Human liver injuries and the effects on udp glucuronosyltransferase

Abstract

UDP glucuronosyltransferases (UDPGT) are found in the hepatic endoplasmic reticulum and conjugate a vast array of drugs and endogenous compounds to the acidic sugar glucuronic acid. These enzymes play a major role in the elimination of many drugs. Patients with liver disease have impairment in the elimination of drugs metabolized by phase I enzymes (oxidation), while many drugs metabolised via the glucuronidation pathway have normal elimination. The expression of UDPGT has been studied in patients with normal liver biopsies (N=4), moderate liver damage (N=5) and cirrhosis (N=6) due to chronic alcohol abuse, and primary biliary cirrhosis (PBC) in an active inflammatory and mildly cirrhotic stage (N=2). Immunohistochemistry using polyclonal antisera to the r 2-5 isoforms of UDPGT, which were raised in goats, was performed. Specific staining in hepatocytes with marked centrilobular accentuation was seen in the normal human livers. Increased staining for UDPGT in all remaining hepatocytes was present in livers damaged by chronic alcohol intake but most marked immunoreactivity was observed in those with cirrhosis. The liver biopsies of patients with PBC also showed increased UDPGT immunostaining in all hepatocytes and in 1 case, periportal accentuation was observed. In conclusion, there is zonal distribution of UDPGT concentration in normal human liver. Chronic liver damage induced by alcohol and PBC resulted in a marked increase in UDPGT activity in remaining viable hepatocytes. These findings may explain the apparent preservation of glucuronidation in patients with chronic liver disease.