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. 1997 Oct 15;327(Pt 2):383–389. doi: 10.1042/bj3270383

Metabolism of exogenous S-adenosylmethionine in isolated rat hepatocyte suspensions: methylation of plasma-membrane phospholipids without intracellular uptake.

F Bontemps 1, G Van Den Berghe 1
PMCID: PMC1218805  PMID: 9359405

Abstract

Administration of S-adenosylmethionine (AdoMet), the main biological methyl donor, has been shown to exert favourable effects on liver disorders in man and animal models. The mechanism of action of AdoMet has, however, remained elusive, mainly owing to controversies with respect to its capacity to enter intact liver cells. Incubation of isolated rat hepatocytes with 2 or 50 microM -methyl-14C-AdoMet showed that it was utilized predominantly to methylate cellular phospholipids, forming mainly phosphatidylcholine, although less than 0.2% of labelled AdoMet was found inside the cells. The concentration of neither AdoMet nor S-adenosylhomocysteine (AdoHcy), its demethylation product, was significantly elevated inside the cells. A slight elevation of intracellular AdoMet was only recorded on incubation with concentrations of AdoMet above 200 microM. AdoHcy, which does not penetrate cells, inhibited phospholipid methylation from [methyl-14C]AdoMet but not from [methyl-14C]Met. Elevation of intracellular AdoHcy by adenosine dialdehyde, an inhibitor of AdoHcy hydrolase, inhibited phospholipid methylation from [methyl-14C]Met, but virtually not at all from [methyl-14C]AdoMet. Taken together, these data indicate that exogenous AdoMet does not penetrate hepatocytes significantly but is utilized for phospholipid methylation on the outer surface of the plasma membrane.

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Selected References

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  1. Aarbakke J., Ueland P. M. Interaction of S-adenosylhomocysteine with isolated rat hepatocytes. Mol Pharmacol. 1981 May;19(3):463–469. [PubMed] [Google Scholar]
  2. Arias-Díaz J., Vara E., García C., Villa N., Rodríguez J. M., Ortiz P., Balibrea J. L. S-adenosylmethionine protects hepatocytes against the effects of cytokines. J Surg Res. 1996 Apr;62(1):79–84. doi: 10.1006/jsre.1996.0177. [DOI] [PubMed] [Google Scholar]
  3. Bartel R. L., Borchardt R. T. Effects of adenosine dialdehyde on S-adenosylhomocysteine hydrolase and S-adenosylmethionine-dependent transmethylations in mouse L929 cells. Mol Pharmacol. 1984 May;25(3):418–424. [PubMed] [Google Scholar]
  4. Bergelson L. D., Barsukov L. I. Topological asymmetry of phospholipids in membranes. Science. 1977 Jul 15;197(4300):224–230. doi: 10.1126/science.327544. [DOI] [PubMed] [Google Scholar]
  5. Bray G. P., Tredger J. M., Williams R. S-adenosylmethionine protects against acetaminophen hepatotoxicity in two mouse models. Hepatology. 1992 Feb;15(2):297–301. doi: 10.1002/hep.1840150220. [DOI] [PubMed] [Google Scholar]
  6. Cantoni G. L. Biological methylation: selected aspects. Annu Rev Biochem. 1975;44:435–451. doi: 10.1146/annurev.bi.44.070175.002251. [DOI] [PubMed] [Google Scholar]
  7. Chawla R. K., Bonkovsky H. L., Galambos J. T. Biochemistry and pharmacology of S-adenosyl-L-methionine and rationale for its use in liver disease. Drugs. 1990;40 (Suppl 3):98–110. doi: 10.2165/00003495-199000403-00010. [DOI] [PubMed] [Google Scholar]
  8. Chiang P. K., Gordon R. K., Tal J., Zeng G. C., Doctor B. P., Pardhasaradhi K., McCann P. P. S-Adenosylmethionine and methylation. FASEB J. 1996 Mar;10(4):471–480. [PubMed] [Google Scholar]
  9. Cui Z., Vance J. E., Chen M. H., Voelker D. R., Vance D. E. Cloning and expression of a novel phosphatidylethanolamine N-methyltransferase. A specific biochemical and cytological marker for a unique membrane fraction in rat liver. J Biol Chem. 1993 Aug 5;268(22):16655–16663. [PubMed] [Google Scholar]
  10. Engstrom M. A., Benevenga N. J. Rates of oxidation of the methionine and S-adenosylmethionine methyl carbons in isolated rat hepatocytes. J Nutr. 1987 Nov;117(11):1820–1826. doi: 10.1093/jn/117.11.1820. [DOI] [PubMed] [Google Scholar]
  11. FOLCH J., LEES M., SLOANE STANLEY G. H. A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem. 1957 May;226(1):497–509. [PubMed] [Google Scholar]
  12. Friedel H. A., Goa K. L., Benfield P. S-adenosyl-L-methionine. A review of its pharmacological properties and therapeutic potential in liver dysfunction and affective disorders in relation to its physiological role in cell metabolism. Drugs. 1989 Sep;38(3):389–416. doi: 10.2165/00003495-198938030-00004. [DOI] [PubMed] [Google Scholar]
  13. GIBSON K. D., WILSON J. D., UDENFRIEND S. The enzymatic conversion of phospholipid ethanolamine to phospholipid choline in rat liver. J Biol Chem. 1961 Mar;236:673–679. [PubMed] [Google Scholar]
  14. Giulidori P., Galli-Kienle M., Catto E., Stramentinoli G. Transmethylation, transsulfuration, and aminopropylation reactions of S-adenosyl-L-methionine in vivo. J Biol Chem. 1984 Apr 10;259(7):4205–4211. [PubMed] [Google Scholar]
  15. HOFSTEE B. H. Non-inverted versus inverted plots in enzyme kinetics. Nature. 1959 Oct 24;184:1296–1298. doi: 10.1038/1841296b0. [DOI] [PubMed] [Google Scholar]
  16. Hirata F., Viveros O. H., Diliberto E. J., Jr, Axelrod J. Identification and properties of two methyltransferases in conversion of phosphatidylethanolamine to phosphatidylcholine. Proc Natl Acad Sci U S A. 1978 Apr;75(4):1718–1721. doi: 10.1073/pnas.75.4.1718. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hoffman D. R., Marion D. W., Cornatzer W. E., Duerre J. A. S-Adenosylmethionine and S-adenosylhomocystein metabolism in isolated rat liver. Effects of L-methionine, L-homocystein, and adenosine. J Biol Chem. 1980 Nov 25;255(22):10822–10827. [PubMed] [Google Scholar]
  18. Hoffman J. L. The rate of transmethylation in mouse liver as measured by trapping S-adenosylhomocysteine. Arch Biochem Biophys. 1980 Nov;205(1):132–135. doi: 10.1016/0003-9861(80)90091-0. [DOI] [PubMed] [Google Scholar]
  19. Lauter C. J., Solyom A., Trams E. G. Comparative studies on enzyme markers of liver plasma membranes. Biochim Biophys Acta. 1972 May 9;266(2):511–523. doi: 10.1016/0005-2736(72)90107-1. [DOI] [PubMed] [Google Scholar]
  20. Levy J., Suzuki Y., Avioli L. V., Grunberger G., Gavin J. R., 3rd Plasma membrane phospholipid content in non-insulin-dependent streptozotocin-diabetic rats--effect of insulin. Diabetologia. 1988 May;31(5):315–321. doi: 10.1007/BF00277414. [DOI] [PubMed] [Google Scholar]
  21. Lieber C. S., Casini A., DeCarli L. M., Kim C. I., Lowe N., Sasaki R., Leo M. A. S-adenosyl-L-methionine attenuates alcohol-induced liver injury in the baboon. Hepatology. 1990 Feb;11(2):165–172. doi: 10.1002/hep.1840110203. [DOI] [PubMed] [Google Scholar]
  22. Murphy J. T., Spence K. D. Transport of S-adenosylmethionine in Saccharomyces cerevisiae. J Bacteriol. 1972 Feb;109(2):499–504. doi: 10.1128/jb.109.2.499-504.1972. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Pezzoli C., Stramentinoli G., Galli-Kienle M., Pfaff E. Uptake and metabolism of S-adenosyl-L-methionine by isolated rat hepatocytes. Biochem Biophys Res Commun. 1978 Dec 14;85(3):1031–1038. doi: 10.1016/0006-291x(78)90646-0. [DOI] [PubMed] [Google Scholar]
  24. Rovinski B., Hosein E. A. Adaptive changes in lipid composition of rat liver plasma membrane during postnatal development following maternal ethanol ingestion. Biochim Biophys Acta. 1983 Nov 23;735(3):407–417. doi: 10.1016/0005-2736(83)90155-4. [DOI] [PubMed] [Google Scholar]
  25. Schanche J. S., Schanche T., Ueland P. M. Inhibition of phospholipid methylation in isolated rat hepatocytes by analogues of adenosine and S-adenosylhomocysteine. Biochim Biophys Acta. 1982 Dec 30;721(4):399–407. doi: 10.1016/0167-4889(82)90095-7. [DOI] [PubMed] [Google Scholar]
  26. Schanche J. S., Schanche T., Ueland P. M. Inhibition of phospholipid methyltransferase(s) from rat liver plasma membranes by analogues of S-adenosylhomocysteine. Mol Pharmacol. 1981 Nov;20(3):631–636. [PubMed] [Google Scholar]
  27. Stet E. H., De Abreu R. A., Bökkerink J. P., Blom H. J., Lambooy L. H., Vogels-Mentink T. M., de Graaf-Hess A. C., van Raay-Selten B., Trijbels F. J. Decrease in S-adenosylmethionine synthesis by 6-mercaptopurine and methylmercaptopurine ribonucleoside in Molt F4 human malignant lymphoblasts. Biochem J. 1994 Nov 15;304(Pt 1):163–168. doi: 10.1042/bj3040163. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Stramentinoli G., Gualano M., Ideo G. Protective role of S-adenosyl-L-methionine on liver injury induced by D-galactosamine in rats. Biochem Pharmacol. 1978 May 15;27(10):1431–1433. doi: 10.1016/0006-2952(78)90097-7. [DOI] [PubMed] [Google Scholar]
  29. Traver J., Varela I., Mato J. M. Effect of exogenous S-adenosyl-L-methionine on phosphatidylcholine synthesis by isolated rat hepatocytes. Biochem Pharmacol. 1984 May 1;33(9):1562–1564. doi: 10.1016/0006-2952(84)90430-1. [DOI] [PubMed] [Google Scholar]
  30. Tsukada K., Abe T., Kuwahata T., Mitsui K. Metabolism of S-adenosylmethionine in rat hepatocytes: transfer of methyl group from S-adenosylmethionine by methyltransferase reactions. Life Sci. 1985 Aug 19;37(7):665–672. doi: 10.1016/0024-3205(85)90434-5. [DOI] [PubMed] [Google Scholar]
  31. Van Phi L., Söling H. D. Methyl group transfer from exogenous S-adenosylmethionine on to plasma-membrane phospholipids without cellular uptake in isolated hepatocytes. Biochem J. 1982 Sep 15;206(3):481–487. doi: 10.1042/bj2060481. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Van den Berghe G., Bontemps F., Hers H. G. Purine catabolism in isolated rat hepatocytes. Influence of coformycin. Biochem J. 1980 Jun 15;188(3):913–920. doi: 10.1042/bj1880913. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Vara E., Arias-Díaz J., Villa N., Hernández J., García C., Ortiz P., Balibrea J. L. Beneficial effect of S-adenosylmethionine during both cold storage and cryopreservation of isolated hepatocytes. Cryobiology. 1995 Oct;32(5):422–427. doi: 10.1006/cryo.1995.1041. [DOI] [PubMed] [Google Scholar]
  34. Varela-Moreiras G., Alonso-Aperte E., Rubio M., Gassó M., Deulofeu R., Alvarez L., Caballería J., Rodés J., Mato J. M. Carbon tetrachloride-induced hepatic injury is associated with global DNA hypomethylation and homocysteinemia: effect of S-adenosylmethionine treatment. Hepatology. 1995 Oct;22(4 Pt 1):1310–1315. [PubMed] [Google Scholar]
  35. Wu J., Söderbergh H., Karlsson K., Danielsson A. Protective effect of S-adenosyl-L-methionine on bromobenzene- and D-galactosamine-induced toxicity to isolated rat hepatocytes. Hepatology. 1996 Feb;23(2):359–365. doi: 10.1053/jhep.1996.v23.pm0008591864. [DOI] [PubMed] [Google Scholar]
  36. Zappia V., Galletti P., Porcelli M., Ruggiero G., Andreana A. Uptake of adenosylmethionine and related sulfur compounds by isolated rat liver. FEBS Lett. 1978 Jun 15;90(2):331–335. doi: 10.1016/0014-5793(78)80398-6. [DOI] [PubMed] [Google Scholar]

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