• Journal of Nutrition and Health
• /
• 제40권1호
• /
• pp.14-23
• /
• 2007

Elevated plasma homocysteine (Hcy) is a risk factor for cognitive dysfunction and Alzheimer disease, although the mechanism is still unknown. Both folate and betaine, a choline metabolite, play essential roles in the remethylation of Hcy to methionine. Choline deficiency may be associated with low folate status and high plasma Hcy. Alterations in DNA methylation also have established critical roles for methylation in development of the nervous system. This study was undertaken to assess the effect of choline and folate deficiency on Hcy metabolism and genomic DNA methylation status of the liver and brain. Groups of adult male Sprague Dawley rats were fed on a control, choline-deficient (CD), folate-deficient (FD) or choline/folate-deficient (CFD) diets for 8 weeks. FD resulted in a significantly lower hepatic folate (23%) (p<0.001) and brain folate (69%) (p<0.05) compared to the control group. However, plasma and brain folate remained unaltered by CD and hepatic folate reduced to 85% of the control by CD (p<0.05). Plasma Hcy was significantly increased by FD $(18.34{\pm}1.62{\mu}M)$ and CFD $(19.35{\pm}3.62{\mu}M)$ compared to the control $(6.29{\pm}0.60{\mu}M)$ (p<0.001), but remained unaltered by CD. FD depressed S-adenosylmethionine (SAM) by 59% (p<0.001) and elevated S-adenosylhomocysteine (SAM) by 47% in liver compared to the control group (p<0.001). In contrast, brain SAM levels remained unaltered in CD, FD and CFD rats. Genomic DNA methylation status was reduced by FD in liver (p<0.05) Genomic DNA hypomethylation was also observed in brain by CD, FD and CFD although it was not significantly different from the control group. Genomic DNA methylation status was correlated with folate stores in liver (r=-0.397, p<0.05) and brain (r = -0.390, p<0.05), respectively. In conclusion, our data demonsoated that genomic DNA methylation and SAM level were reduced by folate deficiency in liver, but not in brain, and correlated with folate concentration in the tissue. The fact that folate deficiency had differential effects on SAM, SAH and genomic DNA methylation in liver and brain suggests that the Hcy metabolism and DNA methylation are regulated in tissue-specific ways.

• Asian Pacific Journal of Cancer Prevention
• /
• 제16권10호
• /
• pp.4383-4386
• /
• 2015

Background: The C1561T variant of the glutamate carboxypeptidase II (GCPII) gene is critical for natural methylfolylpolyglutamte (methylfolate) absorption, and has been associated with perturbations in folate metabolism and disease susceptibility. However, little is known on C1561T-GCPII as a risk factor for colorectal cancer. Therefore, this study examined whether C1561T-GCPII influences folate metabolism and adenomatous polyp occurrence. Materials and Methods: 164 controls and 38 adenomatous polyp cases were analysed to determine blood folate and plasma homocysteine (Hcy) level, dietary intake of natural methylfolate, synthetic pteroylglutamic acid (PteGlu), vitamin C and C1561T-GCPII genotype. Results: In controls and cases, 7.3 and 18.4 percent of subjects respectively, were found to have the CT genotype, increasing the risk for adenomatous polyp occurrence 2.86 times (95% CI:1.37-8.0, p=0.035). Total dietary folate, methylfolate and PteGlu intake and the level of erythrocyte folate and plasma Hcy did not predict the occurrence of an adenomatous polyp. However, dietary natural vitamin C intake was associated with adenomatous polyp risk within C1561T-GCPII CT genotype subjects (p=0.037). Conclusions: The findings suggest that C1561T-GCPII variation may be associated with risk for adenomatous polyp, and vitamin C may modify risk by interacting with the variant gene, its expression product and/or folate substrates.

• Journal of Nutrition and Health
• /
• 제55권3호
• /
• pp.330-347
• /
• 2022

엽산은 비타민 B군에 속하는 수용성 비타민으로, 핵산 합성과 아미노산 대사에서 단일탄소를 전달해 주는 반응의 조효소 역할을 한다. 엽산은 새로운 세포가 형성되어 성장하는 임신기와 성장기에 매우 중요한 영양소이며, 여성의 임신 전 적절한 엽산 영양상태는 신경관 결손증을 예방한다고 알려져 있다. 이 외에도 엽산 섭취 부족은 빈혈, 고호모시스테인혈증, 심혈관질환, 암, 인지 장애, 우울증 등 다양한 질병과도 관련이 있다고 보고되어, 엽산은 전 생애주기 동안 건강을 유지하기 위해 충분히 섭취해야 하는 영양소이다. 본 연구에서는 2020 한국인 엽산 섭취기준의 개정 근거를 살펴보고, 국민건강영양조사로부터 엽산 섭취량과 혈청 엽산 농도를 성별, 연령대별로 분석하였으며, 향후 엽산 섭취기준 개정에 참고할 만한 내용을 제언하였다. 표준체중의 변경에 따라 영아 후기의 충분섭취량과 15-18세의 평균필요량이 2015년과 달리 변경되었으나, 권장섭취량과 상한섭취량에는 변화가 없었다. 2016-2018년 국민건강영양조사 결과에서 대부분의 연령에서 엽산 섭취량은 권장섭취량에 미치지 못하였으며 특히 15-29세 여성의 섭취량이 권장섭취량 대비 매우 낮았다. 임신부와 수유부의 엽산 섭취량도 권장섭취량 대비 60% 이하로 낮았으나, 혈액수준은 다른 연령층에 비해 높아 보충제를 섭취한 결과로 보인다. 앞으로 국민건강영양조사에서 보충제 섭취량도 조사해야 할 것이며, 엽산의 섭취량 평가를 위해서는 생식품, 조리된 식품, 강화식품 중의 엽산 함량에 대한 DB가 구축되어야 할 것이다. 또한 혈청 엽산 뿐 아니라 적혈구 엽산 농도와 혈장 호모시스테인 농도도 분석할 필요가 있으며, 분석방법에 대한 질 관리가 필요하다.

• 한국임상약학회지
• /
• 제10권3호
• /
• pp.120-124
• /
• 2000

Diltiazem inhibits calcium channels and leads to vascular smooth muscle relaxation and negative inotroic and chronotropic effects in the heart. Diltiazem (DTZ) is almost completely absorbed after oral administration, but its bioavailability is reduced because of considerable hepatic first-pass metabolism. The main metabolite of DTZ is deacetyldiltiazem. The purpose of this study was to report the pharmacokinetic changes of DTZ and its metabolite, deacetyldiltiazem (DAD) after intravenous administration of diltiazem to control rabbits and rabbits with mild and medium folate-induced renal failure (FIRRs). The area under the plasma concentration-time curves (AUC) of DTZ were significantly increased in mild and medium FIRRs. The metabolite ratio of the DAD to DTZ were significantly decreased in mild and medium FIRRs. The elimination rate constant $(\beta)$ and total body clearances (CLt) of DTZ were significantly decreased in mild and medium FIRRS. These findings suggest that the hepatic metabolism of diltiazem was inhibited and CLt and ${\beta}$ of DTZ were significantly decreased in mild and in rabbits with medium folate-induced renal failure.

• Molecular & Cellular Toxicology
• /
• 제1권2호
• /
• pp.137-141
• /
• 2005

The critical role of folate in the remethylation pathway for methionine synthesis from homocysteine has been well documented. Hyperhomocysteinemia resulting from inadequate folate nutrition has been implicated in increased incidence of macrovascular diseases, colorectal cancer, neural tube defects, etc. Chronic exposure to ethanol impairs folate nutrition and one-carbon metabolism in the liver, which often results in fatty liver due to a defective remetylation process. This study was carried out to investigate the chronic effects of moderate levels of alcohol and dietary folate on plasma homocysteine levels, and on histopathology and biochemical functions of the liver. Rats were raised on experimental diets with three levels of folate (0, 2, 8 mg/kg diet), and 50% ethanol (1.8 ml/kg body weight) was administered intragastically by intubation tubes three times a week for 10 weeks. Plasma homocysteine concentrations were found to be significantly influenced by dietary folate intake and alcohol administration. Among all treatment groups, plasma homocysteine levels were the highest in the animals receiving a combined treatment of folate deficient diet and alcohol administration. Plasma homocysteine concentrations were negatively correlated with folate concentration in the plasma (p<0.01) and liver (p<0.05). Among alcohol treated rats, increase in plasma homocysteine values due to macrovascular and microvascular fatty changes and spotted necrosis were observed more frequently in folate-deficient animals diet than those on folate-adequate and folate supplemented diets in alcohol-treated rats. These results indicate that folate supplementation above the recommended level might be beneficial in the prevention of alcohol-related hyperhomocysteinemia and abnormal histologic changes in the liver.

• Archives of Pharmacal Research
• /
• 제24권4호
• /
• pp.333-337
• /
• 2001

The pharmacokinetic changes of diltiazem (DTZ) and its main metabolite, deacetyldiltiazem (DAD) were studied after oral administration of DTZ to normal rabbits and mild and medium folate-induced renal failure rabbits. DTZ 10 mg/kg was given to the rabbits either orally (n=6). Plasma concentrations of DTZ and DAD were determined by a high performance liquid chromatography assay. The area under the plasma concentration-time curves (AUC) and maximum plasma concentration ($C_{max}$) of DTZ were significantly increased in mild and medium folate-induced renal failure rabbits. The metabolite ratio of the DTZ to DAD were significantly decreased in mild and medium folate-induced renal failure rabbits. The volume of distribution ($V_{d}$) and total body clearance ($CL_{t}$) of DTZ were significantly decreased in mild and medium folate-induced renal failure rabbits. The elimination rate constant ($\beta$) of DTZ was significantly decreased in folate-induced renal failure rabbits, but that of DAD was significantly increased. These findings suggest that the hepatic metabolism of DTZ was inhibited and the $V_{d}$, $CL_{t}$ and $\beta$ of DTZ were significantly decreased in mild and medium folate-induced renal failure rabbits.

• Nutrition Research and Practice
• /
• 제14권2호
• /
• pp.95-101
• /
• 2020

BACKGROUND/OBJECTIVES: Folate plays a critical role in DNA synthesis and methylation. Intracellular folate homeostasis is maintained by the enzymes folylpolyglutamate synthase (FPGS) and γ-glutamyl hydrolase (GGH). FPGS adds glutamate residues to folate upon its entry into the cell through a process known as polyglutamylation to enhance folate retention in the cell and to maintain a steady supply of utilizable folate derivatives for folate-dependent enzyme reactions. Thereafter, GGH catalyzes the hydrolysis of polyglutamylated folate into monoglutamylated folate, which can subsequently be exported from the cell. The objective of this review is to summarize the scientific evidence available on the effects of intracellular folate homeostasis-associated enzymes on cancer chemotherapy. METHODS: This review discusses the effects of FPGS and GGH on chemosensitivity to cancer chemotherapeutic agents such as antifolates, such as methotrexate, and 5-fluorouracil. RESULTS AND DISCUSSION: Polyglutamylated (anti)folates are better substrates for intracellular folate-dependent enzymes and retained for longer within cells. In addition to polyglutamylation of (anti)folates, FPGS and GGH modulate intracellular folate concentrations, which are an important determinant of chemosensitivity of cancer cells toward chemotherapeutic agents. Therefore, FPGS and GGH affect chemosensitivity to antifolates and 5-fluorouracil by altering intracellular retention status of antifolates and folate cofactors such as 5,10-methylenetetrahydrofolate, subsequently influencing the cytotoxic effects of 5-fluorouracil, respectively. Generally, high FPGS and/or low GGH activity is associated with increased chemosensitivity of cancer cells to methotrexate and 5-fluorouracil, while low FPGS and/or high GGH activity seems to correspond to resistance to these drugs. Further preclinical and clinical studies elucidating the pharmocogenetic ramifications of these enzyme-induced changes are warranted to provide a framework for developing rational, effective, safe, and customized chemotherapeutic practices.

• Journal of Nutrition and Health
• /
• 제31권7호
• /
• pp.1121-1129
• /
• 1998

The critical role of folate vitamin in the remethylation pathway for methionine synthesis from homocysteine has been well documented. Hyperhomocysteinemia resulting from inadequate folate nutrition has been implicated in increased incidence of macrovascular diseases, colorectal cancer, neural tube defects, etc. Chronic exposure to ethanol impairs folate nutrition and one-carbon metabolism in the liver, which often results in fatty liver due to a defective remethylation process. This study was carried out to investigate the chronic effects of moderate levels of alcohol and dietary 131ate on plasma homocysteine levels, and on histopathology and biochemical functions of the liver Rats were raised on experimental diets with three levels of folate(0, 2, 8mg/kg diet), and 50% ethanol(1.8m1/kg body weight) was administered intragastrically by intubation tubes three times a week for 10 weeks. Plasma homocysteine concentrations were found to be significantly influenced by dietary folate intake and alcohol administration. Among all treatment groups, Plasma homocysteine levels were highest in the animals receiving a combined treatment of folate deficient diet and alcohol administration. Plasma homocysteine concentration was negatively correlated with folate concentration in the plasma(p<0.01) and liver(p<0.05). Among alcohol treated rats, increase in plasma homocysteine values due to ethanol was prevented by 131ate supplementation. When liver histological tests were performed, macrovascular and microvascular fatty changes and spotted necrosis were observed more frequently in folate-deficient animals diet than those on folate-adequate and folate-supplemented diets in alcohol-treated rats. These results indicate that folate supplementation above the recommended level might be beneficial in the prevention of alcohol-related hyperhomocystei-nemia and abnormal histologic changes in the liver due. (Korean J Nutrition 31(7) : l121-l129, 1998)

• 대한지역사회영양학회지
• /
• 제6권3호
• /
• pp.507-515
• /
• 2001

The elevation of plasma total homocysteine(tHcy) is now established as a risk factro for cardiovascular disease. It is also well known that plasma levels of folate and vitamin $B_{12}$ influences homocysteine metabolism as cofactors. Recently, the effects of health-related lifestyle factors, such as smoking, alcohol drinking coffee consumption, regular exercise, and etc, on plasma tHcy have been determined. The Hordalane Homocysteine Study revealed that smoking and coffee consumption are major deter minants of plasma tHcy as well as folate levels; however, the influence of alcohol intake is still controversial. In Koreans, the effects of lifestyle factors of plasma tHcy have not yet been determined. Thus, we investigated the relationships of various lifestyle determinants with plasma tHcy, folate, and vitamin $B_{12}$ levels and the erythrocyte folate concentrations in Korean adults (99 males and 96 fermales). Plasma tHcy levels were significantly hight in male subjects. On the contrary, plasma levels of folate and vitamin $B_{12}$ and erythrocyte folate concentration of the females were significantly higher than those of the males. Among the five lifestyle factors determined in the study, regular exercise significantly affects plasma tHcy levels only in the females, Contrary to the expectation, there were on significant differences in plasma tHcy levels between alcohol drinkers and non-alcohol drinkers as well as smokers and non-smokers. And also, plasma tHcy leverls were not different between coffee consumers and non-coffee consumer and between green tea consumers and non-green tea consumers. Although alcohol intake did not influence plasma tHcy levels, the duration, frequency, and amount of alcohol drinking showed significant negative relationships with plasma folate levers. These results indicate the regular exercise and alcohol intake might influence plasma levels of tHcy and folate in Koreans, although the results were not reveled in both sexes.

• 대한지역사회영양학회지
• /
• 제10권6호
• /
• pp.963-970
• /
• 2005

Recently elevated plasma homocysteine concentration is considered an independent risk factor for atherosclerosis and thrombosis with coronary artery disease. Folate and vitamin $B_{12}$ are cofactors and closely related with metabolism of homocysteine. The purpose of this study is to evaluate the correlation between homocysteine and folate and vitamin $B_{12}$ in patients with ischemic heart disease. Twenty-six patients, in whom coronary angiographic finding revealed more than $50\%$ of stenosis at least in one coronary vessel were enrolled as the patient group, and thirty subjects, in whom angiographic finding revealed in not significant stenosis, but complained of chest pain, were selected as the control group. Fasting venous blood was obtained and measured the concentration of plasma total homocysteine, folate and vitamin $B_{12}$ by high performance liquid chromatography and fluorescence detection method. We examined the correlation between homocysteine and folate and/or vitamin $B_{12}$ in the control group and the patient group, respectively. Compared with the control group, the patient group had relatively higher plasma total homocysteine concentration ($10.7\pm4.2\;vs\;9.6\pm3.5$ umol/L), but showed no significant difference. Folate and vitamin $B_{12}$ concentration are low in the patient group, but showed no significant difference between patient and control group. Plasma total homocysteine concentration showed negative correlation with folate and vitamin $B_{12}$ in both the control group and the patient group, and showed significantly negative correlation in patient group {r = -0.550 (p < 0.01) vs r = -0.609 (p < 0.01)}. We knew that the plasma total homocysteine concentration were relatively elevated in patient group compared with the control group. Because plasma total homocysteine concentrations are closely negative correlated with folate and vitamin $B_{12}$ in the patient group, folate and vitamin $B_{12}$ supplement can lower the mortality and morbidity of ischemic heart disease. (Korean J Community Nutrition 10(6) : $963\∼970$, 2005)