LINK BETWEEN DIHYDROPYRIMIDINE DEHYDROGENASE-ACTIVITY IN PERIPHERAL-BLOOD MONONUCLEAR-CELLS AND LIVER

Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme of 5 -fluorouracil (FU) catabolism, which occurs mainly in the liver. Sever al cases of severe FU-related toxicity have been reported in patients exhibiting a marked DPD deficiency measured in peripheral blood mononu clear cells (PBMCs). In addition, it has been shown that PBMC-DPD acti vity correlates to systemic FU clearance. The purpose of the present s tudy was to closely evaluate the link between DPD activity measured in PBMCs and in liver samples obtained from the same patients. This pros pective study was conducted on 27 patients (18 men and 9 women) who un derwent laparotomy for various pathologies. Liver biopsies were perfor med in normal liver and immediately stored in liquid nitrogen. Biologi cal liver function tests were within normal values for all patients. C oncomitantly to the liver biopsy, a blood sample was taken and PBMCs w ere immediately isolated and stored at -80 degrees C. Liver-DPD and PB MC-DPD activities were measured by a radioenzymatic assay using C-14-F U as substrate (sensitivity limit, 5 pmol/min/mg protein; interassay r eproducibility, 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. N either liver-DPD nor PBMC-DPD was significantly different between men and women. A significant linear correlation was demonstrated between l iver- 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/m in/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 rei nforces the interest in DPD investigation in PBMCs for selecting, befo re FU-containing chemotherapy, patients at risk of developing severe t oxicities due to impairment of FU clearance.