In vitro and in vivo inhibition of myeloperoxidase with 5-fluorouracil.
OBJECTIVE
Myeloperoxidase (MPO) exists in neutrophils and has an important bactericidal role. During phagocytosis, MPO catalyzes a peroxidative reaction using chloride ion and hydrogen peroxide (H2O2) as substrate. The aim of the present study was to investigate whether 5-fluorouracil (5-FU), a chemotherapeutic agent, has a direct inhibitory effect on MPO and to evaluate some properties of this inhibition.


METHODS
The inhibitory effect of 5-FU on MPO was studied in rat tissue, human leukocytes, and leukocytes from cancer patients under 5-FU therapy. MPO was solubilized in a detergent-containing buffer. MPO activity was measured spectrophotometrically through the oxidation of a synthetic substrate tetramethyl benzidine in the presence of H2O2.


RESULTS
5-FU inhibited tissue-associated MPO activity in a dose-dependent but not time-dependent manner with an IC50 value of 0.6 mg/ml. 5-FU also inhibited MPO activity in isolated human leukocytes in a dose-dependent manner, and the IC50 value was 0.75 mg/ml. Using this 5-FU concentration, the inhibitory effect was monitored at different substrate concentrations. Leukocyte MPO activities of patients receiving 5-FU therapy were compared before treatment and after the first, second, and third administration cycles. 5-FU treatment resulted in a significant decrease in leukocyte MPO activity, and repeated 5-FU treatment caused additional decrease.


CONCLUSIONS
Our data showed that 5-FU directly inhibited the MPO activity of human leukocytes in vitro and in vivo. We concluded that, the patients treated with 5-FU should be intensively followed for the risk of infections.
Akbiyik
F
F
Hacettepe University Faculty of Medicine, Department of Biochemistry, Ankara, Turkey.
Demirpençe
E
E
Kuzu
M A
MA
Kilinç
K
K
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D003106:Colon / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007962:Leukocytes / Q000201:enzymology; D008297:Male; D009195:Peroxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D000964:Antimetabolites, Antineoplastic; D009195:Peroxidase; D005472:Fluorouracil