title: Folic acid handling by the human gut: implications for food fortification and supplementation.
abstract: BACKGROUND
  Current thinking, which is based mainly on rodent studies, is that physiologic doses of folic acid (pterylmonoglutamic acid), such as dietary vitamin folates, are biotransformed in the intestinal mucosa and transferred to the portal vein as the natural circulating plasma folate, 5-methyltetrahydrofolic acid (5-MTHF) before entering the liver and the wider systemic blood supply.
  
  
  OBJECTIVE
  We tested the assumption that, in humans, folic acid is biotransformed (reduced and methylated) to 5-MTHF in the intestinal mucosa.
  
  
  METHODS
  We conducted a crossover study in which we sampled portal and peripheral veins for labeled folate concentrations after oral ingestion with physiologic doses of stable-isotope-labeled folic acid or the reduced folate 5-formyltetrahydrofolic acid (5-FormylTHF) in 6 subjects with a transjugular intrahepatic porto systemic shunt (TIPSS) in situ. The TIPSS allowed blood samples to be taken from the portal vein.
  
  
  RESULTS
  Fifteen minutes after a dose of folic acid, 80 ± 12% of labeled folate in the hepatic portal vein was unmodified folic acid. In contrast, after a dose of labeled 5-FormylTHF, only 4 ± 18% of labeled folate in the portal vein was unmodified 5-FormylTHF, and the rest had been converted to 5-MTHF after 15 min (postdose).
  
  
  CONCLUSIONS
  The human gut appears to have a very efficient capacity to convert reduced dietary folates to 5-MTHF but limited ability to reduce folic acid. Therefore, large amounts of unmodified folic acid in the portal vein are probably attributable to an extremely limited mucosal cell dihydrofolate reductase (DHFR) capacity that is necessary to produce tetrahydrofolic acid before sequential methylation to 5-MTHF. This process would suggest that humans are reliant on the liver for folic acid reduction even though it has a low and highly variable DHFR activity. Therefore, chronic liver exposure to folic acid in humans may induce saturation, which would possibly explain reports of systemic circulation of unmetabolized folic acid.
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom (IP, MH, and DEJ); the Institute of Food Research, Norwich Research Park, Norwich, United Kingdom (MJK, MP, JRD, AJAW, and PMF); the Centre for Analytical Bioscience, School of Pharmacy, University of Nottingham, Nottingham, United Kingdom (DAB); and the Department of Radiology, Freeman Hospital, Newcastle upon Tyne, United Kingdom (JR and RJ).
authors.forename: Imran
authors.initials: I
authors.lastname: Patanwala
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom (IP, MH, and DEJ); the Institute of Food Research, Norwich Research Park, Norwich, United Kingdom (MJK, MP, JRD, AJAW, and PMF); the Centre for Analytical Bioscience, School of Pharmacy, University of Nottingham, Nottingham, United Kingdom (DAB); and the Department of Radiology, Freeman Hospital, Newcastle upon Tyne, United Kingdom (JR and RJ).
authors.forename: Maria J
authors.initials: MJ
authors.lastname: King
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom (IP, MH, and DEJ); the Institute of Food Research, Norwich Research Park, Norwich, United Kingdom (MJK, MP, JRD, AJAW, and PMF); the Centre for Analytical Bioscience, School of Pharmacy, University of Nottingham, Nottingham, United Kingdom (DAB); and the Department of Radiology, Freeman Hospital, Newcastle upon Tyne, United Kingdom (JR and RJ).
authors.forename: David A
authors.initials: DA
authors.lastname: Barrett
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom (IP, MH, and DEJ); the Institute of Food Research, Norwich Research Park, Norwich, United Kingdom (MJK, MP, JRD, AJAW, and PMF); the Centre for Analytical Bioscience, School of Pharmacy, University of Nottingham, Nottingham, United Kingdom (DAB); and the Department of Radiology, Freeman Hospital, Newcastle upon Tyne, United Kingdom (JR and RJ).
authors.forename: John
authors.initials: J
authors.lastname: Rose
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom (IP, MH, and DEJ); the Institute of Food Research, Norwich Research Park, Norwich, United Kingdom (MJK, MP, JRD, AJAW, and PMF); the Centre for Analytical Bioscience, School of Pharmacy, University of Nottingham, Nottingham, United Kingdom (DAB); and the Department of Radiology, Freeman Hospital, Newcastle upon Tyne, United Kingdom (JR and RJ).
authors.forename: Ralph
authors.initials: R
authors.lastname: Jackson
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom (IP, MH, and DEJ); the Institute of Food Research, Norwich Research Park, Norwich, United Kingdom (MJK, MP, JRD, AJAW, and PMF); the Centre for Analytical Bioscience, School of Pharmacy, University of Nottingham, Nottingham, United Kingdom (DAB); and the Department of Radiology, Freeman Hospital, Newcastle upon Tyne, United Kingdom (JR and RJ).
authors.forename: Mark
authors.initials: M
authors.lastname: Hudson
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom (IP, MH, and DEJ); the Institute of Food Research, Norwich Research Park, Norwich, United Kingdom (MJK, MP, JRD, AJAW, and PMF); the Centre for Analytical Bioscience, School of Pharmacy, University of Nottingham, Nottingham, United Kingdom (DAB); and the Department of Radiology, Freeman Hospital, Newcastle upon Tyne, United Kingdom (JR and RJ).
authors.forename: Mark
authors.initials: M
authors.lastname: Philo
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom (IP, MH, and DEJ); the Institute of Food Research, Norwich Research Park, Norwich, United Kingdom (MJK, MP, JRD, AJAW, and PMF); the Centre for Analytical Bioscience, School of Pharmacy, University of Nottingham, Nottingham, United Kingdom (DAB); and the Department of Radiology, Freeman Hospital, Newcastle upon Tyne, United Kingdom (JR and RJ).
authors.forename: Jack R
authors.initials: JR
authors.lastname: Dainty
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom (IP, MH, and DEJ); the Institute of Food Research, Norwich Research Park, Norwich, United Kingdom (MJK, MP, JRD, AJAW, and PMF); the Centre for Analytical Bioscience, School of Pharmacy, University of Nottingham, Nottingham, United Kingdom (DAB); and the Department of Radiology, Freeman Hospital, Newcastle upon Tyne, United Kingdom (JR and RJ).
authors.forename: Anthony J A
authors.initials: AJ
authors.lastname: Wright
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom (IP, MH, and DEJ); the Institute of Food Research, Norwich Research Park, Norwich, United Kingdom (MJK, MP, JRD, AJAW, and PMF); the Centre for Analytical Bioscience, School of Pharmacy, University of Nottingham, Nottingham, United Kingdom (DAB); and the Department of Radiology, Freeman Hospital, Newcastle upon Tyne, United Kingdom (JR and RJ).
authors.forename: Paul M
authors.initials: PM
authors.lastname: Finglas
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom (IP, MH, and DEJ); the Institute of Food Research, Norwich Research Park, Norwich, United Kingdom (MJK, MP, JRD, AJAW, and PMF); the Centre for Analytical Bioscience, School of Pharmacy, University of Nottingham, Nottingham, United Kingdom (DAB); and the Department of Radiology, Freeman Hospital, Newcastle upon Tyne, United Kingdom (JR and RJ).
authors.forename: David E
authors.initials: DE
authors.lastname: Jones
mesh_terms: D000284:Administration, Oral; D000328:Adult; D001711:Biotransformation; D002250:Carbon Radioisotopes; D015331:Cohort Studies; D018592:Cross-Over Studies; D019587:Dietary Supplements; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D005527:Food, Fortified; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D007700:Kinetics; D002955:Leucovorin / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism; D008297:Male; D008745:Methylation; D008875:Middle Aged; D011169:Portal Vein; D019168:Portasystemic Shunt, Transjugular Intrahepatic; D013763:Tetrahydrofolates / Q000097:blood / Q000378:metabolism*
chemical_list: D002250:Carbon Radioisotopes; D013763:Tetrahydrofolates; D005492:Folic Acid; D002955:Leucovorin; C005984:5-methyltetrahydrofolate