Dihydropyrimidine dehydrogenase circadian rhythm in mouse liver: comparison between enzyme activity and gene expression

Eur J Cancer. 2003 Apr;39(6):822-8. doi: 10.1016/s0959-8049(02)00598-1.


Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme of 5-fluorouracil (FU) catabolism. The relevance of the measurement of DPD activity for identifying DPD-deficient patients is lessened by circadian variability in DPD activity. Our purpose was to determine whether or not DPD mRNA is sustained by a circadian rhythm. Synchronised mice (male B6D2F1) were sacrificed at 3, 7, 11, 15, 19 or 23 Hours After Light Onset (HALO; eight mice per time-point). Liver DPD activity was determined by a radio-enzymatic assay and liver DPD expression by a reverse transcriptase-polymerase chain reaction (RT-PCR) enzyme-linked immunosorbent assay (ELISA) method. Mice synchronisation was controlled by leucocyte and neutrophil counts. Individual DPD activity ranged from 555 to 1575 pmol/min/mg prot; mean DPD activity was highest at 3 HALO (mean+/-standard error of the mean (S.E.M.); 1105+/-70) and lowest at 15 HALO (889+/-71). Individual liver DPD expression varied from 761 to 3481 units (DPD/beta actin ratio); the mean was lowest at 3 HALO (1406+/-112) and highest at 15 HALO (2067+/-214). Cosinor analysis indicated that respective double amplitudes of DPD activity and expression were 21 and 30% of the 24-h mean. The acrophases for activity and expression were 6:40 and 14:10 HALO, respectively, meaning that maximum activity occurred 16 h after the maximum observed expression. These results, revealing the existence of a circadian rhythm in DPD expression, should stimulate further studies to enhance our understanding of the molecular mechanisms involved in the circadian regulation of the DPD enzyme.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Circadian Rhythm / physiology*
  • Dihydrouracil Dehydrogenase (NADP)
  • Enzyme-Linked Immunosorbent Assay
  • Liver / enzymology*
  • Male
  • Mice
  • Oxidoreductases / metabolism*
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction


  • RNA, Messenger
  • Oxidoreductases
  • Dihydrouracil Dehydrogenase (NADP)