Regulation of dihydropyrimidine dehydrogenase gene expression in regenerating mouse liver.

5-fluorouracil (5-FU) is one of the most commonly used agents in treatment of the cancer. The administered 5-FU is degraded mainly in the liver by dihydropyrimidine dehydrogenase (DPD), which is the initial rate-limiting enzyme in the catabolic pathway of pyrimidine. This enzyme activity in the tumors has been shown to correlate with the effectiveness of 5-FU against tumors. Therefore, to understand the regulation of DPD gene expression is critical in cancer chemotherapy. Since several studies suggested correlation of DPD activity with the cell proliferation rate we studied the DPD gene expression during liver regeneration. DPD enzyme activity decreased rapidly [24 h after partial hepatectomy (PH): 57% of the control] and remained low until 72 h after PH. Protein content also decreased after PH, however, the lowest level (43.2+/-6.3% of control) was reached only 48 h after PH. The DPD mRNA decreased rapidly to about 20% of control 24 h after PH and then recovered to the control level 72 h after PH. The present results indicate that the DPD gene expression is regulated first at the mRNA level when the hepatocytes enter the cell cycle. The protein content of DPD changed in proportion to the level of DPD mRNA with a 24-h lag, suggesting very little regulation at the translational level. There was a discrepancy between the DPD enzyme activity and the protein content, 24 and 72 h after PH, suggesting that the enzyme activity is modulated also by modification of the protein, and the cell proliferation rate is one of the factors that influences the modification.

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