Caryl L. Campbell

Kinetics of the Normal Folate Enterohepatic Cycle

Detailed studies were undertaken to better define the role of the liver and the folate enterohepatic cycle in folate homeostasis. Three isotopes of folate were employed in a rat model to study several parameters: (a) intestinal transport; (b) variation in hepatic uptake after different routes of administration; (c) hepatic reduction, methylation, and polyglutamate formation; (d) biliary excretion; (e) transport of folate to tissue and its return to liver for re-entry into the enterohepatic cycle. Folate absorption was not affected by the type of folate administered, but subsequent liver accumulation was greater when PteGlu(1) was given rather than CH(3)H(4)PteGlu(1). After liver uptake, CH(3)H(4)PteGlu(1) is rapidly and quantitatively excreted into bile, whereas nonmethylated folates are either methylated and transported into bile or incorporated into a hepatic polyglutamate pool. Bile folate is then reabsorbed for distribution to both tissue and liver, completing the enterohepatic cycle. The importance of this cycle was demonstrated by long-term bile drainage and by transport studies with two isotopes of CH(3)H(4)PteGlu(1). With bile drainage, serum folate levels fell to 30-40% of normal within 6 h, a much more dramatic drop than that seen with folate-free diets alone. Studies with labeled CH(3)H(4)PteGlu(1) demonstrated that about one-third was taken up by tissue, demethylated, and returned to liver for remethylation and recirculation through the bile and gut. This establishes the enterohepatic cycle as a major factor in folate homeostasis and, for the first time, demonstrates a transport pathway between tissue and liver for nonmethylated folate.

The role of the enterohepatic cycle in folate supply to tumour in rats

SUMMARY. The importance of the folate enterohepatic cycle in governing the supply of folate to implants of a rapidly‐growing tumour were studied in a new animal model. Following enteric administration of tritiated pteroylglutamic acid, [3H]PteGlu1, tumour uptake of labelled folate was limited to CH3[3H]H4PteGlu1 produced by the gut mucosal cells during absorption or subsequently recirculated through the enterohepatic cycle. 50% of the labelled folate reaching the tumour nodules in the first 6 h after enteric administration first circulated through the enterohepatic cycle. In addition, labelled folate taken up by tumour was immediately incorporated into a polyglutamyl folate pool. There was no evidence for a release of labelled folate from tumour for recirculation to the liver. Therefore the liver and folate enterohepatic cycle appear to play a major role in regulating the supply of folate to rapidly proliferating tissues such as tumour by acutely storing folate from the diet and then secreting it into bile for reabsorption and transport to tissue.

The effect of nitrous oxide-induced vitamin B12 deficiency on invivo folate metabolism

Abstract The effect of N2O-induced vitamin B12 deficiency on in vivo folate metabolism was studied in an animal model previously developed for studies of the folate enterohepatic cycle, and in rats with localized, subcutaneous tumor nodules. While N2O inhibited liver folate polyglutamate formation, it did not affect the absorption of (3H)PteGlu1 from the gut, its reduction, methylation, and transport to the liver, or the subsequent secretion of CH3H4(3H)PteGlu1 into bile—the folate enterohepatic cyle. In addition, N2O did not impair folate polyglutamate formation in the fibrosarcoma tumor nodule suggesting that tumor tissue can either demethylate CH3H4PteGlu1 by an alternate pathway or can utilize it as a substrate for polyglutamate formation without demethylation.