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

Abstract

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. Thus patients with liver‐kidney microsomal‐1 positive chronic active hepatitis express functionally intact P450 db1 in their livers. However, the activity of this enzyme is not significantly diminished in vivo by circulating liver‐kidney microsomal‐1 autoantibodies that react with the active site of P450 db1 and inhibit its function in vitro. (HEPATOLOGY 1990;12:127–132). Copyright © 1990 American Association for the Study of Liver Diseases