• Asian Pacific Journal of Cancer Prevention
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• 제14권11호
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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.

• 약학회지
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• 제51권6호
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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.

• 대한유전성대사질환학회지
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• 제16권1호
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• pp.1-9
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• 2016

국내 정부 지원 무료 검사로 진행 중인 6종 신생아 선별 검사에서 호모시스틴뇨증을 진단하기 위해 메티오닌의 증가가 마커로 사용되고 있다. 그러나 실제 고메티오닌혈증에서 감별해야 하는 질환들에는 간질환, tyrosinemia type I (MIM #276700), methionine adenosyltransferase (MAT) I/III 결핍, glycine N-methyltransferase (GNMT) 결핍, adenosylhomocy-steine hydrolase (SAHH) 결핍, adenosine kinase (ADK) 결핍, citrin deficiency (citrullinemia type I) 등이 있다. 고메티오닌혈증의 흔한 원인이자 양성 질환으로 알려졌던 MAT I/III 결핍 질환은 유전 방식에 따라 신경학적 증상 발현 및 치료의 필요성이 보고되고 있어 신생아 선별검사에서 고메티오닌혈증 양성으로 나올 경우 감별 진단 및 처치에 대한 가이드라인이 필요하겠다. 신생아 선별검사에서 고메티오닌혈증 양성으로 나올 경우, 간수치 및 혈장 아미노산 분석, 혈장 총 호모시스테인 수치를 통해 여러 질환 들을 감별할 수 있으며 혈장 총 호모시스테인의 증가가 40 umol/L 미만의 경우에서는 MAT I/III 결핍을 먼저 고려해 볼 수 있겠다. MAT I/III 결핍에서는 우성 유전형일 경우에는 치료가 필요 없지만 열성 유전형에서는 정기적인 발달 지표, 혈장 메티오닌과 총 호모시스테인 수치의 추적이 필요하겠으며 심한 고메티오인혈증(>800umol/L)에서는 저메티오닌식이를, 발달 지연, 뇌말이집 형성 장애가 동반한 경우에는 S-adenosylmethio-nine (SAM) 복용을 고려한다. 호모시스틴뇨증에서는 절반에서 피리독신 반응형을 보이고 피리독신 반응형은 조기에 메티오닌 증가가 없을 수 있기에 선별검사에서 놓칠 수 있다. 치료에는 저메티오닌 식이, 피리독신, 베타인, 엽산 등이 있으며 베타인 투약시 메티오닌 증가로 인한 뇌부종에 대한 주의가 필요하다. 그 외 GNMT, SAHH, ADK 결핍은 현재 환자 수와 예후가 제한적으로 조기 진단 및 치료에 대한 뚜렷한 이득이 명확하지 않은 상태이다. 미국, 유럽의 일부 기관들에서는 낮은 메티오닌 수치로 재메칠화 장애에 대한 선별검사도 시행하고 있어 국내에도 관련 질환에 대한 현황 및 선별검사 도입의 필요성에 대해 논의가 필요하겠다.

• 약학회지
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• 제38권4호
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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.

• 대한유전성대사질환학회지
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• 제13권2호
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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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• 제24권4호
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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.

• 생명과학회지
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• 제24권6호
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• pp.686-693
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• 2014

영양분의 제한공급은 인체에 큰 스트레스중의 하나로서, 분자수준의 유전자발현과 생리기능에 영향을 미친다. 영양고갈-스트레스 동안에 일어나는 세포반응을 이해하는 것은 다이어트를 실시할 때에 일어나는 부작용을 최소화할 수 있는 실마리를 제공해준다. Got1 유전자의 발현은 starvation 1시간부터 발현이 증가하다가 24시간에서 정상상태로 돌아왔다. Mat1 유전자의 발현은 starvation 1시간부터 24시간까지 지속적으로 발현이 증가하였다. Rat를 1-3일간 starvation에 의해서는 Got1 유전자의 발현은 큰 변화를 보이지 않았지만, Mat1 유전자의 발현은 cerebral cortex에서 현저하게 줄어드는 반면에 cerebellum과 lung에서는 1-2일간의 starvation에 의해서 유전자 발현이 증가하다가 3일째는 발현이 줄어들었다. Heart에서는 starvation에 의해서 유전자 발현이 관찰되지 않을 정도로 줄어들었다. 간헐 starvation (2일간 starvation 군과 2일간 starvation후 1일간 먹이를 공급한 것과 2일간 starvation + 1일간 먹이를 공급 + 2일간 starvation 군)으로 나누었다. Got1 유전자의 발현은 lung에서만 starvation 후 1일간 먹이를 공급한 군에서 아주 강한 발현을 보였다. liver의 경우는 2일 간 starvation 군과 2일간 starvation후 1일간 먹이를 공급한 군에서 발현이 약해진 후 2일간 starvation + 1일간 먹이를 공급 + 2일간 starvation 군에서 강한 발현을 보였다. Muscle에서는 starvation 시작과 동시에 발현이 현저히 감소 후 2일간 starvation후 1일간 먹이를 공급하면 정상상태로 돌아왔다. Mat1 유전자는 의미 있는 발현 변화가 없었다. Got1 유전자 발현은 ♂의 경우 NaCl 공급에 의해서 lung에서는 강한 발현을 보이고 thymus에서는 감소하였고 나머지에서는 뚜렷한 발현 변화가 관찰되지 않았다. ♀의 경우는 물 공급 보다가 NaCl 공급에 의해서 모두 약한 발현 양상을 보였다. Mat1 유전자의 발현은 ♂의 경우 NaCl 공급에 의해서 lung, kidney, muscle에서 약하지만 상승 발현이 관찰되었다. ♀의 경우는 NaCl 공급에 의해서 상승 발현 하는 것이 관찰되지 않았다.