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 chro nically treated with low-dose oral methotrexate (MTX) [Sonneveld, Schu ltz, Nooter and Hahlen (1986) Cancer Chemother. Pharmacol. 18, 111-116 ]. The K-i values for MTX and 7-OH-MTX for avian liver 5-aminoimidazol e-4-carboxamide ribonucleotide transformylase differ by 4.5-fold in fa vour of 7-OH-MTX as the better inhibitor, while Ki values for avian li ver glycinamide ribonucleotide transformylase differ by 1.9-fold favou ring 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 t herapies used to treat autoimmune disease.