RESUMO
The effect of 9-beta-arabinofuranosyladenine 5'-monophosphate (ara-AMP) on the purine salvage pathway has been studied. On a dose-dependent basis ara-AMP inhibits the incorporation of adenine-8-14C into nucleotides in intact erythrocytes. The partially purified enzymes of the purine salvage pathway, the adenine phosphoribosyltransferase and the 5'-phosphoribosyl-1-pyrophosphate (PP-ribose-P) synthetase, but not the hypoxanthine-guanine phosphoribosyltransferase, are inhibited by ara-AMP in a non-competitive manner. The possible adverse drug interactions which might occur by the simultaneous use of ara-AMP and other antimetabolites are discussed.
Assuntos
Adenina Fosforribosiltransferase/antagonistas & inibidores , Arabinonucleotídeos/farmacologia , Hipoxantina Fosforribosiltransferase/antagonistas & inibidores , Pentosiltransferases/antagonistas & inibidores , Fosfotransferases/antagonistas & inibidores , Ribose-Fosfato Pirofosfoquinase/antagonistas & inibidores , Fosfato de Vidarabina/farmacologia , Adenina/metabolismo , Relação Dose-Resposta a Droga , Eritrócitos/efeitos dos fármacos , Humanos , Cinética , Especificidade por SubstratoAssuntos
Eritrócitos/metabolismo , Nucleotídeos de Purina/biossíntese , Uremia/sangue , Adenina Fosforribosiltransferase/metabolismo , Adulto , Centrifugação com Gradiente de Concentração , Eritrócitos/enzimologia , Humanos , Hipoxantina Fosforribosiltransferase/metabolismo , Fosforribosil Pirofosfato/biossíntese , Ribose-Fosfato Pirofosfoquinase/metabolismoRESUMO
The enzyme inosinic acid dehydrogenase (EC 1.2.1 [14]) was measured and partially purified (10- to 15-fold) from normal and leukemic leukocytes. From the normal blood cells, the highest activities could be detected in lymphocytes and bone marrow cells. Dependent on the blast cell count, the leukemic IMP dehydrogenase had a higher mean specific activity than the enzymes of fractionated, immature bone marrow cells, or normal granulocytes. The partially purified enzymes from the various blood cells were apparently identical; they exhibited hyperbolic substrate saturation kinetics and were inhibited by a number of purine nucleotides. For the leukemic blast cell enzyme, the Km values for the substrates, IMP and NAD+, were 28 +/- 11; 227 +/- 98 microM, and 34 +/- 10; 240 +/- 67 microM for the partially purified enzyme from normal, immature bone marrow cells. The hypoxanthine-guanine and adenine phosphoribosyltransferase activities increased in the leukemic cells when compared with mature granulocytes, but nearly always showed similar activities when compared with fractionated bone marrow cells. Only one of the 30 investigated leukemic patients exhibited a marked decrease in hypoxanthine phosphoribosyltransferase activity of 0.5 nmol/mg/h. The phosphoribosyltransferase-specific activities of the leukemic cells are more variable than for the normal ones and no correlation of enzyme activities and blast cell count was apparent.