RGD Reference Report - Circadian variation in intestinal dihydropyrimidine dehydrogenase (DPD) expression: a potential mechanism for benefits of 5FU chrono-chemotherapy. - Rat Genome Database

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Circadian variation in intestinal dihydropyrimidine dehydrogenase (DPD) expression: a potential mechanism for benefits of 5FU chrono-chemotherapy.

Authors: Abolmaali, K  Balakrishnan, A  Stearns, AT  Rounds, J  Rhoads, DB  Ashley, SW  Tavakkolizadeh, A 
Citation: Abolmaali K, etal., Surgery. 2009 Aug;146(2):269-73.
RGD ID: 5133425
Pubmed: PMID:19628084   (View Abstract at PubMed)
DOI: DOI:10.1016/j.surg.2009.05.005   (Journal Full-text)

BACKGROUND: 5-fluorouracil (5FU) is associated with significant GI side-effects. Randomized trials have shown a 50% reduction in severe diarrhea with chrono-chemotherapy versus conventional regimens at similar doses. Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme in 5FU breakdown. We hypothesized that DPD has a circadian expression pattern, accounting for the reduced GI side effects of chrono-modulated 5FU therapy. METHODS: Fifty-one rats were killed at 3-hourly intervals over 24 hours. DPD and thymidylate synthase (TS) mRNA in jejunal and colonic mucosa were measured using qRT-PCR. Cosinor analysis was used for statistical comparison. RESULTS: There was a significant circadian rhythm in the DPD mRNA expression in jejunum (1.7-fold, P < .001) and colon (1.5 fold, P < .01), with a peak expression in early sleep phase, and a trough at mid-wake cycle. TS also followed a circadian rhythm in jejunal mucosa with a peak at early rest phase. CONCLUSION: This rhythm in DPD expression may explain the benefit of chrono-chemotherapy. The peak of DPD expression in sleep phase in rats corresponds to time for lower GI adverse effects in chrono-chemotherapy in human trials. We believe better understanding of this process allows development of novel approaches to optimize the timing of chemotherapy without the administrative challenges of chronotherapy.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
circadian rhythm  IEP 5133425; 5133425 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Dpyd  (dihydropyrimidine dehydrogenase)
Tyms  (thymidylate synthetase)


Additional Information