CYTOCHROME-P450 ENZYMES AND UDP-GLUCURONOSYLTRANSFERASES AS HEPATOCELLULAR AUTOANTIGENS

Cytochromes P450 and UDP-Glucuronosyltransferases (UGT) are targets of microsomal autoantibodies in liver and kidney (LKM). LKM autoantibodi es are observed in autoimmune hepatitis, in some patients with viral h epatitis, drug-induced hepatitis and autoimmune hepatitis as disease c omponent of the autoimmune polyglandular syndrome type 1 (APS-I). In a utoimmune hepatitis LKM antibodies are markers of autoimmune hepatitis type 2. The major target of LKM-1 antibodies is cytochrome P450 2D6; a second less frequent target was the described UGTs of family 1. In a utoimmune hepatitis LKM-1 autoantibodies are usually directed against small linear epitopes. LKM autoantibodies are also associated with inf ection with hepatitis viruses C and D. In hepatitis C about 1-2% of pa tients develop LKM-1 autoantibodies. About 60% of these autoantibodies are conformation dependent. The presence of LKM autoantibodies in hep atitis C may be associated with an increased risk in interferon treatm ent. LKM-3 autoantibodies are found in about 8% of patients with hepat itis D and are directed against conformational epitopes. Patients trea ted with certain drugs may develop drug induced hepatitis. In hepatiti s induced by tienilic acid, tienilic acid is activated by and covalent ly bound to cytochrome P450 2C9. Activation of the immune system resul ts in the formation of autoantibodies against cytochrome P450 2C9 (LKM -2) and infiltration of the liver with immune cells. A similar mechani sm has been described for dihydralazine induced hepatitis, where autoa ntibodies are directed against P450 1A2 (LM). Autoantibodies directed against cytochrome P450 1A2 also are found in patients suffering from hepatitis as a disease component of APS-1.