The absorption and malabsorption of folic acid and its polyglutamates

Abstract

Folic polyglutamate, the principal dietary form of folate, consists of folic acid bound to one to six glutamic acid residues in a gamma peptide linkage. Small intestinal conjugase is necessary for the hydrolysis and absorption of these polyglutamates. Folic acid absorption is an active process that occurs primarily in the duodenum and jejunum. Following absorption, folic acid present in human and canine portal blood is not methylated, although methylation may occur later in the liver following reduction. Because of its essential role in folate absorption, intestinal conjugase has been the subject of considerable experimental study recently. The enzyme can be inhibited by sulfobromophthalein sodium, and in vitro by unconjugated dihydroxy bile salts, as well as by conjugated lithocholate. The low serum folate level present in some women taking oral contraceptives may also be due to conjugase inhibition. Enzyme inhibition has been suggested as the cause of megaloblastic anemia occasionally seen in patients receiving diphenylhydantoin, but this has not been consistently confirmed. Both conjugase and unmethylated folic acid monoglutamate are present in human bile. The role of biliary conjugase, if any, is unclear at present. The recent synthesis of radioactive folic polyglutamate has provided a significant new tool for the study of normal absorption and malabsorption of folate as well as for the assay of conjugases. Although folic acid deficiency is almost always present in tropical sprue, deficiency of this substance alone is insufficient to explain the many abnormalities in small intestinal structure and function. An additional factor(s) has therefore been suggested to explain the pathogenesis of this malabsorptive disorder. The response of patients with this disease to certain antibiotics, the occasional epidemic nature of sprue and the finding of increased small intestinal colony counts suggest that bacteria or a bacterial metabolite(s) may be responsible for the disorder. Recent evidence indicates that folic polyglutamate is malabsorbed to a greater degree than free folic acid, suggesting that intestinal conjugase deficiency or inhibition may play an important role in pathogenesis.