CONFORMATIONAL EPITOPES ON CYP2D6 ARE RECOGNIZED BY LIVER-KIDNEY MICROSOMAL ANTIBODIES

Background/Aims Four linear antigenic sites have been shown on the CYP 2D6 molecule that are recognized by serum positive for liver/kidney mi crosomal antibody (LKM) type 1. The aim of this study was to search fo r antibodies against CYP2D6 conformational antigenic sites in LKM-1-po sitive sera. Methods: The capacity of four LKM-1-positive sera, before and after absorption with synthetic peptides representing CYP2D6 line ar antigenic sites, and rabbit sera against linear antigenic sites bet ween CYP2D6 amino acids 254-271 and 373-389 to inhibit the O-demethyla tion of dextromethorphan by CYP2D6 was tested in vitro. Results: Inhib ition of O-demethylation of dextromethorphan was not modified by absor ption of antibodies against linear CYP2D6 antigenic sites. In addition , rabbit sera against two of these sites did not inhibit the reaction. These results strongly suggest that antibodies against CYP2D6 conform ational antigenic sites were present in LKM-1-positive sera. Conclusio ns: The autoimmune response against CYP2D6 is directed against linear and conformational antigenic sites. These results strengthen the argum ent that the LKM-1 response is polyclonal and antigen driven.