title: Tetrahydrofolate and 5-methyltetrahydrofolate are folates with high antioxidant activity. Identification of the antioxidant pharmacophore.
abstract: The presumed protective effect of folic acid on the pathogenesis of cardiovascular, hematological and neurological diseases and cancer has been associated with the antioxidant activity of folic acid. Peroxynitrite (PON) scavenging activity and inhibition of lipid peroxidation (LPO) of the physiological forms of folate and of structurally related compounds were tested. It was found that the fully reduced forms of folate, i.e. tetrahydrofolate (THF) and 5-methyltetrahydrofolate (5-MTHF), had the most prominent antioxidant activity. It appeared that their protection against LPO is less pronounced than their PON scavenging activity. The antioxidant activity of these forms of folic acid resides in the pterin core, the antioxidant pharmacophore is 4-hydroxy-2,5,6-triaminopyrimidine. It is suggested that an electron donating effect of the 5-amino group is of major importance for the antioxidant activity of 4-hydroxy-2,5,6-triaminopyrimidine. A similar electron donating effect is probably important for the antioxidant activity of THF and 5-MTHF.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Medicine, Universiteit Maastricht, P.O. Box 616, NL 6200 MD, Maastricht, The Netherlands.
authors.forename: Bashir M
authors.initials: BM
authors.lastname: Rezk
authors.forename: Guido R M M
authors.initials: GR
authors.lastname: Haenen
authors.forename: Wim J F
authors.initials: WJ
authors.lastname: van der Vijgh
authors.forename: Aalt
authors.initials: A
authors.lastname: Bast
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000737:chemistry* / Q000494:pharmacology*; D052160:Benzothiazoles; D005227:Fatty Acids / Q000494:pharmacology; D005492:Folic Acid / Q000378:metabolism / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000037:antagonists & inhibitors; D011622:Pterins / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D013451:Sulfonic Acids / Q000032:analysis / Q000378:metabolism; D013763:Tetrahydrofolates / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D052160:Benzothiazoles; D005227:Fatty Acids; D016166:Free Radical Scavengers; D011622:Pterins; D013451:Sulfonic Acids; D013763:Tetrahydrofolates; C013584:lipid peroxidation inhibitor; D030421:Peroxynitrous Acid; C002502:2,2'-azino-di-(3-ethylbenzothiazoline)-6-sulfonic acid; C030371:5,6,7,8-tetrahydrofolic acid; D005492:Folic Acid; C005984:5-methyltetrahydrofolate