Characterization of autoantibodies against uridine-diphosphate glucuronosyltransferase in patients with inflammatory liver diseases.

Abstract

Uridine diphosphate glucuronosyltransferase (UGT) was identified as an antigenic target in a subgroup of liver-kidney microsomal autoantibodies and was termed LKM-3. To evaluate the nature of LKM-3 antibodies, we screened sera from 80 untreated patients with autoimmune hepatitis (AIH) type 1 and 2, primary biliary cirrhosis (PBC), AIH/PBC, hepatitis C virus (HCV) infection, and 12 healthy individuals (controls) against 7 recombinant human UGT isoenzymes (UGT1A1, UGT1A4, UGT1A6, UGT1A7, UGT1A9, UGT1A10, and UGT2B7). Autoantibodies reacting against various UGT isoenzymes were observed in sera from 3 of 18 AIH type 2 and 1 of 27 of the HCV patients. The anti-UGT-positive sera from AIH type 2 patients revealed the strongest immunoreactivity against UGT1A1, the main UGT-isoform involved in the bilirubin glucuronidation. Additionally, these sera were able to block UGT-mediated substrate glucuronidation in vitro. The prevalence for UGT1A1 was shown by 2 independent techniques: (1) UGT1A1 was identified as the main antigen by Western blotting. Preabsorption of sera with UGT1A1 prevented reaction against all tested UGT-isoforms. (2) In vitro immunoinhibition experiments showed that glucuronidation of the anticancer drug flavopiridol by UGT1A1 was more strongly inhibited than its UGT1A9-mediated biotransformation. In contrast, the serum from the HCV-patient reacted predominately with UGT1A6, and moreover, the immunoreactivity pattern was different from that of the AIH group. To summarize, we show the subtype preference of antibodies against UGT1A1 in a subgroup of AIH type 2 patients. These autoantibodies inhibit UGT-mediated glucuronidation in vitro, but it is unlikely that anti-UGT antibodies will have a marked effect on the patients capacity for drug biotransformation, as serum bilirubin levels in patients remained within the normal range.

• Authors: T Bachrich, T Thalhammer, W Jäger, P Haslmayer, B Alihodzic, S Bakos, E Hitchman, A M Senderowicz, E Penner
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 33 Issue 5 Pg. 1053-9 (May 2001) ISSN: 0270-9139 [Print] United States
• PMID: 11343231 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Autoantibodies
• Flavonoids
• Glucuronides
• Immunosuppressive Agents
• Isoenzymes
• Piperidines
• Recombinant Proteins
• anti-liver kidney microsome antibody
• Hymecromone
• alvocidib
• UGT1A1 enzyme
• Glucuronosyltransferase

Topics

• Autoantibodies (analysis, pharmacology)
• Child
• Cross Reactions
• Female
• Flavonoids (antagonists & inhibitors, metabolism)
• Glucuronides (antagonists & inhibitors, biosynthesis)
• Glucuronosyltransferase (immunology, metabolism)
• Hepatitis C, Chronic (immunology)
• Hepatitis, Autoimmune (immunology, therapy)
• Humans
• Hymecromone (metabolism)
• Immunosuppressive Agents (therapeutic use)
• Isoenzymes (immunology)
• Liver Cirrhosis, Biliary (immunology)
• Male
• Piperidines (antagonists & inhibitors, metabolism)
• Recombinant Proteins (immunology)
• Reference Values