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

Background/Aims Four linear antigenic sites have been shown on the CYP2D6 molecule that are recognized by serum positive for liver/kidney microsomal antibody (LKM) type 1. The aim of this study was to search for antibodies against CYP2D6 conformational antigenic sites in LKM-1-positive sera. Methods: The capacity of four LKM-1-positive sera, before and after absorption with synthetic peptides representing CYP2D6 linear antigenic sites, and rabbit sera against linear antigenic sites between CYP2D6 amino acids 254-271 and 373-389 to inhibit the O-demethylation of dextromethorphan by CYP2D6 was tested in vitro. Results: Inhibition of O-demethylation of dextromethorphan was not modified by absorption 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 conformational antigenic sites were present in LKM-1-positive sera. Conclusions: The autoimmune response against CYP2D6 is directed against linear and conformational antigenic sites. These results strengthen the argument that the LKM-1 response is polyclonal and antigen driven.