LOCALIZATION OF URIDINE 5'-DIPHOSPHATE-GLUCURONOSYLTRANSFERASE IN HUMAN LIVER-INJURY

Background/Aims: Pharmacokinetic studies in patients with cirrhosis have shown a decreased clearance of drugs metabolized by cytochrome P450, whereas drugs metabolized by glucuronidation frequently have a normal elimination. The mechanism for the apparent preservation of glucuronidation has not been elucidated. The aim of this study was to examine the expression of uridine 5'-diphosphate-glucuronosyltransferase (UGT) in human liver injuries. Methods: UGT was measured by immunohistochemistry using a UGT polyclonal antibody, which was then compared with a representative isoform of cytochrome P450. Normal liver biopsy specimens (n = 8) and a spectrum of liver injury biopsy specimens (n = 47) were examined. Results: Compared with normal liver, increased staining for UGT in remaining hepatocytes was seen in liver damaged by chronic alcohol abuse, but the most intense immunoreactivity was observed in remaining and regenerative hepatocytes in specimens with cirrhosis. Primary biliary cirrhosis showed diffusely increased immunoreactivity. Other nonmalignant groups showed an increased staining relative to chronicity of liver disease. In contrast, in all liver injuries, cytochrome P450 staining was reduced as compared with controls. Conclusions: Chronic liver damage results in increased UGT in remaining viable hepatocytes. Mechanisms may operate in liver injury to preserve expression of UGT in functional hepatocytes, and this may explain the preservation of glucuronidation in cirrhosis.