Autoregulation of 5-fluorouracil metabolism.
5-Fluorouracil (5-FU) is a commonly used anticancer agent for the treatment of gastrointestinal, head and neck, and breast tumours. This study determined the influence of 5-FU on dihydropyrimidine dehydrogenase (DPD) activity, the enzyme responsible for its in vivo degradation. DPD activity was measured in mononuclear cells obtained prior to and after the administration of 5-FU in 20 patients with colorectal cancer. Following the results from the human studies, DPD activity was measured in Sprague-Dawley rat liver up to 72 h after administration of 5-FU 200 mg/kg as a single injection. Total liver P450 content and the production of testosterone metabolites (indicative of CYP3A activity) were also analysed to determine the specificity of 5-FU-associated alteration in rat liver metabolism. Human mononuclear cell DPD activity decreased by a median of 38.7% following the administration of 5-FU (P = 0.001). 5-FU-induced alterations in rat liver DPD were also observed, with the lowest activity occurring 48 h after injection (50% of control activity; P = 0.009). Rat liver DPD activity returned to near control values by 72 h postinjection. Rat liver total P450 content and CYP3A activity were not significantly different in 5-FU treated or control tissues. Thus, 5-FU demonstrates autoregulation of its metabolism through inhibition of DPD activity. Although this inhibition appears to be specific for DPD, the mechanism for enzyme inhibition is not clear. These findings may aid in the design of 5-FU treatment regimens and provide the basis for further studies into the regulation of DPD.
McLeod
H L
HL
Department of Medicine, University of Aberdeen, Foresterhill, U.K.
Sludden
J
J
Hardy
S C
SC
Lock
R E
RE
Hawksworth
G M
GM
Cassidy
J
J
D000818:Animals; D000931:Antidotes / Q000008:administration & dosage; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil / Q000378:metabolism*; D006487:Hemostasis; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D008099:Liver / Q000378:metabolism; D008297:Male; D009000:Monocytes / Q000201:enzymology; D010088:Oxidoreductases / Q000378:metabolism*; D051381:Rats; D013739:Testosterone / Q000378:metabolism
D000931:Antidotes; D013739:Testosterone; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D002955:Leucovorin; D005472:Fluorouracil