DIFFERENCES IN THE REGULATION OF CYTOCHROME-P450 FAMILY MEMBERS DURING LIVER-REGENERATION

Background/Aims: Cytochrome P450 enzymes (P450s) metabolise endogenous substances and a vast variety of drugs. Little is known about the reg ulation of P450s during pathophysiological conditions in the liver. Th erefore we studied the regulation of P450 1A1, 1A2, 2E1 and 3A during liver regeneration after two-thirds hepatectomy. Methods: Partial hepa tectomy or sham surgery was performed in Sprague-Dawley rats. At diffe rent time points after surgery, microsomal proteins were isolated and the RNA was prepared. Northern blot analysis, Western blot analysis an d enzyme assays for the different P450s were performed. Results: North ern blot analysis showed a transient downregulation of cytochromes P45 0 1A2 and 2E1 after hepatectomy, while the expression of cytochrome P4 50 3A remained unaffected. Western blot analysis of microsomal protein s showed that changes of the mRNA levels are not reflected in the prot ein level, most likely because the half-life of the P450 proteins in h epatocytes is long, and thus a transient mRNA downregulation has littl e impact on the total amount of protein detected. Differences in the r egulation of the enzymatic activities were found for P450 1A2 and 2E1. Interestingly, the metabolic activity of cytochrome P450 2E1 decrease d dramatically post-hepatectomy, while the P450 2A1 activity remained unchanged. Conclusions: Regulatory mechanisms were found on the RNA le vel and by post-translational mechanisms which downregulate P450 expre ssion and activity during liver regeneration. These results indicate p rolonged half-life of drugs during hepatocyte proliferation, and thus also have important implications for therapy in humans.