Antibodies against human cytochrome P-450db1 in autoimmune hepatitis type II.
In a subgroup of children with chronic active hepatitis, circulating autoantibodies occur that bind to liver and kidney endoplasmic reticulum (anti-liver/kidney microsome antibody type I or anti-LKM1). Anti-LKM1 titers follow the severity of the disease and the presence of these antibodies serves as a diagnostic marker for this autoimmune hepatitis type II. We demonstrate that anti-LKM1 IgGs specifically inhibit the hydroxylation of bufuralol in human liver microsomes. Using two assay systems with different selectivity for the two cytochrome P-450 isozymes catalyzing bufuralol metabolism in human liver, we show that anti-LKM1 exclusively recognizes cytochrome P-450db1. Immunopurification of the LKM1 antigen from solubilized human liver microsomes resulted in an electrophoretically homogenous protein that had the same molecular mass (50 kDa) as purified P-450db1 and an identical N-terminal amino acid sequence. Recognition of both purified P-450db1 and the immunoisolated protein on western blots by several monoclonal antibodies confirmed the identity of the LKM1 antigen with cytochrome P-450db1. Cytochrome P-450db1 has been identified as the target of a common genetic polymorphism of drug oxidation. However, the relationship between the polymorphic cytochrome P-450db1 and the appearance of anti-LKM1 autoantibodies as well as their role in the pathogenesis of chronic active hepatitis remains speculative.
Zanger
U M
UM
Department of Pharmacology, University of Basel, Switzerland.
Hauri
H P
HP
Loeper
J
J
Homberg
J C
JC
Meyer
U A
UA
D000911:Antibodies, Monoclonal; D001323:Autoantibodies / Q000032:analysis; D002846:Chromatography, Affinity; D003577:Cytochrome P-450 Enzyme System / Q000276:immunology*; D004591:Electrophoresis, Polyacrylamide Gel; D004721:Endoplasmic Reticulum / Q000276:immunology; D004983:Ethanolamines / Q000494:pharmacology; D006521:Hepatitis, Chronic / Q000201:enzymology* / Q000276:immunology; D006801:Humans; D007527:Isoenzymes / Q000276:immunology*; D007668:Kidney / Q000276:immunology; D008099:Liver / Q000276:immunology
D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D004983:Ethanolamines; D007527:Isoenzymes; C010831:bufuralol; D003577:Cytochrome P-450 Enzyme System