocellular exocytosis and mobilizes extracellular Ca++ mechanisms defective in cholestasis. J Clin Invest 92:2984–2993, 1993

    Google Scholar 

  21. Talalay P: Enzymatic analysis of steroid hormones. Methods Biochem Anal 8:119–149, 1960

    Google Scholar 

  22. Sewell BR, Grinpukel SA, Yeomans ND: Ethanol impairs biliary lysosomal enzyme release in rats. Clin Exp Pharmacol Physiol 13:745–750, 1986

    Google Scholar 

  23. Worthington Biochemical Corporation. Enzymes and related biochemicals.In Worthington Manual. Freehold, New Jersey, Worthington Biochemical Life Sciences Division, 1987, pp 145–146

    Google Scholar 

  24. Hacki W, Paumgartner G: Determination of biliary dead space using14C-taurocholate as a marker. Experentia 29:1091–1093, 1973

    Google Scholar 

  25. Tietze F: Enzymic method for quantitative determination of nanogram amounts of total and oxidized glutathione: Applications to mammalian blood and other tissue. Anal Biochem 27:502–522, 1972

    Google Scholar 

  26. Buege JA, Aust SD: Microsomal lipid peroxidation. Methods Enzymol 52:302–310, 1978

    Google Scholar 

  27. Recknagel RO, Glende EA: Spectrophotometric detection of lipid conjugated dienes. Methods Enzymol 105:331–337, 1984

    Google Scholar 

  28. Boelsterli UA, Rakhit G, Balazs T: Modulation byS-adenosyl-l-methionine of hepatic Na+,K+-ATPase, membrane fluidity, and bile flow in rats with ethynil estradiol-induced cholestasis. Hepatology 3:12–17, 1983

    Google Scholar 

  29. Mills PR, Mejer PJ, Smith DJ, Ballatori N, Boyer JL, Gordon ER: The effect of changes in the fluid state of rat liver plasma membrane on the transport of taurocholate. Hepatology 7:61–68. 1987

    Google Scholar 

  30. Gordon LM, Sauerheber RD, Esgate JA, Dipple I, Marchmont RJ, Houslay MD: The increase in bilayer fluidity of rat liver plasma membranes achieved by the local anesthetic benzyl alcohol affects the activity of intrinsic membrane enzymes. J Biol Chem 255:4519–4527, 1980

    Google Scholar 

  31. Miner PB, Sneller M, Crawford SS: Spironolactone- and canrenone-induced changes in hepatic (Na+,K+)-ATPase activity, surface membrane cholesterol and phospholipid, and fluorescence polarization in the rat. Hepatology 3:481–488, 1983

    Google Scholar 

  32. Concari M, Guicciardi ME, Carubbi F, Bozzoli M, Tagliazuechi M, Crema G, Loria P, Carulli N:S-Adenosyl-l-methionine (SAMe) reduced hepatotoxicity induced by hydrophobic bile salts (BS) in HepG2 cell line. J Hepatol 21:S77, 1994

    Google Scholar 

  33. Okanoue T, Kondo I, Ihrig TJ, French SW: Effect of ethanol and chlorpromazine on transhepatic transport and biliary secretion of horseradish peroxidase. Hepatology 4:253–260, 1984

    Google Scholar 

  34. Crawford JM, Berken CA, Gollan JL: Role of the hepatocyte microtubular system in the excretion of bile salts and biliary lipid: Implication for intracellular vesicular transport. J Lipid Res 29:144–156, 1988

    Google Scholar 

  35. Benedetti A, Strazzabosco M, Ng OC, Boyer JL: Regulation of activity and apical targeting of the Cl−/HCO3 exchanger in rat hepatocytes. Proc Natl Acad Sci USA 91:792–796, 1994

    Google Scholar 

  36. Boyer JL, McGrath, JW, Ng OC: Microtubule dependent targeting of transporters to the apical membrane determines the canalicular excretion of bile acids in hepatocyte couplets. Hepatology 18:197A, 1993

    Google Scholar 

  37. Keller F, Snyder AB, Petracek FJ, Sancier KM: Hepatic free radical levels in ethanol-treated and carbon tetrachloride-treated rats. Biochem Pharmacol 20:2507–2511, 1971

    Google Scholar 

  38. Videla LA, Fernandez V, Ugarte G, Valenzuela A: Effect of acute ethanol intoxication on the content of reduced glutathione of the liver in relation, to its lipoperoxidative capacity in the rat. FEBS Lett 111:6–10, 1980

    Google Scholar 

  39. Strubelt O, Younes M, Pentz R: Enhancement by glutathione depletion of ethanol-induced acute hepatoxicityin vitro andin vivo. Toxicology 45:213–223, 1987

    Google Scholar 

  40. Videla LA, Fernandez V, Valenzuela A: Age-dependent changes in rat liver lipid peroxidation and glutathione content induced by acute ethanol ingestion. Cell Biochem Funct 5:273–280, 1987

    Google Scholar 

  41. Tsukamoto H, Gaal K, French SW: Insight into the pathogenesis of alcoholic liver necrosis and fibrosis: Status report. Hepatology 12:599–608, 1990

    Google Scholar 

  42. Thurman RG, Sholz T: Interaction of glycolysis and respiration in perfused rat liver. Eur J Biochem 75:13–21, 1975

    Google Scholar 

  43. Hijioka T, Sato N, Matsumura T, Yoshihara H, Takey Y, Fukui H, Oshita M, Kawano S, Kamada T: Ethanol-induced disturbance of hepatic microcirculation and hepatic hypoxia. Biochem Pharmacol 41:1551–1557, 1991

    Google Scholar 

  44. Lieber CS, Baraona E, Hernandez-Munoz R, Kubota S, Sato N, Kawano S, Matsumura T, Inatomi N: Impaired oxygen utilization. A new mechanism for the hepatotoxicity of ethanol in sub-human primates. J Clin Invest 83:1682–1690, 1989

    Google Scholar 

  45. Younes M, Wagner H, Strubelt O: Enhancement of acute ethanol hepatotoxicity under conditions of low oxygen supply and ischemia/reperfusion. The role of oxygen radicals. Biochem Pharmacol 38:3573–3581, 1989

    Google Scholar 

  46. Paredes SR, Kozicki PA, Fukuda H, Rossetti MV, Batlle AM:S-Adenosyl-l-methionine: Its effect on aminolevulinate dehydratase and glutathione in acute ethanol intoxication. Alcohol 4:81–85, 1987

    Google Scholar 

  47. García-Ruiz C, Morales A, Ballesta A, Rodés J, Kaplowitz N, Fernàndez-Checa JC: Effect of chronic ethanol, feeding on glutathione and functional integrity of mitochondria in periportal and perivenous rat hepatocytes. J Clin Invest 94:193–202, 1994

    Google Scholar 

  48. Di Padova C, Tritapepe R, Rovagnati P, Pozzoli P, Stramentinoli G: Decreased blood levels of ethanol and acetaldehyde byS-adenosyl-l-methionine in humans Arch Toxicol 7(suppl):240–242, 1984

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. II Department of Gastroenterology, University of Rome “La Sapienza.”, Viale dell'Universitá 37, 00185, Rome, Italy

    D. Alvaro MD, A. Gigliozzi MD, C. Piat MD, L. Carli MD, A. Bini MD, T. La Rosa MD, S. Furfaro MD & L. Capocaccia MD

Authors
  1. D. Alvaro MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. Gigliozzi MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C. Piat MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L. Carli MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A. Bini MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. T. La Rosa MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. S. Furfaro MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. L. Capocaccia MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Alvaro, D., Gigliozzi, A., Piat, C. et al. Effect ofS-adenosyl-l-methionine on ethanol cholestasis and hepatotoxicity in isolated perfused rat liver. Digest Dis Sci 40, 1592–1600 (1995). https://doi.org/10.1007/BF02285216

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02285216

Key Words

Search

Navigation