UDP glucuronosyltransferase mRNA levels in human liver disease.

Abstract

The UDP glucuronosyltransferases (UGT) are a family of enzymes in which substrates include drugs, xenobiotics, and products of endogenous catabolism. The main source of most UGT enzymes is the liver, a major organ in the detoxification and inactivation of compounds. Previous studies have indicated that glucuronidation, as measured by pharmacokinetic studies, is relatively spared in liver disease. Because UGT activity toward most substrates is the result of metabolism by different isoforms with overlapping specificities, these studies may not indicate the effect of disease on the levels of individual isoforms. We sought to extend these studies to the measurement of mRNA for individual isoforms in the liver of patients with various forms of liver disease. RNA was extracted from liver tissue samples of patients undergoing clinically necessary percutaneous liver biopsies. UGT mRNA levels for isoforms 1A1, 1A3, 1A4, 1A6, 1A9, 2B4, 2B7, 2B10, 2B11, 2B15, and 2B17 were determined by real-time reverse transcription-polymerase chain reaction. Biopsies were graded using the Metavir system. Results from patients with low fibrosis or inflammatory scores were compared with those with high scores. We found large interindividual variation in the levels of the various isoforms. This was greatest for UGT2B17. A consistent downward trend, reaching statistical significance for UGT1A4, UGT2B4, and UGT2B7, was observed in samples from patients with high inflammation scores. There was no such correlation with the degree of fibrosis. Our results indicate that hepatic UGT mRNA levels are reduced while the tissue is inflamed, but they are not affected in the noninflamed, chronically diseased liver.