S-adenosylmethionine and methylthioadenosine are antiapoptotic in cultured rat hepatocytes but proapoptotic in human hepatoma cells

Authors

  • Eduardo Ansorena,

    1. Departamento de Bioquímica, Universidad de Navarra, Pamplona, Spain
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    • E.A. and E.R.G.-T. contributed equally to this work.

  • Elena R. García-Trevijano,

    1. División de Hepatología y Terapia Génica, Departamento de Medicina Interna, Universidad de Navarra, Pamplona, Spain
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    • E.A. and E.R.G.-T. contributed equally to this work.

  • Maria L. Martínez-Chantar,

    1. División de Hepatología y Terapia Génica, Departamento de Medicina Interna, Universidad de Navarra, Pamplona, Spain
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  • Zong-Zhi Huang,

    1. Division of Gastrointestinal and Liver Diseases, USC Liver Disease Research Center, USC-UCLA Research Center for Alcoholic Liver and Pancreatic Diseases, Keck School of Medicine USC, Los Angeles, CA
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  • Lixin Chen,

    1. Division of Gastrointestinal and Liver Diseases, USC Liver Disease Research Center, USC-UCLA Research Center for Alcoholic Liver and Pancreatic Diseases, Keck School of Medicine USC, Los Angeles, CA
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  • José M. Mato,

    1. División de Hepatología y Terapia Génica, Departamento de Medicina Interna, Universidad de Navarra, Pamplona, Spain
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  • Maria Iraburu,

    1. Departamento de Bioquímica, Universidad de Navarra, Pamplona, Spain
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  • Shelly C. Lu,

    Corresponding author
    1. Division of Gastrointestinal and Liver Diseases, USC Liver Disease Research Center, USC-UCLA Research Center for Alcoholic Liver and Pancreatic Diseases, Keck School of Medicine USC, Los Angeles, CA
    • Keck School of Medicine USC, HMR 415, 2011 Zonal Ave., Los Angeles, CA 90033. fax: 323-442-3234; or Matias A. Avila, Ph.D., Departamento de Medicina Interna, Edificio Los Castaños, Universidad de Navarra, C/ Irunlarrea 1, 31008 Pamplona, Spain. fax: (34) 948-425677.
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  • Matías A. Avila

    1. División de Hepatología y Terapia Génica, Departamento de Medicina Interna, Universidad de Navarra, Pamplona, Spain
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Abstract

S-adenosylmethionine (AdoMet) is an essential compound in cellular transmethylation reactions and a precursor of polyamine and glutathione synthesis in the liver. In liver injury, the synthesis of AdoMet is impaired and its availability limited. AdoMet administration attenuates experimental liver damage, improves survival of alcoholic patients with cirrhosis, and prevents experimental hepatocarcinogenesis. Apoptosis contributes to different liver injuries, many of which are protected by AdoMet. The mechanism of AdoMet's hepatoprotective and chemopreventive effects are largely unknown. The effect of AdoMet on okadaic acid (OA)-induced apoptosis was evaluated using primary cultures of rat hepatocytes and human hepatoma cell lines. AdoMet protected rat hepatocytes from OA-induced apoptosis dose dependently. It attenuated mitochondrial cytochrome c release, caspase 3 activation, and poly(ADP-ribose) polymerase cleavage. These effects were independent from AdoMet-dependent glutathione synthesis, and mimicked by 5'-methylthioadenosine (MTA), which is derived from AdoMet. Interestingly, AdoMet and MTA did not protect HuH7 cells from OA-induced apoptosis; conversely both compounds behaved as proapoptotic agents. AdoMet's proapoptotic effect was dose dependent and observed also in HepG2 cells. In conclusion, AdoMet exerts opposing effects on apoptosis in normal versus transformed hepatocytes that could be mediated through its conversion to MTA. These effects may participate in the hepatoprotective and chemopreventive properties of this safe and well-tolerated drug.

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