title: Link between dihydropyrimidine dehydrogenase activity in peripheral blood mononuclear cells and liver.
abstract: Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme of 5-fluorouracil (FU) catabolism, which occurs mainly in the liver. Several cases of severe FU-related toxicity have been reported in patients exhibiting a marked DPD deficiency measured in peripheral blood mononuclear cells (PBMCs). In addition, it has been shown that PBMC-DPD activity correlates to systemic FU clearance. The purpose of the present study was to closely evaluate the link between DPD activity measured in PBMCs and in liver samples obtained from the same patients. This prospective study was conducted on 27 patients (18 men and 9 women) who underwent laparotomy for various pathologies. Liver biopsies were performed in normal liver and immediately stored in liquid nitrogen. Biological liver function tests were within normal values for all patients. Concomitantly to the liver biopsy, a blood sample was taken and PBMCs were immediately isolated and stored at -80 degreesC. Liver-DPD and PBMC-DPD activities were measured by a radioenzymatic assay using 14C-FU as substrate (sensitivity limit, 5 pmol/min/mg protein; interassay reproducibility, 10%). Liver-DPD (mean, 178; median, 186; range, 54-290 pmol/min/mg protein) and PBMC-DPD (mean, 196; median, 205; range, 80-275 pmol/min/mg protein) exhibited the same pattern of distribution. Neither liver-DPD nor PBMC-DPD was significantly different between men and women. A significant linear correlation was demonstrated between liver- and PBMC-DPD activity (liver-DPD = 0.6 x PBMC-DPD + 59, r = 0.56, P = 0.002). Interestingly, the patient who exhibited the lowest PBMC-DPD activity (80 pmol/min/mg protein, at risk value for developing FU-related side effects) also had very low liver-DPD activity (98 pmol/min/mg protein). In conclusion, in patients with normal liver function, DPD activity measured in PBMCs reflects DPD activity expressed in the liver. The demonstrated link between liver- and PBMC-DPD activity reinforces the interest in DPD investigation in PBMCs for selecting, before FU-containing chemotherapy, patients at risk of developing severe toxicities due to impairment of FU clearance.
authors.affiliation: Oncopharmacology Department, Centre Antoine Lacassagne, 33 avenue de Valombrose, 06050 Nice, Cedex 1, France.
authors.forename: M
authors.initials: M
authors.lastname: Chazal
authors.forename: M C
authors.initials: MC
authors.lastname: Etienne
authors.forename: N
authors.initials: N
authors.lastname: Renée
authors.forename: A
authors.initials: A
authors.lastname: Bourgeon
authors.forename: H
authors.initials: H
authors.lastname: Richelme
authors.forename: G
authors.initials: G
authors.lastname: Milano
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D042943:Dihydrouracil Dehydrogenase (NADP); D005260:Female; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000201:enzymology*; D008099:Liver / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D010088:Oxidoreductases / Q000378:metabolism*; D011446:Prospective Studies
chemical_list: D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP)