Nonenzymatic degradation and salvage of dietary folate: physicochemical factors likely to influence bioavailability.
We investigated the oxidative degradation pathway of 5CH3-H4PteGlu, the main extracellular folate and the predominant form of the vitamin found in food and blood. 5CH3-H4PteGlu is oxidized to 5CH3-5,6-H2PteGlu which subsequently undergoes C9-N10 bond cleavage yielding a pteridine residue and P-ABG, the latter step resulting in irreversible loss of vitamin activity. Under moderately acid conditions typical of the postprandial gut (pH 3.5) 5CH3-H4PteGlu is fairly stable (t1/2 = 273.6 min), while 5CH3-5,6-H2PteGlu is rapidly degraded (t1/2 = 16.9 min). In a neutral environment (pH 6.4) stability is reversed; 5CH3-H4PteGlu t1/2 = 12.0 mins, 5CH3-5,6-H2PteGlu t1/2 = 1504.6 min. Ascorbic acid was efficacious in the facile salvage of 5CH3-H4PteGlu from 5CH3-5,6-H2PteGlu which occurred rapidly and with significant efficiency (100% conversion) under acid (pH 3.5) conditions, t1/2 = 1.3 min (1 mmol/liter ascorbate), but was less efficient under neutral (pH 6.4) conditions t1/2 = 273.6 min (36% conversion). The presence of zinc and iron broadly maintains the pattern of effect, but increases all reaction rates. PteGlu was stable under all conditions studied. These results obtained in an artificial environment were supported by findings in human gastric juice: at a gastric pH of 1.47 with low endogenous ascorbate (7.0 mumol/liter), 5CH3-5,6-H2PteGlu and 5CH3-H4PteGlu both degrade instantly via C9-N10 bond cleavage to yield an equimolar amount of P-ABG. If the same gastric juice is spiked at 58.0 mumol/liter ascorbate (moderate endogenous concentration), 5CH3-H4PteGlu is stable (t1/2 = 334.7 min), while 5CH3-5,6-H2PteGlu is instantly salvaged to 5CH3-H4PteGlu with 43.3% efficiency, and the remaining 5CH3-5,6-H2PteGlu is degraded to P-ABG. In gastric juice with an elevated pH of 7.0 and no endogenous ascorbate, 5CH3-5,6-H2PteGlu and 5CH3-H4PteGlu are both stable, with no C9-N10 bond cleavage. This, for 5CH3-H4PteGlu, is in apparent contrast to findings at pH 6.4 in an artificial environment. The same gastric juice spiked to 50 mumol/liter ascorbate did not result in 5CH3-H4PteGlu salvage from 5CH3-5,6-H2PteGlu.(ABSTRACT TRUNCATED AT 400 WORDS)
Lucock
M D
MD
Department of Clinical Medicine, University of Leeds, United Kingdom.
Priestnall
M
M
Daskalakis
I
I
Schorah
C J
CJ
Wild
J
J
Levene
M I
MI
D001205:Ascorbic Acid / Q000378:metabolism / Q000494:pharmacology; D001682:Biological Availability; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004032:Diet; D005492:Folic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D005750:Gastric Juice / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D007700:Kinetics; D010084:Oxidation-Reduction; D013763:Tetrahydrofolates / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics
D013763:Tetrahydrofolates; C012429:5-methyldihydrofolate; D005492:Folic Acid; D001205:Ascorbic Acid; C005984:5-methyltetrahydrofolate