UDP-GLUCURONOSYLTRANSFERASE IN THE REGENERATING RAT-LIVER

In both acute and chronic liver disease in man, elimination of drugs m etabolized by the cytochrome P450 (CYP) enzymes is impaired. In contra st, those drugs metabolized by UDP-glucuronosyltransferase (UGT) have a relatively normal elimination. Studies in rats with experimentally i nduced liver injury also show this relative preservation of glucuronid ation. In liver disease, a number of factors, including inflammation, fibrosis and regeneration, may be associated with this differential ef fect on drug metabolism. Partial hepatectomy provides a model in which to isolate the effects of liver regeneration on drug metabolism Parti al hepatectomy or sham operation was performed in 24 male Sprague-Dawl ey rats and three rats from each group were studied at days 1, 2, 4 an d 6. Comparison between CYP and UGT was made at the protein level usin g immunohistochemistry and immunoblotting probed with a polyclonal ant ibody to UGT, identifying both family 1 and family 2 isoforms, and an antibody to the CYP isoform CYP2C11. Steady state messenger RNA levels of four isoforms of UGT were assessed by northern blot analysis. By b oth immunohistochemistry and immunoblotting, the level of CYP protein decreased from day 2 to 6 after hepatectomy. In contrast, the UGT prot ein level was not altered by partial hepatectomy. Northern blot analys is of UGT isoforms demonstrated differential regulation of isoforms fr om the two major families. The UGT family 1 isoforms were initially ma rkedly depressed following partial hepatectomy and then steadily rose over 6 days to greater than the level in controls. In contrast, there was an apparent increase in UGT2B1 mRNA (not significant) on day 2, wh ile UGT2B3 mRNA was maintained over the six days. These results demons trate that during hepatic regeneration the protein content of total UG T is normal, while CYP2C11 protein is markedly reduced. Northern blot analysis suggests that individual isoforms of UGT are differentially r egulated during the regeneration process.