Differences in methotrexate and 7-hydroxymethotrexate inhibition of folate-dependent enzymes of purine nucleotide biosynthesis.
7-Hydroxymethotrexate (7-OH-MTX) is the major and, frequently the only, pteridine metabolite found in bone-marrow aspirates of patients chronically treated with low-dose oral methotrexate (MTX) [Sonneveld, Schultz, Nooter and Hahlen (1986) Cancer Chemother. Pharmacol. 18, 111-116]. The Ki values for MTX and 7-OH-MTX for avian liver 5-amino-imidazole-4-carboxamide ribonucleotide transformylase differ by 4.5-fold in favour of 7-OH-MTX as the better inhibitor, while Ki values for avian liver glycinamide ribonucleotide transformylase differ by 1.9-fold favouring MTX as the better inhibitor. Thus 7-OH-MTX possesses a different enzyme-inhibiting repertoire from its parent drug and this information may be useful in explaining the mechanism of action of low-dose MTX therapies used to treat autoimmune disease.
Department of Nutrition Sciences, University of Alabama at Birmingham 35294.
J E
JE
Baggott
S L
SL
Morgan
W H
WH
Vaughn
D000217:Acyltransferases / Q000037:antagonists & inhibitors*; D000818:Animals; D019877:Hydroxymethyl and Formyl Transferases; D066298:In Vitro Techniques; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D008727:Methotrexate / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051027:Phosphoribosylaminoimidazolecarboxamide Formyltransferase; D051026:Phosphoribosylglycinamide Formyltransferase; D011685:Purine Nucleotides / Q000096:biosynthesis*
D011685:Purine Nucleotides; D019877:Hydroxymethyl and Formyl Transferases; D051026:Phosphoribosylglycinamide Formyltransferase; D051027:Phosphoribosylaminoimidazolecarboxamide Formyltransferase; D000217:Acyltransferases; C011864:7-hydroxymethotrexate; D008727:Methotrexate