Serum 5-Methyltetrahydrofolate Status Is Associated with One-Carbon Metabolism-Related Metabolite Concentrations and Enzyme Activity Indicators in Young Women

Abstract

Maintaining optimal one-carbon metabolism (OCM) is essential for health and pregnancy. In this cross-sectional study, folate status was assessed based on 5-methyltetrahydrofolate (5-MTHF) levels, and the association between 5-MTHF and OCM-related metabolites was investigated in 227 female Japanese university students aged 18–25 years. The participants were divided into high and low 5-MTHF groups based on their folate status. Serum samples of the participants were collected while they were fasting, and 18 OCM-related metabolites were measured using stable-isotope dilution liquid chromatography–electrospray tandem mass spectrometry. The association between serum 5-MTHF and OCM-related metabolite concentrations was assessed using Spearman’s rank correlation coefficient. Serum 5-MTHF concentrations were negatively correlated with total homocysteine (tHcy) concentrations and positively correlated with S-adenosylmethionine (SAM) and total cysteine (tCys) concentrations. Serum 5-MTHF concentrations demonstrated a stronger negative correlation with tHcy/tCys than with tHcy alone. The negative correlation between betaine and tHcy concentrations was stronger in the low 5-MTHF group than in the high 5-MTHF group. The 5-MTHF status could be linked to Hcy flux into the transsulfuration pathway via SAM. Therefore, the tHcy/tCys ratio may be a more sensitive indicator of the 5-MTHF status than tHcy alone. Furthermore, a low 5-MTHF status can enhance Hcy metabolism via betaine.

Longitudinal Analysis of One-Carbon Metabolism-Related Metabolites in Maternal and Cord Blood of Japanese Pregnant Women

“…Continuous variables are presented as a median and interquartile range because of the skewed distribution of serum OCM-related metabolites. Consistent with our previous report [ 8 ], we used specific ratios as indicator of activity of the metabolic pathway (substrate to product concentration ratios): the betaine/DMG ratio for indicator of betaine–homocysteine methyltransferase (BHMT) pathway [ 21 ], the SAM/SAH ratio for indicator of methyltransferase pathway [ 22 ], and the tCys/tHcy ratio for indicator of the metabolic pathway in the transsulfuration pathway flux (cystathionine β-synthase and cystathionine γ-lyase) [ 23 ]. We also measured the cord blood/maternal blood metabolite ratio at birth, indicating the number of times the concentration of metabolites in cord blood corresponds to that in maternal blood at birth.…”

“…Furthermore, in our study, the betaine/DMG ratios were negatively correlated with tHcy levels in maternal and cord blood at all sampling periods, and these correlations strengthened with advancing gestational age ( Table 3 ). Previously, we reported that in nonpregnant young women, when serum 5-MTHF concentrations in young women were divided into high-and low-MTHF groups by median, the low 5-MTHF group showed a possible enhancement of betaine-mediated Hcy metabolism compared with the high 5-MTHF group [ 8 ]. As gestation progresses, maternal serum 5-MTHF levels decrease [ 8 ].…”

“…Previously, we reported that in nonpregnant young women, when serum 5-MTHF concentrations in young women were divided into high-and low-MTHF groups by median, the low 5-MTHF group showed a possible enhancement of betaine-mediated Hcy metabolism compared with the high 5-MTHF group [ 8 ]. As gestation progresses, maternal serum 5-MTHF levels decrease [ 8 ]. In addition to 5-MTHF, previous studies have shown that cobalamin, a cofactor for the enzyme methionine synthase, which remethylates homocysteine by methyl group donation of 5-MTHF, decreases maternal blood levels and increases homocysteine as the pregnancy progresses [ 34 ].…”

“…We previously reported a detailed method for measuring OCM-related metabolites in serum [ 8 , 19 ]. In brief, we quantified 18 OCM-related metabolites [5-MTHF, folic acid, choline, betaine, dimethylglycine (DMG), methionine, SAM, SAH, total tHcy, cystathionine, total cysteine (tCys), taurine, serine, glycine, riboflavin, pyridoxamine, and pyridoxine] in serum using stable isotope dilution liquid chromatography/tandem mass spectrometry.…”

“…In our previous study, we observed that 5-MTHF levels decreased with advancing gestational age [ 19 ]. Furthermore, we hypothesized that 5-MTHF status may be linked to metabolic fluxes in the choline metabolic pathway, SAM, and transsulfuration pathway based on studies in nonpregnant young women [ 8 ]. In this study, we investigated whether similar associations exist during pregnancy.…”