Patients with type II autoimmune hepatitis express functionally intact cytochrome P-450 db1 that is inhibited by LKM-1 autoantibodies in vitro but not in vivo.
Liver-kidney microsomal-1 autoantibodies characterize a subgroup of autoimmune chronic active hepatitis. The liver antigen of liver-kidney microsomal-1 antibodies has been identified as cytochrome P450 db1, a microsomal enzyme catalyzing the oxidative metabolism of more than 20 drugs, including debrisoquine, sparteine and bufuralol. A genetic polymorphism (debrisoquin-sparteine polymorphism) is responsible for the lack of P450 db1 protein in the livers of 5% to 10% of Caucasians, leading to impaired drug metabolism and a distinct poor metabolizer phenotype. We investigated whether liver-kidney microsomal-1 positive autoimmune chronic active hepatitis patients express functionally intact P450 db1 in their livers. In four patients with liver-kidney microsomal-1 positive chronic active hepatitis, but not in five patients with various liver-kidney microsomal-1 negative liver diseases, the presence of circulating liver-kidney microsomal-1 antibodies was confirmed by immunofluorescence, radioimmunoassay and immunoblotting analysis using recombinant P450 db1. Moreover, only sera from liver-kidney microsomal-1 positive autoimmune chronic active hepatitis patients strongly inhibited the enzymatic activity of P450 db1 in human liver microsomes in vitro. Immunoblotting detected 50-kd P450 db1 protein in liver biopsy specimens from all patients. The in vivo function of P450 db1 was investigated by determining the metabolic ratio for sparteine and its 2-dehydro and 5-dehydro metabolites in 12-hr urine samples after oral administration of sparteine sulfate. In vivo P450 db1-mediated drug metabolism was of the extensive metabolizer phenotype and did not differ significantly between liver-kidney microsomal-1 positive (metabolic ratio = 1.15 +/- 0.32) and liver-kidney microsomal-1 negative (metabolic ratio = 1.18 +/- 0.48) patients.(ABSTRACT TRUNCATED AT 250 WORDS)
Manns
M
M
I. Medizinische Klinik und Poliklinik, University Mainz, FRG.
Zanger
U
U
Gerken
G
G
Sullivan
K F
KF
Meyer zum Büschenfelde
K H
KH
Meyer
U A
UA
Eichelbaum
M
M
D000328:Adult; D001323:Autoantibodies / Q000032:analysis*; D001327:Autoimmune Diseases / Q000378:metabolism*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006801:Humans; D015151:Immunoblotting; D007700:Kinetics; D008103:Liver Cirrhosis / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D008875:Middle Aged; D013034:Sparteine / Q000378:metabolism
D001323:Autoantibodies; D065607:Cytochrome P-450 Enzyme Inhibitors; C060729:anti-liver kidney microsome antibody; D013034:Sparteine; D003577:Cytochrome P-450 Enzyme System