Circadian rhythm of dihydrouracil/uracil ratios in biological fluids: a potential biomarker for dihydropyrimidine dehydrogenase levels.
1. In many cancer patients, 5-fluorouracil (5-FUra) treatment is toxic and even causes death. Nevertheless, all patients are subjected to a standard therapy regimen because there is no reliable way to identify beforehand those patients who are predisposed to 5-FUra-induced toxicity. In this study, we identified the dihydrouracil/uracil (UH2/Ura) ratio in plasma or urine as a potential biomarker reflecting the activity of dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme in 5-FUra metabolism. 2. UH2/Ura ratios were measured by high-performance liquid chromatography tandem triple quadrupole mass spectrometry (HPLC-MS/MS) in both healthy subjects (n=55) and in patients (n=20) diagnosed with grade I/II gestational trophoblastic tumours. In addition, rats (n=18) were used as an animal model to verify a correlation between UH2/Ura ratios and DPD levels in the liver. 3. A significant circadian rhythm was observed in UH2/Ura ratios in healthy subjects, whereas a disrupted rhythm occurred in cancer patients who were continuously infused with a high dose of 5-FUra. In rats, UH2/Ura ratios, liver DPD levels and PBMC DPD levels showed a definite circadian rhythm. Significant linear correlations with liver DPD levels were demonstrated for plasma UH2/Ura ratios (r=0.883, P<0.01), urine UH2/Ura ratios (r=0.832, P<0.01) and PBMC DPD levels (r=0.859, P<0.01). 4. The UH2/Ura ratio in biological fluid was significantly correlated with liver DPD levels; hence, this ratio could be a potential biomarker to identify patients with a deficiency in DPD.
Jiang
Hao
H
Clinical Pharmacology Research Center, Peking Union Medical College Hospital & Chinese Academy of Medical Science, Beijing 100730, China. haojiang@mail.med.upenn.edu
Lu
Jing
J
Ji
Jiang
J
D000328:Adult; D000818:Animals; D015415:Biomarkers; D002940:Circadian Rhythm / Q000187:drug effects*; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005472:Fluorouracil / Q000493:pharmacokinetics; D006801:Humans; D007262:Infusions, Intravenous; D008099:Liver / Q000201:enzymology; D008297:Male; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014498:Uracil / Q000031:analogs & derivatives* / Q000378:metabolism*
D015415:Biomarkers; C007419:dihydrouracil; D014498:Uracil; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil