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. 1971 Oct;50(10):2009–2021. doi: 10.1172/JCI106694

Studies on the absorption and metabolism of folic acid

I. Folate absorption in the dog after exposure of isolated intestinal segments to synthetic pteroylpolyglutamates of various chain lengths

C M Baugh 1, C L Krumdieck 1, H J Baker 1, C E Butterworth Jr 1
PMCID: PMC292134  PMID: 5000560

Abstract

Folic acid absorption was studied in anesthetized dogs by determining the amount and chemical nature of folate in venous blood emerging from isolated intestinal segments containing free folic acid and/or pteroylpolyglutamates of a known chain length. Chromatographically pure test materials placed in the lumen were prepared by unambiguous solid phase synthetic methods. This synthetic procedure not only yields compounds of known structure, it also provides a means by which glutamic acid residues at any given position in the gamma glutamyl chain can be made radioactive. For example, teropterin (pteroyltriglutamate) was synthesized in such a way that 14C was present only in the middle glutamic acid unit. Suitable placement of label permitted assessment of the extent of peptide cleavage. The action of plasma conjugase was inhibited by copper chloride. Plasma samples were analyzed by Lactobacillus casei and Streptococcus faecalis assay, by column chromatography, and by quantitative measurement of pteridine-bound radioactivity.

It was observed that biologically active folate appeared in the mesenteric vein with either pteroylmono-, di-, tri-, penta-, or heptaglutamate in the lumen. Generally speaking the absorption rate appeared to be inversely related to the length of the gamma glutamyl side chain. Roughly twice as much folic acid appeared in the circulation from 3H-labeled pteroylmonoglutamate as from 14C-labeled pteroylpentaglutamate when equimolar amounts of each were placed simultaneously in a single intestinal segment. Pteroylmonoglutamate appeared to be the predominant form entering the blood from each of the precursors tested. However, evidence was obtained that pteroyldiglutamate may enter the mesenteric vein soon after placing pteroyldi-, or triglutamate in the lumen, but not with the higher polyglutamates. Comparison of radioactivity and biological activity patterns suggests little conversion, if any, to reduced or methylated forms during the first 30 min of passage through the intestinal mucosa. We conclude that both pteroylmonoglutamates and pteroyldiglutamates may across the intestinal mucosa of the dog, and that reduction and methylation are not essential to the absorption process.

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2009

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. BAKER H., FRANK O., FEINGOLD S., ZIFFER H., GELLENE R. A., LEEVY C. M., SOBOTKA H. THE FATE OF ORALLY AND PARENTERALLY ADMINISTERED FOLATES. Am J Clin Nutr. 1965 Aug;17:88–95. doi: 10.1093/ajcn/17.2.88. [DOI] [PubMed] [Google Scholar]
  2. BAKER H., FRANK O., SOBOTKA H. MECHANISMS OF FOLIC ACID DEFICIENCY IN NONTROPICAL SPRUE. JAMA. 1964 Jan 11;187:119–121. doi: 10.1001/jama.1964.03060150043010. [DOI] [PubMed] [Google Scholar]
  3. BAKERMAN H. A. A method for measuring the microbiological activity of tetrahydrofolic acid and other labile reduced folic acid derivatives. Anal Biochem. 1961 Dec;2:558–567. doi: 10.1016/0003-2697(61)90023-9. [DOI] [PubMed] [Google Scholar]
  4. BAKER S. J., KUMAR S., SWAMINATHAN S. P. EXCRETION OF FOLIC ACID IN BILE. Lancet. 1965 Mar 27;1(7387):685–685. doi: 10.1016/s0140-6736(65)91836-2. [DOI] [PubMed] [Google Scholar]
  5. BURGEN A. S., GOLDBERG N. J. Absorption of folic acid from the small intestine of the rat. Br J Pharmacol Chemother. 1962 Oct;19:313–320. doi: 10.1111/j.1476-5381.1962.tb01194.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. BUTTERWORTH C. E., Jr, NADEL H., PEREZ-SANTIAGO E., SANTINI R., Jr, GARDNER F. H. Folic acid absorption excretion, and leukocyte concentration in tropical sprue. J Lab Clin Med. 1957 Nov;50(5):673–681. [PubMed] [Google Scholar]
  7. Baker H., Thomson A. D., Feingold S., Frank O. Role of the jejunum in the absorption of folic acid and its polyglutamates. Am J Clin Nutr. 1969 Feb;22(2):124–132. doi: 10.1093/ajcn/22.2.124. [DOI] [PubMed] [Google Scholar]
  8. Baron J. H., Williams J. A. The use of gastric function tests by members of the British Society of Gastroenterology. Gut. 1970 Dec;11(12):1056–1056. [PMC free article] [PubMed] [Google Scholar]
  9. Baugh C. M., Krumdieck C. L. Effects of phenytoin on folic-acid conjugases in man. Lancet. 1969 Sep 6;2(7619):519–521. doi: 10.1016/s0140-6736(69)90218-9. [DOI] [PubMed] [Google Scholar]
  10. Baugh C. M., Stevens J. C., Krumdieck C. L. Studies on gamma-glutamyl carboxypeptidase. I. The solid phase synthesis of analogs of polyglutamates of folic acid and their effects on human liver gamma-glutamyl carboxypeptidase. Biochim Biophys Acta. 1970 Jul 15;212(1):116–125. doi: 10.1016/0005-2744(70)90184-1. [DOI] [PubMed] [Google Scholar]
  11. Bernstein L. H., Gutstein S., Weiner S. V. Gamma glutamyl carboxypeptidase (conjugase), the folic acid-releasing enzyme of intestinal mucosa. Am J Clin Nutr. 1970 Jul;23(7):919–925. doi: 10.1093/ajcn/23.7.919. [DOI] [PubMed] [Google Scholar]
  12. Butterworth C. E., Jr, Baugh C. M., Krumdieck C. A study of folate absorption and metabolism in man utilizing carbon-14--labeled polyglutamates synthesized by the solid phase method. J Clin Invest. 1969 Jun;48(6):1131–1142. doi: 10.1172/JCI106070. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. CONDIT P. T., GROB D. Studies on the folic acid vitamins. I. Observations on the metabolism of folic acid in man and on the effect of aminopterin. Cancer. 1958 May-Jun;11(3):525–536. doi: 10.1002/1097-0142(195805/06)11:3<525::aid-cncr2820110311>3.0.co;2-8. [DOI] [PubMed] [Google Scholar]
  14. CREAMER B., SHINER M. EXCRETION OF FOLIC ACID IN BILE. Lancet. 1965 Apr 24;1(7391):913–913. doi: 10.1016/s0140-6736(65)92648-6. [DOI] [PubMed] [Google Scholar]
  15. Chanarin I., Perry J. Evidence for reduction and methylation of folate in the intestine during normal absorption. Lancet. 1969 Oct 11;2(7624):776–778. doi: 10.1016/s0140-6736(69)90483-8. [DOI] [PubMed] [Google Scholar]
  16. Cooperman J. M., Pesci-Bourel A., Luhby A. L. Urinary excretion of folic acid activity in man. Clin Chem. 1970 May;16(5):375–381. [PubMed] [Google Scholar]
  17. GIRDWOOD R. H. A folic-acid excretion test in the investigation of intestinal malabsorption. Lancet. 1953 Jul 11;265(6776):53–60. doi: 10.1016/s0140-6736(53)91084-8. [DOI] [PubMed] [Google Scholar]
  18. Hepner G. W., Booth C. C., Cowan J., Hoffbrand A. V., Mollin D. L. Absorption of crystalline folic acid in man. Lancet. 1968 Aug 10;2(7563):302–306. doi: 10.1016/s0140-6736(68)90523-0. [DOI] [PubMed] [Google Scholar]
  19. Hepner G. W. The absorption of pteroylglutamic (folic) acid in rats. Br J Haematol. 1969 Mar;16(3):241–249. doi: 10.1111/j.1365-2141.1969.tb00399.x. [DOI] [PubMed] [Google Scholar]
  20. Hoffbrand A. V., Necheles T. F. Mechanism of folate deficiency in patients receiving phenytoin. Lancet. 1968 Sep 7;2(7567):528–530. doi: 10.1016/s0140-6736(68)92404-5. [DOI] [PubMed] [Google Scholar]
  21. JANDL J. H., LEAR A. A. The metabolism of folic acid in cirrhosis. Ann Intern Med. 1956 Dec;45(6):1027–1044. doi: 10.7326/0003-4819-45-6-1027. [DOI] [PubMed] [Google Scholar]
  22. KORN E. D., NORTHCOTE D. H. Physical and chemical properties of polysaccharides and glycoproteins of the yeast-cell wall. Biochem J. 1960 Apr;75:12–17. doi: 10.1042/bj0750012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Krumdieck C. L., Baugh C. M. The solid-phase synthesis of polyglutamates of folic acid. Biochemistry. 1969 Apr;8(4):1568–1572. doi: 10.1021/bi00832a036. [DOI] [PubMed] [Google Scholar]
  24. Large P. J., Quayle J. R. Microbial growth on C(1) compounds. 5. Enzyme activities in extracts of Pseudomonas AM1. Biochem J. 1963 May;87(2):386–396. doi: 10.1042/bj0870386. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Rosenberg I. H., Godwin H. A., Streiff R. R., Castle W. B. Impairment of intestinal deconjugation of dietary folate. A possible explanation of megaloblastic anaemia associated with phenytoin therapy. Lancet. 1968 Sep 7;2(7567):530–532. doi: 10.1016/s0140-6736(68)92405-7. [DOI] [PubMed] [Google Scholar]
  26. WOOD R. C., WISE M. F. CONVERSION OF FOLIC ACID DERIVATIVES TO THEIR CONJUGATED FORMS BY CELLS OF STREPTOCOCCUS FAECALIS. Tex Rep Biol Med. 1965;23:512–529. [PubMed] [Google Scholar]
  27. WRIGHT B. E. The rôle of polyglutamyl pteridine coenzymes in serine metabolism. II. A comparison of various pteridine derivatives. J Biol Chem. 1956 Apr;219(2):873–883. [PubMed] [Google Scholar]
  28. Whitehead V. M., Cooper B. A. Absorption of unaltered folic acid from the gastro-intestinal tract in man. Br J Haematol. 1967 Sep;13(5):679–686. doi: 10.1111/j.1365-2141.1967.tb08833.x. [DOI] [PubMed] [Google Scholar]

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