• Asian Pacific Journal of Cancer Prevention
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• v.14 no.11
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• pp.6433-6438
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• 2013

In hepatocellular cancer (HCC), lack of response to chemotherapy and radiation treatment can be caused by a loss of epigenetic modifications of cancer cells. Methionine adenosyltransferase 1A is inactivated in HCC and may be stimulated by an epigenetic change involving promoter hypermethylation. Therefore, drugs releasing epigenetic repression have been proposed to reverse this process. We studied the effect of the demethylating reagent 5-aza-2'-deoxycitidine (5-Aza-CdR) on MAT1A gene expression, DNA methylation and S-adenosylmethionine (SAMe) production in the HCC cell line Huh7. We found that MAT1A mRNA and protein expression were activated in Huh7 cells with the treatment of 5-Aza-CdR; the status of promoter hypermethylation was reversed. At the same time, MAT2A mRNA and protein expression was significantly reduced in Huh7 cells treated with 5-Aza-CdR, while SAMe production was significantly induced. However, 5-Aza-CdR showed no effects on MAT2A methylation. Furthermore, 5-Aza-CdR inhibited the growth of Huh7 cells and induced apoptosis and through down-regulation of Bcl-2, up-regulation of Bax and caspase-3. Our observations suggest that 5-Aza-CdR exerts its anti-tumor effects in Huh7 cells through an epigenetic change involving increased expression of the methionine adenosyltransferase 1A gene and induction of S-adenosylmethionine production.

• YAKHAK HOEJI
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• v.51 no.6
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• pp.383-388
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• 2007

It has been reported that sulfur-containing intermediates or products in the transsulfuration pathway including S-adenosylmethionine, 5'-methylthioadenosine, glutathione and taurine can prevent liver injury mediated by inflammation response induced by lipopolysaccharide (LPS) treatment. The present study examines the modulation of hepatic metabolism of sulfur amino acid in a model of acute sepsis induced by LPS treatment (5 mg/kg, iv). Serum TNF-alpha and hepatotoxic parameters were significantly increased in rats treated with LPS, indicating that LPS results in sepsis at the doses used in this study. LPS also induced oxidative stress determined by increases in malondialdehyde levels and decreases in total oxy-radical scavenging capacities. Hepatic methionine and glutathione concentrations were decreased, but S-adenosylho-mocysteine, cystathionine, cysteine, hypotaurine and taurine concentrations were increased. Hepatic protein expression of methionine adenosyltransferase, cystathionine beta-synthase and cysteine dioxygenase were induced, but gamma-glutamylcysteine ligase catalytic subunit levels were decreased. The results show that sepsis activates transsulfuration pathway from methionine to cysteine, suggesting an increased requirement for methionine during sepsis.

• Journal of The Korean Society of Inherited Metabolic disease
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• v.16 no.1
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• pp.1-9
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• 2016

Newborn screening (NBS) is important if early intervention is effective in a disorder and if there are sensitive and specific biochemical markers to detect disorder. Methionine is a useful marker to detect abnormal methionine-homocysteine metabolism, especially homocystinuria which needs urgent medical intervention. However, hypermethioninemia could occur in other metabolic disorder including liver disease, tyrosinemia type I, methionine adenosyltransferase (MAT) I/III deficiency, glycine N-methyltransferase (GNMT) deficiency, or adenosylhomocysteine hydrolase deficiency. However, experience with NBS for homocystinurias and methylation disorders is limited. Especially, MAT I/III deficiency which is the most common cause of persistent hypermethioninemia have two inheritance, autosomal recessive (AR) and autosomal dominant (AD), and their clinical manifestation is different between AR and AD. Here, author reviewed recent articles of guideline and proposed guideline for homocystinuria and methylation disorder.

• YAKHAK HOEJI
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• v.38 no.4
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• pp.430-439
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• 1994

S-Adenosyl-L-methionine synthetase (ATP: methionine S-Adenosyltransferase, EC 2.5.1.6; AdoMet synthetase) catalyzes the biosynthesis of S-Adenosyl-L-methionine(AdoMet) from methionine in the presence of ATP. To elucidate the role of transmethylation reaction in the pancreatic tissues, we examined AdoMet synthetase and isozyme activities, and AdoMet contents in the various tissues. The activities of AdoMet synthetase marked the highest in the kidney, and the lowest in the testis among the various tissues of rat. Considerable amounts of AdoMet synthetase activities were detected in the pancreatic tissues of various animals except for those of frog. The level of ${\alpha}$ and ${\gamma}$ isozyme activities were present in the pancreatic tissues of various animals, while ${\beta}$ isozyme activities were detected as trace. AdoMet synthetase activities of rat brain, liver, testis were decreased with growth. In the rat pancreatic tissues, AdoMet synthetase activities were increased during 16 days after birth and then decreased between 16 and 47 days of age. Levels of AdoMet contents of rat brain and testis were decreased with growth. However, AdoMet contents of rat pancreas were decreased until 26 days of age, and then increased thereafter. AdoMet synthetase isozyme patterns did not vary with growth in the pancreas and testis. But, in the liver, ${\beta}$ form is strikingly increased with growth.

• Journal of The Korean Society of Inherited Metabolic disease
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• v.13 no.2
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• pp.98-103
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• 2013

Purpose: MAT-I/III deficiency by MAT1A gene mutation causes isolated hypermethioninemia, which is considered to be a clinically benign disease. But in some patients, mental retardation, developmental delay, myelination disorder may be shown. This study was performed to find out the clinical manifestations and genetic characteristics of patients with isolated hypermethioninemia. Methods: Clinical, biochemical and genetic analysis were done to 10 patients with isolated hypermethioninemia who were referred to department of pediatrics, Soonchunhyang University Hospital from March 1999 to March 2012. Results: At first visit, all patients' mean plasma methionine level was 5.5 mg/dL (2.1-14.6) and there were no increase of amino acid levels including homocystine in all patients. Serum homocysteine level was evaluated in seven patients who visited after year 2003, and ranged from 4.96 to $11.15{\mu}mol/L$ (normal < $25{\mu}mol/L$). Methionine restricted diet was started to all patients. Nine patients who managed regularly showed normal development, but one patient whose initial plasma methionine level was 14.6 mg/dL showed language delay at 1 year of age and was diagnosed as mild mental retardation (IQ=66) at 6 years of age. Genetic analysis was done to eight patients, R264H mutation was identified in seven patients. Also, both R299C and R356Q mutation were identified in one patient. Conclusion: Clinical findings in patients with isolated hypermethioninemia were generally good, but one patient showed mental retardation and language difficulty. R264H mutation which usually inherits as an autosomal dominant trait was most frequently found in our patients, and R299C/R356Q mutation were also identified.

• Toxicological Research
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• v.24 no.4
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• pp.281-287
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• 2008

Impairment of hepatic metabolism of sulfur-containing amino acids has been known to be linked with induction of liver injury. We determined the early changes in the transsulfuration reactions in liver of rats challenged with a toxic dose of $CCl_4$ (2 mmol/kg, ip). Both hepatic methionine concentration and methionine adenosyltransferase activity were increased, but S-adenosylmethionine level did not change. Hepatic cysteine was increased significantly from 4 h after $CCl_4$ treatment. Glutathione (GSH) concentration in liver was elevated in $4{\sim}8$ h and then returned to normal in accordance with the changes in glutamate cysteine ligase activity. Cysteine dioxygenase activity and hypotaurine concentration were also elevated from 4 h after the treatment. However, plasma GSH concentration was increased progressively, reaching a level at least several fold greater than normal in 24 h. ${\gamma}$-Glutamyltransferase activity in kidney or liver was not altered by $CCl_4$, suggesting that the increase in plasma GSH could not be attributed to a failure of GSH cycling. The results indicate that acute liver injury induced by $CCl_4$ is accompanied with extensive alterations in the metabolomics of sulfurcontaining amino acids and related substances. The major metabolites and products of the transsulfuration pathway, including methionine, cysteine, hypotaurine, and GSH, are all increased in liver and plasma. The physiological significance of the change in the metabolomics of sulfur-containing substances and its role in the induction of liver injury need to be explored in future studies.

• Journal of Life Science
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• v.24 no.6
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• pp.686-693
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• 2014

Restricted supply of nutrients may affect genes at the molecular level as well as physiological functions. Understanding the cellular responses during starvation is necessary for developing strategies to reduce damage caused by starvation stress. After 1 h of starvation, Got1 gene expression was increased but its expression returned to the normal state after 24 h. Mat1 gene expression continuously increased with starvation from 1 h until 24 hr. Rats starved for 1-3 days showed significant changes in expression of the Got1 and Mat1 genes, which were significantly reduced in the cerebral cortex and cerebellum. In the lung, gene expression was increased by starvation for 1-2 days but decreased on the third day. No differences were observed in gene expression in the heart. Strong Got1 lung gene expression was seen in the starvation group one day after restoration of the food supply. Muscle mass was significantly reduced at the start of starvation and remained the same after two days of starvation and one day after the food supply was restored. The Mat1 gene expression did not change. The Got1 was induced by NaCl and showed strong expression in the lung and the thymus, but the apparent decrease of the remaining changes were not observed in male rats. The Mat1 gene was not as sensitive as the Got1 gene to induction by NaCl. However, differences in gene induction by NaCl were evident between males and females, indicating that diet control of gene expression is associated with hormones.