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Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions

-Glutamyl Hydrolase, Not Glutamate Carboxypeptidase II, Hydrolyzes Dietary Folate in Rat Small Intestine^1,2

Department of Internal Medicine, Clinical Nutrition, University of California, Davis, CA 95616

^* To whom correspondence should be addressed. E-mail:chalsted{at}ucdsom.ucdavis.edu.

Dietary polyglutamyl folates are hydrolyzed to monoglutamyl folate derivatives prior to intestinal transport. In humans and pigs, the reaction occurs at pH 6.5 at the jejunal brush border membrane by folate hydrolase and is encoded by the glutamate carboxypeptidase II (GCPII) gene. Intracellular folate hydrolase with an optimal pH of 4.5 is encoded by the -glutamyl hydrolase (-GH) gene and predominates in rats. We determined the respective roles of GCPII and -GH in dietary folate hydrolysis in rat small intestine. Duodenal, jejunal, and ileal mucosa, pancreas, and duodenal luminal fluid were collected from 10 Sprague-Dawley rats that had not been food deprived. Folate hydrolase was assayed at pH 4.5 and 6.5 with and without parahydroxymercuribenzoate (pHMB), an inhibitor of intracellular folate hydrolase. Folate hydrolase activity occurred at pH 4.5 in all tissues, was significantly inhibited by the addition of pHMB at both pH 4.5 and 6.5, and was virtually absent from brush border fractions at pH 6.5. The highest activity was in the postprandial duodenal luminal fluid at pH 4.5. Rat-specific primers for GCPII and -GH were used to detect mRNA expression in pancreas, jejunal mucosa, and liver. GCPII expression was detected only in the liver, whereas -GH was expressed in all 3 tissues. These results suggest that the hydrolysis of polyglutamyl folates in rats requires the intracellular folate hydrolase that is expressed by pancreatic -GH, in contrast to GCPII that is expressed in the jejunal mucosal brush border in pigs and humans. -GH folate hydrolase is abundant in rat postprandial pancreatic secretions and appears to hydrolyze dietary folates in the intestinal lumen prior to intestinal absorption.

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