• Journal of Nutrition and Health
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• v.40 no.1
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• pp.14-23
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• 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
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• v.16 no.10
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• pp.4383-4386
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• 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
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• v.55 no.3
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• pp.330-347
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• 2022

Folate, a water-soluble vitamin, acts as a coenzyme for one-carbon metabolism in nucleic acid synthesis and amino acid metabolism. Adequate folate nutritional status during the periconceptional period is known to prevent neural tube defects. In addition, insufficient folate intake is associated with various conditions, such as anemia, hyperhomocysteinemia, cardiovascular disease, cancer, cognitive impairment, and depression. This review discusses the rationale for the revision of the 2020 Korean dietary reference intakes for folate, and suggestions for future revisions. Based on the changes in the standard body weight in 2020, the adequate intake (AI) for infants (5-11 months) and the estimated average requirements (EARs) for 15-18 years of age were revised, but there were no changes in the recommended nutrient intakes (RNIs) and tolerable upper intake levels (ULs) for all age groups. Mean folate intake did not reach RNI in most age groups and was particularly low in women aged 15-29 years, according to the results of the 2016-2018 Korea National Health and Nutrition Examination Survey (KNHANES). The percentages of folate intake to RNI were lower than 60% in pregnant and lactating women, but serum folate concentrations were higher than those in other age groups, presumably due to the use of supplements. Therefore, total folate intake, from both food and supplements, should be evaluated. In addition, the database of folate in raw, cooked, and fortified foods should be further expanded to accurately assess the folate intake of Koreans. Determination of the concentrations of erythrocyte folate and plasma homocysteine as well as serum folate is recommended, and quality control of the analysis is critical.

• Korean Journal of Clinical Pharmacy
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• v.10 no.3
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• pp.120-124
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• 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
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• v.1 no.2
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• pp.137-141
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• 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
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• v.24 no.4
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• pp.333-337
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• 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
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• v.14 no.2
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• pp.95-101
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• 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
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• v.31 no.7
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• pp.1121-1129
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• 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)

• Korean Journal of Community Nutrition
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• v.6 no.3
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• pp.507-515
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• 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.

• Korean Journal of Community Nutrition
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• v.10 no.6
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• pp.963-970
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• 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)