Trimethoprim-induced elevation of dihydrofolate reductase activity in human leukocytes.
The administration of trimethoprim (TMP)--a diamino benzylpyrimidine compound which binds very tightly the bacterial dihydrofolate reductase--was accompanied by the appearance of measurable levels of dihydrofolate reductase in peripheral leukocytes from patients with nonhematological diseases. In all instances, enzyme activity rose rapidly between the fourth and eighth day after TMP. The time course of the rise and fall of dihydrofolate activity approaches cellular life span and is similar to that obtained after methotrexate or triamterene administration. Dihydrofolate reductases, partially purified from leukocytes of patients treated with TMP, bone marrow and leukemic leukocytes, had simila  molecular weights, pH optima, Ki of inhibitor (methotrexate); they were stimulated to the same degree by KCl and urea. Electrophoresis of the enzyme on cellulose acetate strip resulted in the separation of two enzymatically active protein components.  No differences in the electrophoretic behavior of the three blood cell enzymes were noted. The findings noted above are consistent with the suggestion that the observed rise in dihydrofolate reductase activity is a quantitative one. Moreover, the effect of TMP in vivo is discussed in comparison with the currently held hypothesis for methotrexate action (stabilization by the drug of a previously synthetized enzyme).
D004588:Electrophoresis, Cellulose Acetate; D004789:Enzyme Activation / Q000187:drug effects; D005493:Folic Acid Antagonists; D006801:Humans; D006863:Hydrogen-Ion Concentration; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology; D007962:Leukocytes / Q000187:drug effects / Q000201:enzymology*; D008727:Methotrexate / Q000494:pharmacology; D008970:Molecular Weight; D013762:Tetrahydrofolate Dehydrogenase / Q000097:blood* / Q000302:isolation & purification; D013997:Time Factors; D014295:Trimethoprim / Q000494:pharmacology*
D005493:Folic Acid Antagonists; D014295:Trimethoprim; D013762:Tetrahydrofolate Dehydrogenase; D008727:Methotrexate