Estudio del metabolismo y las propiedades inmunomoduladoras de la mta en el higado enfermo

Abstract

METHYLTHIOADENOSINE: A MOLECULE WITH IMMUNOMODUUATORY PROPERTIES AND A DEFECTIVE METABOLlSM IN DISEASED LlVER Methylthioadenosine phosphorylase (MTAP) is a key enzyme in the methionine and adenine salvage pathways. in mammals, the "liver plays a central role in methionine metabolism, and this essential function is lost in the progression from liver cirrhosis to hepatocarcinoma. Deficient mtap gene expression has been recognized in many transformed cell lines and tissues. In the present work, we have studied the expression of mtap in human and experimental liver cirrhosis and hepatocarcinoma. we observe that mtap gene expression is significantly reduced in human hepatocarcinoma tissues and cell lines. Interestingly, mtap gene expression was also impaired in the liver of CCl4-cirrhotic rats and cirrhotic patients. we provide evidence indicating that epigenetic mechanisms, involving dna methylation and histone deacetylation, may play a role in the silencing of mtap gene expression in hepatocarcinoma. Given the recently proposed tumor suppressor activity of mtap, our observations can be relevant to the elucidation of the molecular mechanisms of multistep hepatocarcinogenesis. On the other hand, we have observed that the levéis of 5'-methylthioadenosine (mta), a nucleoside generated from s-adenosylmethionine (AdoMet) during polyamine synthesis, are inhibited in the cirrhotic patients. mta exerts hepatoprotector efects in hepatotoxic conditions with an inflammatory component. we have evaluated the anti-inflammatory properties of mta in bacterial lipopolysaccharide (LPS) challenged mice, murine macrophage RAW 264.7 cells (treated with LPS), human PBMCs (treated with PHA) and isolated rat hepatocytes (treated with pro-inflammatory cytokines). mta administration completely Erevented LPS-induced lethality. The life-sparing effect of MTA was accompanied y the suppression of circuíating tumor necrosis factor-alpha (TNF-alpha), inducible NO synthase (iNOS) expression, and by the stimulation of IL-10 synthesis. In conclusión, these observations demónstrate novel immunomodulatory properties for MTA that may be of valué in the management of inflammatory diseases.