Reduced mRNA abundance of the main enzymes involved in methionine metabolism in human liver cirrhosis and hepatocellular carcinoma.

Abstract Background/Aims: It has been known for at least 50 years that alterations in methionine metabolism occur in human liver cirrhosis. However, the molecular basis of this alteration is not completely understood. In order to gain more insight into the mechanisms behind this condition, mRNA levels of methionine adenosyltransferase ( MAT1A ), glycine methyltransferase ( GNMT ), methionine synthase ( MS ), betaine homocysteine methyltransferase ( BHMT ) and cystathionine β-synthase ( CBS ) were examined in 26 cirrhotic livers, five hepatocellular carcinoma (HCC) tissues and ten control livers. Methods: The expression of the above-mentioned genes was determined by quantitative RT-PCR analysis. Methylation of MAT1A promoter was assessed by methylation-sensitive restriction enzyme digestion of genomic DNA. Results: When compared to normal livers MAT1A , GNMT, BHMT, CBS and MS mRNA contents were significantly reduced in liver cirrhosis. Interestingly, MAT1A promoter was hypermethylated in the cirrhotic liver. HCC tissues also showed decreased mRNA levels of these enzymes. Conclusions: These findings establish that the abundance of the mRNA of the main genes involved in methionine metabolism is markedly reduced in human cirrhosis and HCC. Hypermethylation of MAT1A promoter could participate in its reduced expression in cirrhosis. These observations help to explain the hypermethioninemia, hyperhomocysteinemia and reduced hepatic glutathione content observed in cirrhosis.

[1]  J. Henderson,et al.  Evidence for impairment of transsulfuration pathway in cirrhosis , 1981 .

[2]  N. Kaplowitz,et al.  Feeding S‐adenosyl‐l‐methionine attenuates both ethanol‐induced depletion of mitochondrial glutathione and mitochondrial dysfunction in periportal and perivenous rat hepatocytes , 1995, Hepatology.

[3]  J. Mato,et al.  S‐adenosyl‐L‐methionine synthetase and phospholipid methyltransferase are inhibited in human cirrhosis , 1988, Hepatology.

[4]  R. Pugh,et al.  Transection of the oesophagus for bleeding oesophageal varices , 1973, The British journal of surgery.

[5]  L. Franco,et al.  DNA methylation and histone acetylation of rat methionine adenosyltransferase 1A and 2A genes is tissue-specific. , 2000, The international journal of biochemistry & cell biology.

[6]  P. Ueland,et al.  Total homocysteine in plasma or serum: methods and clinical applications. , 1993, Clinical chemistry.

[7]  Cho-il Kim,et al.  S‐Adenosyl‐L‐methionine attenuates alcohol‐induced liver injury in the baboon , 1990, Hepatology.

[8]  M. Simile,et al.  Genomic abnormalities in hepatocarcinogenesis. Implications for a chemopreventive strategy. , 1993, Anticancer research.

[9]  M. Ávila,et al.  Induction of TIMP-1 expression in rat hepatic stellate cells and hepatocytes: a new role for homocysteine in liver fibrosis. , 1999, Biochimica et biophysica acta.

[10]  S. Alemany,et al.  Specific loss of the high‐molecular‐weight form of S‐adenosyl‐L‐methionine synthetase in human liver cirrhosis , 1988, Hepatology.

[11]  G. Vendemiale,et al.  Effects of oral S-adenosyl-L-methionine on hepatic glutathione in patients with liver disease. , 1989, Scandinavian journal of gastroenterology.

[12]  M. Kotb,et al.  Consensus nomenclature for the mammalian methionine adenosyltransferase genes and gene products. , 1997, Trends in genetics : TIG.

[13]  M. Pajares,et al.  S-adenosylmethionine synthesis: molecular mechanisms and clinical implications. , 1997, Pharmacology & therapeutics.

[14]  J. Finkelstein,et al.  Methionine metabolism in mammals. , 1990, The Journal of nutritional biochemistry.

[15]  M. Pajares,et al.  S‐adenosylmethionine treatment prevents carbon tetrachloride—induced S‐adenosylmethionine synthetase inactivation and attenuates liver injury , 1992, Hepatology.

[16]  H. Harper,et al.  Rate of disappearance from plasma of intravenously administered methionine in patients with liver damage. , 1947, Science.

[17]  J. Tredger,et al.  S‐adenosylmethionine protects against acetaminophen hepatotoxicity in two mouse models , 1992, Hepatology.

[18]  H. Jakubowski.  Protein homocysteinylation: possible mechanism underlying pathological consequences of elevated homocysteine levels , 1999, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[19]  H. Yang,et al.  Cloning and functional characterization of the 5'-flanking region of human methionine adenosyltransferase 1A gene. , 2000, The Biochemical journal.

[20]  Shelly C. Lu,et al.  Liver‐specific methionine adenosyltransferase MAT1A gene expression is associated with a specific pattern of promoter methylation and histone acetylation: implications for MAT1A silencing during transformation , 2000, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[21]  J. Christman,et al.  Rapid appearance of hypomethylated DNA in livers of rats fed cancer-promoting, methyl-deficient diets. , 1989, Cancer research.

[22]  V. Marras,et al.  Chemoprevention of rat liver carcinogenesis by S-adenosyl-L-methionine: a long-term study. , 1992, Cancer research.

[23]  J. Hwang,et al.  Changes in S‐adenosylmethionine synthetase in human liver cancer: Molecular characterization and significance , 1996, Hepatology.

[24]  M. Zoli,et al.  Defective methionine metabolism in cirrhosis: Relation to severity of liver disease , 1992, Hepatology.

[25]  H. Shinozuka,et al.  On the role of compensatory mitogenesis in the hepatocarcinogenicity of choline and multiple-lipotrope devoid diets. , 1994, Carcinogenesis.

[26]  E. Goldman,et al.  Synthesis of homocysteine thiolactone by methionyl‐tRNA synthetase in cultured mammalian cells , 1993, FEBS letters.

[27]  S. Mudd,et al.  Labile methyl balances for normal humans on various dietary regimens. , 1975, Metabolism: clinical and experimental.

[28]  A. E. Rogers,et al.  Labile methyl groups and the promotion of cancer. , 1986, Annual review of nutrition.

[29]  G. Varela-Moreiras,et al.  Carbon tetrachloride–induced hepatic injury is associated with global DNA hypomethylation and homocysteinemia: Effect of S‐adenosylmethionine treatment , 1995, Hepatology.

[30]  D. Weir,et al.  The effect of ethanol on one‐carbon metabolism: Increased methionine catabolism and lipotrope methyl‐group wastage , 1993, Hepatology.

[31]  O. Hino,et al.  Clonal growth of hepatitis B virus-integrated hepatocytes in cirrhotic liver nodules. , 1992, Cancer research.

[32]  R. Hoffman,et al.  Altered methionine metabolism, DNA methylation and oncogene expression in carcinogenesis. A review and synthesis. , 1984, Biochimica et biophysica acta.

[33]  G. Stramentinoli,et al.  Protective role of S-adenosyl-L-methionine on liver injury induced by D-galactosamine in rats. , 1978, Biochemical pharmacology.

[34]  J. Rodés,et al.  S-adenosylmethionine in alcoholic liver cirrhosis: a randomized, placebo-controlled, double-blind, multicenter clinical trial. , 1999, Journal of hepatology.

[35]  P. Gérard,et al.  Alcoholic cirrhosis and cobalamin metabolism. , 1997, Digestion.

[36]  D. Tuma,et al.  Effects of prolonged ethanol feeding on methionine metabolism in rat liver. , 1987, Biochemistry and cell biology = Biochimie et biologie cellulaire.

[37]  H. Hasegawa,et al.  Clonal origin of atypical adenomatous hyperplasia of the liver and clonal identity with hepatocellular carcinoma. , 1988, Gastroenterology.